Strategies and Tactics in Organic Synthesis Lucidi_papagni

Chemistry creates its subject. This creative ability, similar to that of art, essentially distinguishes Chemistry among the natural sciences. Berthelot, J. 1860

The ultimate goal of Organic Synthesis is to assemble a given organic compound (target molecule) from readily available starting materials and reagents in the most efficient way. This process usually begins with the design of a synthetic plan (strategy) which calls upon various synthetic reactions to address individual synthetic objectives in a certain sequence. If a transformation or a strategic maneuver required by the synthetic plan has to be demonstrated before, the plan must rely on the development of a suitable synthetic method or tactic to solve the particular problem at hand. Thus, the science of organic synthesis is constantly enriched by new inventions and discoveries pursued deliberately for their own sake or as subgoals within a program directed towards the synthesis of a target molecule. Nicolaou, K. C. Classics in Total Synthesis

Name Reaction !!!!

Organic Synthesis The Practice of Total Synthesis With its share of glorious moments, setbacks, and frustrations Total Synthesis can be compared to the game of chess. The object of this game is to capture the opponent's king by a series of allowed moves played out in such a combination and order as outmaneuver the opponent. Similarly, in total synthesis the object is to reach the target molecule by a series of reactions which have to be carried out in the right sequence to outmaneuver natural barriers. Studying and applying the moves (reactions) to capture the king (make the molecule) then becomes the object of total synthesis. The practice and elegance of total synthesis involves and depends of the following stages: 1. Selection of the target: natural product or designed molecule 2. DESIGN OF THE SYNTHETIC STRATEGY: RETROSYNTHETIC ANALYSIS 3. Selection of the reagents and conditions 4. Experimental execution Design is a term that refers to a creative activity within the realm of technology, an activity that, to be sure, can ascend into the domain of great art. The design of a chemical synthesis is not science a priori: it is a fruit of science; its prerequisite is comprehensive matured, and approved scientific knowledge. Robert Burns Woodward. Architect and Artist in the World of Molecules

Serratosa defined Synthesis as a heuristic activity "According to the Oxford Dictionary, the word heuristic derives from the Greek heurisko ("I find') and it is used as an adjective to describe activities directed towards the act of discovering , including all those reasonings and arguments that are persuasive and plausible without being logically rigorous... The heuristic principles, in contrast with the mathematical theorems and the rules of proof, do not pretend to be laws, an only suggest lines of activities“ Serratosa, F. Organic Chemistry in Action.

Organic Synthesis: The targets can be Natural Products ... Brevetoxin B marine neurotoxin associated with the red tide catastrophes [Nicolaou 1995]

Vancomycin antibiotic of last resort against anti-drug resistant bacteria Evans 1995]

Swinholide A cytotoxic potent activity against multi-drug-resistant (MDR) carcinoma cell lines [Paterson 1994]

Organic Synthesis: The targets can be compounds with interesting activities...

Acetylsalicilic acid (Aspirin, Bayer)

Parathion insecticide

Fluoxetine (Prozac, Eli Lilly) depressions

Crivixan (Merck) anti AIDS

Allura red AC (Allied Chem) red pigment

Sildenafil (Viagra, Pfizer) male erection disfunction

Organic Synthesis: The targets can be compounds with artistic or anthropomorphic attributes...

NanoPutians Tour, J. M. JOC 2003, 8750

Classifications of Synthesis: The Power of "Convergent Synthesis " The first principle of retrosynthetic planning: convergent strategies are the most efficient strategies for the assembly of complex molecules

Classifications of Synthesis Divergent synthesis : • A divergent synthesis is a strategy with the aim to improve the efficiency of chemical synthesis. It is often an alternative to convergent synthesis or linear synthesis. In one strategy divergent synthesis aims to generate a library of chemical compounds by first reacting a molecule with a set of reactants. This methodology quickly diverges to large numbers of new compounds

Classifications of Synthesis Combinatorial synthesis : The characteristic of combinatorial synthesis is that different compounds are generated simultaneously under identical reaction conditions in a systematic manner, so that ideally the products of all possible combinations of a given set of starting materials (termed building blocks) will be obtained at once.

Organic Synthesis In the beginning until Second World War organic synthesis was based on the Direct Associative Approach (i.e. associative thinking or thinking by analogy was sufficient) With the exception of a minor proportion which clearly depended on a more subtle way to thinking about, the planning syntheses were initially based on the availability of starting materials that contained a major portion of the final atomic framework and on the knowledge of reaction suitable for forming polycyclic molecules

By the mid 1960's, a different and more systematic approach was developed: Retrosynthetic Analysis Retrosynthetic (or antithetic) analysis is a problem solving technique for transforming the structure of a synthetic target (TGT) molecule to a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. The transformation of a molecule to a synthetic precursor is accomplished by the application of a transform, the exact reverse of a synthetic reaction, to a target structure. Each structure derived antithetically from a TGT then itself becomes a TGT for a further analysis. Repetition of this process eventually produces a tree of intermediates having chemical structures as nodes and pathways from bottom to top corresponding to possible synthetic routes to the TGT.

Organic Synthesis In The Direct Associative Approach, the chemist directly recognizes within the structure of the target molecule a number of readily available structural subunits, which can be properly joined by using standard reactions with which he is familiar

In the synthesis of peptides, recognition of the constituent aminoacids is almost immediate. However, the realization of the synthesis in the laboratory may be one of the most arduous tasks which the synthetic organic chemist faces

Strategies and Tactics in Organic Synthesis Retrosynthetic Analysis: The key to the design of efficient syntheses "The end is where we start from....“T. S. Eliot ". . . the grand thing is to be able to reason backwards. That is a very useful accomplishment, and a very easy one, but people do not practice it much.“ Sherlock Holmes

Strategy

Tactics

1 overall plan to achieve the ultimate synthetic target 2 Intellectual 3 retrosynthetic planning 4 TRANSFORMS

1 means by which plan is implemented 2 experimental 3 synthetic execution 4 REACTIONS

Synthetic versus retrosynthetic analysis tactic

Strategy and Tactic

Strategy

Ho, T.-L. Tactics of Organic Synthesis

In pursuit a total synthesis, a chemist tries to foresee the key disconnections which will allow him to reach the target. The set of these main disconnections defines and establishes the strategy. However thoroughly proficient the strategy formulation (the retrosynthetic analysis) ..., still needs tactical coordination to smooth the progression, otherwise the success will be ardous and unspectacular ... although the demarcation between certain tactics and strategies is difficult to make.

Strategies and Tactics in Organic Synthesis

E. J. Corey

"Retron: The minimal substructural element in a target structure which keys the direct application of a transform to generate a synthetic precursor.“ from E. J. Corey and X.-M. Cheng, "The Logic of Chemical Synthesis", 1989 For instance, in Diels-Alder reaction the retron, a minimal keying element, is 6-membered ring with a π-bond:

retron "...even in the earliest stages of the process of simplification of a synthetic problem, the chemist must make use of a particular form of analysis which depends on the interplay between structural features that exist in the target molecule and the types of reactions or synthetic operations available from organic chemistry for the modification or assemblage of structural units. The synthetic chemist has learned by experience to recognize within a target molecule certain units which can be synthesized, modified, or joined by known or conceivable synthetic operations...it is convenient to have a term for such units; the term "synthon" is suggested. These are defined as structural units within a molecule which are related to possible synthetic operations... a synthon may be almost as large as the molecule or as small as a single hydrogen; the same atoms within a molecule may be constituents of several overlapping synthons...“ from "General Methods for the Construction of Complex Molecules“ E. J. Corey, Pure Appl. Chem. 1969, 14, 19 Retron Structural unit that signals the application of a particular strategy algorithm during retrosynthetic analysis. Transform Imaginary retrosynthetic operation transforming a target molecule into a precursor molecule in a manner such that bond(s) can be reformed (or cleaved) by known or reasonable synthetic reactions. The exact reverse of a synthetic reaction; the formation of starting materials from a single product. Strategy Algorithm Step-by-step instructions for performing a retrosynthetic operation.

Strategies and Tactics in Organic Synthesis Retrosynthesis analysis is a problem solving technique for transforming the structure of synthetic target molecule (TM) to a sequence of progressively simpler structures along the pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. (E.J Corey) The transformation of a molecule to a synthetic precursor is accomplished by: · Disconnection: the reverse operation to a synthetic reaction. The retrosynthetic step involving the breaking of bond(s) to form two (or more) synthons is referred to as a disconnection. · Functional Group Interconversion (FGI): is the process of the transformation of one functional group to another to help synthetic planning and to allow disconnections corresponding to appropriate reactions. In planning a synthetic strategy, apart from devising means of constructing the carbon skeleton with the required functionality, there are other factors which must be addressed including the control of regiochemistry and stereochemistry. The converting process transform one functional group into another by substitution, addition, elimination, reduction, or oxidation. The central point in this methodology Each structure thus derived from TM then itself becomes a TM for further analysis. Repetition of the process eventually produces a tree of intermediates having chemical structures in the nodes and possible chemical transformations as pathways from bottom to TM. One should avoid excessive branching and proliferation of useless pathways. Strategies for control and guidance are of the utmost importance. Synthetic Strategies: Choosing the way along the retrosynthetic tree or the synthetic planning. Synthetic Tactics: How a specific bond or set of bonds at a given site can be efficiently created.

is a rational and penetrating analysis of the structure of TGT. Such analysis leads to a limited logical set of intermediate structures which can be transformed into the original in just one reaction or synthetic step. Every structure generated is then carefully analysed as before to give another set of structures, which can be transformed into the preceding structures in one step. The process is repeated for every intermediate until a "tree“ of such intermediate structure is obtained. By this process a set of possible alternative synthetic pathways is generated which correspond to sequences of synthetic intermdiates structures that go from possible starting materials to TGT: it is the so-called "synthesis tree".

Strategies and Tactics in Organic Synthesis Some Useful Definitions Target molecule: the molecule to be synthetized Retrosynthetic analysis or retrosynthesis the process of menthally breaking down a molecule into starting material Transform: the exact reverse of a synthetic reaction Retron: structural subunit on the target that enables a transform to operate Disconnection: an imaginary bond cleavage corresponding to the reverse of a real reaction Synthon: idealized fragments, usually a cation, anion or radical, resulting from a disconnection Reagent: a real chemical compound used as the equivalent of a synthon

Synthesis tree: set of all the possible disconnections and synthons leading from the target to the starting materials of a synthesis

Some Useful Guidelines 1. There are many approaches to the synthesis of a TGT. 2. All the synthetic routes can be derived through a rational and penetrating analysis of the structure of TGT, which should consider i) symmetry, either real or potential, ii) functional group relationships (it is imperative to remove or modify the highly unstable groups) iii) carbon skeleton: chains, rings and appendages iv) stereochemistry 3. Then, the synthetic possibilities derive from the identification of retrons and the application of transforms, which permit the generation of synthons. These synthons are next evaluated. This repeating analysis produces the synthesis tree. 4. The best route is the most simple, flexible, and efficient. 5. It is desirable that disconnections correspond to known and reliable reactions. It is worth identifying the most difficult steps and to provide alternative routes (flexibility) 6. Problems associated to the construction of the skeleton, the manipulation of functional groups, and the introduction of stereochemistry must be considered simultaneously. i) consider alternative disconnections and choose routes that avoid chemo- and regioselectivity problems ii) use two-group disconnections wherever possible.

Strategies and Tactics in Organic Synthesis Transform & Retron The transformation of a molecule into a synthetic precursor is accomplished by application of a transform (antithesis process), the exact reverse of a synthetic reaction, to a target structures.

In order for a transform to operate on a target structure to generate a synthetic predecessor,the enabling structural subunit or retron for that transform must be present in the target.

It is possible to have partial Diels-Alder retron as in the case of cyclohexane unit

Strategies and Tactics in Organic Synthesis Transforms & Molecular Complexity There are many thousands of transforms which are potentially useful in retrosynthetic analysis just as there are very many known and useful chemical reactions ... One feature of major significance is the overall effect of transform application on molecular complexity. Molecular complexity elements are: (1) Molecular size (2) Cyclic connectivity or topology moderate complexity

(3) Element or functional group content (4) Stereocenter content/density (5) Centers of high chemical reactivity (6) Kinetic (thermal) stability high complexity

Strategies and Tactics in Organic Synthesis

Types of Transforms

1. Structurally simplifying transforms effect molecular simplification by disconnecting molecular skeleton, and/or functional groups and/or stereocenters. 2. There are transforms which bring about no essentially no change in molecular complexity, but which can be useful because they modify a TGT to allow the subsequent application of simplifying transforms. They include rearrangements of molecular skeleton, functional group interchange (FGI), and inversion/transfer of stereocenters. 3. Opposite to 1, structurally increasing complexity transforms includes addition of rings or stereocenters and addition functional groups (FGA),.

Strategies and Tactics in Organic Synthesis Types of Transforms 1. Structurally simplifying transforms by disconnecting molecular skeleton and by disconnecting functional groups or stereocenters..

Strategies and Tactics in Organic Synthesis Types of Transforms 2. Structurally "neutral" transforms ...by rearrangements of molecular skeleton,

or functional group interchange (FGI)

Strategies and Tactics in Organic Synthesis Types of Transforms 3. Structurally increasing complexity transforms includes addition of rings, functional groups (FGA), or stereocenters.

Strategies and Tactics in Organic Synthesis Guidelines in action: Symmetry A TGT molecule is said to have real symmetry if the structure possesses symmetry elements: axis, plane or centre. Otherwise, it is said to have potential symmetry when, although asymmetrical molecule, may be disconnected to give either a symmetrical structure or two synthetically equivalent structures. The recognition of symmetry in the structure of the TGT may be of paramount importance in the choices of disconnections to simplify the molecular complexity

regioselective esterification

Paterson, I. JACS 1994, 2615, 9391 Tetrahedron 1995, 9393–9437

See: Two-directional Chain Synthesis. Chem. Scripta 1987, 563; Acc. Chem. Res. 1994, 9; Tetrahedron 1995, 2167; Angew. Chem. Int. Ed 2003, 1096

Strategies and Tactics in Organic Synthesis

Guidelines in action: Symmetry

Robinson, R. J. Chem. Soc. 1917, 762

Bartlett, R. J. Am. Chem. Soc. 1984, 5304 Fleming, I. J. Chem. Soc. Chem. Commun. 1994, 2285

Strategies and Tactics in Organic Synthesis Guidelines in action: Symmetry See also these works

Barton, D. H. R. Chem&Ind 1955, 1039; J. Chem. Soc. 1956, 530

Chapman, O. L. J. Am. Chem. Soc. 1971, 93, 6696

Schreiber, S.L. J. Am. Chem. Soc. 1992, 114, 2525

Strategies and Tactics in Organic Synthesis Guidelines in action: Unstable functional groups? It is imperative to remove or modify the highly unstable groups: Early strategic disconnections must address this type of problems. If this information is not available, preliminary studies are often required. At the outset of the project, no NMR spectroscopic or chemical stability data are available for the natural product. Since such information is invaluable in the design stages of any complex synthesis plan, both spectroscopic and chemical studies have to be undertaken. Evans, D. A. JACS 1990 7001.

Strategies and Tactics in Organic Synthesis Guidelines in action: Unstable functional groups? The facile epimerization of taxol at C-7 is well documented, and in this synthesis the authors decide to pursue a synthetic strategy in which this stereocenter would be introduced at an early stage or the synthetic plan and carried throughout most of the synthesis in the absence of the C-9 carbonyl group

Taxol

Holton, R. A. J. Am. Chem. Soc. 1994, 116, 1597

Strategies and Tactics in Organic Synthesis Guidelines in action: functional groups relationships Taking into account that most common synthetic reactions are polar, a bond forming process (and the corresponding transform) can be viewed as a combination of donor, d, and acceptor, a, synthons. Then, it might be useful to consider the carbon framework of any molecule as an ionic aggregate, whose origin relies on the presence of functional groups.

Following this idea, Evans suggested an heuristic (from the Greek heurisko: "I find') classification of functional groups (Attention: only the heteroatom is considered as the functional group)

Strategies and Tactics in Organic Synthesis Guidelines in action: functional groups relationships

Strategies and Tactics in Organic Synthesis Guidelines in action: stereochemical issues

The selective removal of stereocenters depends on the availability of stereosimplifying transforms, the establishment of the required retrons (complete with defined stereocenter relationships) and the presence of a favorable spatial environment in the precursor generated by application of such a transform... The most powerful transforms produce an overall simplification on the stereochemistry, the functional group and the skeleton of the target molecules. Remember that stereocontrol can rely on the same molecule (substrate control) or on external reagents (reacting control) and that just one or several elements can play a crucial role (single or double asymmetric reactions, matched and mismatched cases)

Corey, E. J. The Logic of Chemical Synthesis Masamune, S. Angew. Chem. Int. Ed. Eng. 1985, 1 Evans, D. A. Chem Rev. 1993,1307

Strategies and Tactics in Organic Synthesis Synthon Corey defined synthon in 1967 as: structural units within a molecule which are related to possible synthetic operations or units which can be formed and/or assembled by known or conceivable synthetic operations" Corey, E. J. Pure&Appl. Chem. 1967, 14, 19. ... but later, he avoids this term and uses synthetic precursor instead. Corey, E. J. The Logic ...; Angew. Chem. Int. Ed. Eng. 1990, 1320 However, this concept easily rooted in the synthetic language and nowadays is commonly used. Additionally, polar synthons have been classified... Taking into account that the most common synthetic reactions are polar, they can be viewed as combination of a negatively polarized (electronegative) carbon atom, or electron donor, d, of one synthon and a positively polarized (electropositive) carbon atom, or electon acceptor, a, of another synthon. Synthons are numbered (d0, d1, d2,... or a0, a1, a2, ....) with respect to the relative positions of a functional group (FG) and the reacting site

Strategies and Tactics in Organic Synthesis

Synthon

Donor Synthons

Acceptor Synthons

Strategies and Tactics in Organic Synthesis Synthon

Strategies and Tactics in Organic Synthesis Synthon

Strategies and Tactics in Organic Synthesis Some “natural Synthons”

Strategies and Tactics in Organic Synthesis Some “Unnatural Synthons”

Strategies and Tactics in Organic Synthesis Disconnections Other guidelines for retrosynthesis are given below: 1. It is better to use convergent approach rather than divergent for many complex molecules. 2. Use only disconnections corresponding to disconnect C–C bonds and C–X bonds wherever possible. 3. Disconnect to readily recognizable synthons by using only known reactions (transform). 4. The synthesis must be short. 5. It is better to use those reactions which do not form mixtures. 6. The focus is on the removal of stereocentres under stereocontrol. Stereocontrol can be achieved through either mechanistic control or substrate control.

Where should I choose to disconnect? Disconnections very often take place immediately adjacent to, or very close to functional groups in the target molecule (i.e. the one being disconnected). This is pretty much inevitable, given that functionality almost invariably arises from the forward reaction.

Strategies and Tactics in Organic Synthesis Disconnections How do I recognize a good disconnection? A good disconnection visibly simplifies the target molecule. Otherwise, the synthesis challenge doesn’t get any easier!

How do I decide which synthon carries which charge? A good trick here is to consider whether you can draw a resonance form of the synthon which looks more like a real reactive intermediate… If it does, you’ve clearly made a good choice of polarity, and you’ve most likely gone a long way to identifying the synthetic equivalent!

Strategies and Tactics in Organic Synthesis Disconnections Basic Guidelines: 1. Use disconnections corresponding to known reliable reactions, choose disconnection corresponding to the highest yielding reaction.

Diazonium salt and propargylic Grignard phenylGrignard and propargylic halide

synthons

reagents

Benzyl-halide and propyne.Grignard

BenzylGrignard and propyne-halide.

Strategies and Tactics in Organic Synthesis Disconnections 2. Disconnect C-C bond according to the present FGs in the molecule: a. C-C bond with no neighbouring functional groups

b. C-C bond with one oxygen substituent

c. Allylic C-C bond

d. C-C bond with two oxygen substituents in positions 1,3

Strategies and Tactics in Organic Synthesis Disconnections 2. Disconnect C-C bond according to the present FGs in the molecule: e. C-C bond with two heteroatom substituents in positions 1,2 or 1,4. Umpolung methods.

3. Aim for simplification: a) Disconnect C-X bond (RCO-X)

Strategies and Tactics in Organic Synthesis Disconnections 3. Aim for simplification: b) disconnect in the middle of the molecule

Tetrahedron Lett. 1981, 22, 5001 c) disconnect at a branch point d) use symmetry

K.C.Nicolaou Angew. Chem. Int. Ed. 2001, 40, 761

Strategies and Tactics in Organic Synthesis Disconnections 3. Aim for simplification: e) disconnect rings from chain

f) use rearrangements

Org. Lett. 2001, 3, 115

Strategies and Tactics in Organic Synthesis f) use rearrangements

Disconnections

HO

HO

O

Oxy-Cope

4. Carbocyclic Rings: If one or more 6-membered carbocyclic unit present in the molecule consider a set of disconnection available for construction of 6-membered rings: Diels-Alder, Robinson annulation, aldol, Dieckmann, internal SN2, Birch reduction, etc. Some types of Diels-Alder disconnections:

Strategies and Tactics in Organic Synthesis Disconnections 5. Examples of cleavage of C-C bond as a retrosynthetic reconnection

TM

TM

TM Via retro [2+2] and ketene formation

TM

TM More electronrich double bond ozonolysis

TM TM

Strategies and Tactics in Organic Synthesis Disconnections

Those disconnections leading to two fragments of similar complexity are specially appealing. Alkyl, aryl,... subunits may be considered as building blocks and they should not be disconnected When an heteroatom (X = N, O, S), is embodied in the carbon framework, the C–X bond disconnection uses to be strategic

C–C disconnections far from functional groups or stereocentres are not favored. C=C disconnections are used to be strategic.

Strategies and Tactics in Organic Synthesis Disconnections

In the case of cyclic systems it is more difficult to elaborate general trends because of the different shapes present in these systems.

But in the case of a monocyclic system ...

Strategies and Tactics in Organic Synthesis Disconnections Disconnection of molecules according to the present FGs in the molecule: The potential of carbonyl functionality

Latent Polarity Latent polarity is the imaginary pattern of alternating positive and negative charges used to assist in the choice of disconnections and synthons. Sticking to latent polarity usually gives the best choice of synthons. However, this is not always possible!

Willis p. 15

Strategies and Tactics in Organic Synthesis Disconnections Guidelines in action: functional groups relationships According to these ideas, it is possible to identify difunctional relationships (consonant or dissonant) among the functional groups in a TGT

1,2-difunctional dissonant relationship

1,3-difunctional consonant relationship

1,4-difunctional dissonant relationship

1,5-difunctional consonant relationship

Consonant relationships usually permit to devise easy disconnections. However, dissonant relationships often require to introduce umpolung tactics, radical or perycyclic reactions

Strategies and Tactics in Organic Synthesis Disconnections Guidelines in action: dissonant disconnection examples + -+

Masked acylanion: unpolung H

1,2-Difunctional Compounds

1,2-Difunctional Compounds

Strategies and Tactics in Organic Synthesis Disconnections Guidelines in action: consonant disconnection examples

+ - + 1,5-difunctionalised compounds

+ -+ -+

1,3-Difunctional Compounds

1,4-Difunctional Compounds

1,4-Difunctional Compounds

1,4-Difunctional Compounds

1,5-Difunctional Compounds

1,5-Difunctional Compounds

1,6-Difunctional Compounds

1,6-Difunctional Compounds

1,6-Difunctional Compounds

Disconnection Guidelines

Warren, p. 86-92

Disconnection Guidelines

Disconnection Guidelines

Available Starting Materials A list of starting materials

Warren p.90

Available Starting Materials Chiral and enanthiopure compounds

Summary of Useful Reactions

Summary of Useful Reactions

Regioselective Enolate Formation

Regioselective Enolate Formation

Regioselective Enolate Formation

Strategies and Tactics in Organic Synthesis Functional Group Interconversion (FGI):

Classification of functional groups by oxidation state of carbon atoms: Oxidation state of carbon in alkanes (cycloalkanes ) is usually negative, the carbon in the fragment C-H is approximated as carbanion. The replacement of the hydrogen with a higher electronegative atom (C and heteroatoms) is equivalent to oxidation

Strategies and Tactics in Organic Synthesis Functional Group Interconversion (FGI):

FGI can be divided into two groups: Type 1. Isohypsic transformations with no change to the oxidation level of carbon Type 2. Non-isohypsic transformations, where carbon atom is either reduced or oxidised. In general, on the same oxidation level any functional group interconversion can be performed in more or less easy way. However, transformations between levels can be achieved only on certain derivatives. +2

0

+2+2

0 oxidation

Very difficult

+2

simple

0

reduction

Strategies and Tactics in Organic Synthesis Functional Group Interconversion (FGI): Type 1 (no change in oxidation state), Level 1. The most common functions resulting from C-C bond construction are alcohol (Grignard addition to carbonyl compounds, aldol reaction, etc) and olefin (Wittig and related processes, croton condensation, olefin methathesis, etc). In addition, FGI of type 2 often lead to alcohols and olefins (reduction of carbonyl compounds, partial hydrogention)

synthons

Conclusion: in practice all functions of oxidation level 1 are synthetically equivalent as they can be easily transformed into each other.

Strategies and Tactics in Organic Synthesis Functional Group Interconversion (FGI): Type 1 (no change in oxidation state), Level 2. The main functional groups are carbonyl compounds (aldehydes and ketones) and alkynes. Formation of synthetic equivalents of carbanions:

Formation of vinyl derivatives.

In organic synthesis vinyl halides can play a dual role: as electrophiles in reaction with organocuprates and as nucleophiles when transformed themselves into organometallic derivatives.

Strategies and Tactics in Organic Synthesis Functional Group Interconversion (FGI): Compounds having two functional groups of level 1 which react as a whole belong to level 2 (1,2-disubstituted compounds, oxiranes, allylic systems)

Formation of epoxides in a C-C bond forming procedure (apart from epoxidation of olefines):

Formation of allylic systems:

Strategies and Tactics in Organic Synthesis Functional Group Interconversion (FGI): Type 1 (no change in oxidation state), Level 3. The main functional group that allows formation of any other derivative on the same level is acid halide. This is a typical electrophile used to make derivatives of carboxylic acids and in Friedel-Crafts C-C bond forming reactions.

Polyfunctional compounds of level 3 are α,β-unsaturated aldehydes and ketones – good Michael acceptors:

Strategies and Tactics in Organic Synthesis Functional Group Interconversion (FGI): Type 2 transformations (change in oxidation state). Availability of methods to go from alcohol to carboxylic acid derivatives and back makes alcohol, carbonyl and carboxyl functions synthetically equivalent.

Other important kind of transformations – interconversion of nitrogen containing functions.

Conclusions: 1. Many functional groups, especially on the same level of oxidation, can be considered as synthetically equivalent so their retrosynthetic interconversions can be planned. 2. As any functional group can be removed, retrosynthetically we can put a functional group in any position of alkane or cycloalkane chain and that would allow assembly of a given C-C fragment. Unfortunately, reverse is not achievable as yet.

Strategies and Tactics in Organic Synthesis Example of FGI and FGA approach

FGA= functional group addition

Strategies and Tactics in Organic Synthesis Atom economy The concept of atom economy was developed by B. M. Trost which deals with chemical reactions that do not waste atoms. Atom economy describes the conversion efficiency of a chemical process in terms of all atoms involved. It is widely used to focus on the need to improve the efficiency of chemical reactions. A logical extension10 of B. M. Trost’s concept of atom economy is to calculate the percentage atom economy. This can be done by taking the ratio of the mass of the utilized atoms to the total mass of the atoms of all the reactants and multiplying by 100.

Even if the reaction were to proceed with 100% yield, only 44.14% (by weight) of the atoms of the reactants are incorporated into the desired product, with 55.86% of the reactant atoms ending up as unwanted by-products.

Trost, B. M., Science, 1991, 254, 1471. Trost, B. M., Angew. Chem., Int. Ed. Engl., 1995, 34, 259.

Strategies and Tactics in Organic Synthesis Atom economy Other examples: Boots and Hoechst Celanese Corporation synthesis of ibuprofen

The total MFW of all the reactants used is 514.5 (C20H42NO10ClN9) and the total MFW of atoms utilized is 206 (ibuprofen; C13H18O2).

new three stage process with an atom economy of 77.4%.

Efficiency and Selectivity in Organic Synthesis

Selectivity:

Efficiency

Stereoselectivity: Formation of one stereoisomer over others

Regioselectivity:

Tactical Efficiency: High Yield Atom Economy

Formation of one regioisomer over others

Chemoselectivity: Reaction of one functional groups over others

Specificity : complete selectivity - chemo-, regio-, stereo

Strategic Efficiency: Minimum of Steps Convergence

Protecting groups in organic synthesis As seen, the selectivity may concern stereo- and regiochemistry, but may also be a question of which functional groups in the molecule are transformed preferentially: the so called chemoselectivity. Sometimes it simply isn't possible to devise a reaction which carries out a desired transformation whilst leaving other functional groups in the molecule untouched. This is often the case in multi-stage syntheses of complex, polyfunctional molecules. When this happens, it is necessary to mask or protect functional groups temporarily, in order that they are not affected by reactions transforming functions in other parts of the molecule. The functional group used to effect this protection is called a protecting group (PG). Properties of protecting groups. An ideal protecting group has the following properties: 1) It must be introduced selectively in the first instance in high yield, using reagents which are readily available, stable and easily handled; 2) It must be stable to a wide range of reaction conditions; 3) It must be readily removed by a specific, mild reagent, to regenerate the starting functional group; 4) It must itself possess a minimum of functionality to avoid the possibility of side reactions; 5) It must be achiral, in order to avoid the formation of diastereomers; 6) It must confer solubility, and facilitate purification; 7) It must stabilize the whole molecule (e.g. avoids racemisation or epimerisation); 8) Participation of the protecting group in any reaction should be either complete or absent. 9) It must be small compared to the mass of what you are trying to make.. Of course, few protecting groups meet all of these criteria, although it is not always necessary for them to do so, and generally a compromise must be found Comprehensive Synthetic Organic Chemistry, 6, 631-701. Protective Groups in Organic Synthesis 2nd ed. Greene, T.W.; Wuts, P.G.M Synthetic Organic Chemistry Michael B. Smith, 629-672. A very smart discussion. Advanced Organic Chemistry part B: Reactions and Synthesis. Carey,J., capter 13, pp. 677-92

Protecting groups in organic synthesis

Strategies For Protection 1. None This could be achieved with selective reagents (so called Reagent Control), but is limited by the availability of such reagents. The next best thing is the use of transient protection. 2. Substrate Control - use of steric bulk to block reactivity; - use of chelation control; - use of negative electron density to repel reagents e.g. via dianions. 3. Multiple protection - Orthogonal Protection (a set of PG whose removal can be accomplished in any order with reagents and conditions which do not affect other PG); - Graded Protection (deprotection relies upon differences in relative rates of reaction of various PG under the same reaction conditions); - Uniform Protection ( use of PG which are all removed under the same conditions) - Convert protecting groups to other functionality 4. Protecting groups which block more than one functional group.

Protecting groups in organic synthesis

Some things to consider before you use protecting groups 1) Know why and when do you need to protect a functional group. 2) Don’t just protect a group because you have to go through x number of steps. 3) One must use protecting groups when the functionality (you wish to preserve) and the reaction conditions necessary to accomplish a desired transformation are incompatible (non-orthogonal). 4) If you can avoid protection of a group in a synthesis, you should 5) It is much better to plan ahead and avoid protection 6) Protecting groups add extra steps to your synthesis more steps cost time and money. These aspects are often against the efficiency in terms of Tactical Efficiency (i.e. Atom Economy) and Strategic Efficiency (i.e. Minimum of Steps) Remember the Efficiency: Tactical Efficiency: High Yield Atom Economy: the atom of PGs are not included in the final product. Strategic Efficiency: Minimum of Steps: each PG introduces at least two extra steps to the synthesis Convergence

Protecting groups in organic synthesis Types of protecting groups (by method of cleavage) - acid labile -base labile - hydrogenolytically labile 1) H2 and catalyst 2) catalytic transfer hydrogenation (NH4 + HCOO-) and catalyst; -other conditions – 1) Reductive - Zn/HOAc; 2) SN2-type cleavage PhSe-, Nu-; F3) Organometallic: Pd(0); 4) Lewis acid: ZnCl2. 5) Oxidative 6) Photolytic Protecting groups for a variety of functional groups heteroatom functional groups, i.e. ROH, carboxylic acid and derivatives, RNH2 and RSH - carbonyls - unsaturated carbon-carbon bonds - α-methylene groups of ketones - phosphate

Protecting groups in organic synthesis Hydroxyl Protecting Groups Ethers Methyl ethers R-OH → R-OMe difficult to remove except for on phenols Formation: - CH2N2 , (J. Chem. Soc., Perkin Trans. 1 1996, 2619). silica or HBF4; NaH, MeI, THF (Org Synth., Collect. Vol. IV 1963, 836). Cleavage: - AlBr3 /EtSH, EtS- (J. Org. Chem. 1977, 42, 1228); PhSe- or Ph2PMe3SiI (J. Org. Chem. 1977, 42, 3761); 9-Bromo-9-borabicyclo[3.3.0]nonane, J. Organomet. Chem. 1978,156, 221

Benzyl Ethers (R-OBn) R-OH → R-OCH2Ph, stable to acid and base Formation: - KH, THF, PhCH2Cl; PhCH2OC(=NH)CCl3, F3CSO3H J. Chem. Soc. P1 1985, 2247 Cleavage: H2 / PtO2; Li / NH3

Protecting groups in organic synthesis Hydroxyl Protecting Groups 2-Napthylmethyl Ethers (NAP)

O-R

formation: 2-chloromethylnapthalene, KH, J. Org. Chem. 1998, 63, 4172 cleavage: hydrogenolysis H2 / PtO2 p- Methoxybenzyl Ethers (PMB) Formation: - KH, THF, p-MeOPhCH2Cl p-MeOPhCH2OC(=NH)CCl3, F3CSO3H Tetrahedron Letters 1988, 29 , 4139 Cleavage: H2 / PtO2; Li / NH3; DDQ; Ce(NH4)2(NO3)6 (CAN), electrochemically Allyl ether Formation CH2=CHCH2OC(=NH)CCl3, H+. For base-sensitive substrates. J. Chem. Soc., Perkin Trans. 1 1985, 2247 and Tetrahedron 1998, 54, 2967.

Pd(Ph3P)4, RSO2Na, CH2Cl2. J. Org. Chem. 1997, 62, 8932

Protecting groups in organic synthesis Hydroxyl Protecting Groups t-Butyldiphenylsilylethyl (TBDPSE) ether formation: The TBDPSE group is stable to 5% TFA/CH2Cl2, 20% piperidine–CH2Cl2, catalytic hydrogenation, n-BuLi, and lead tetraacetate. The TBDPSE group has been cleaved using TBAF (2.0 equiv, 40 °C, overnight) or 50% TFA/CH2Cl2. J. Org. Chem. 2005, 70, 1467.

o-Nitrobenzyl ethers Review: Synthesis 1980, 1; Organic Photochemistry, 1987, 9 , 225

Cleavage: - photolysis at 320 nm

p-Nitrobenzyl Ether Tetrahedron Letters 1990, 31 , 389 -selective removal with DDQ, hydrogenolysis or electrochemically

Protecting groups in organic synthesis Hydroxyl Protecting Groups

9-Phenylxanthyl- (pixyl, px) ,Tetrahedron Letters 1998, 39, 1653

Protecting groups in organic synthesis Hydroxyl Protecting Groups Trityl Ethers -CPh3 = Tr R-OH → R-OCPh3 - selective for 1°alcohols removed with mild acid; base stable formation: - Ph3C-Cl, pyridine, DMAP or Ph3C+ BF4Cleavage: - mild acid Methoxytrityl Ethers, JACS 1962, 84 , 430; methoxy group(s) make it easier to remove

Tr-OR < MMTr-OR < DMTr-OR t-BuO2CNHR > BnO2CNHR ≈ tBuOR > BnOR > allylOR > t-BuO2CR ≈ 2° alkylOR > BnO2CR > 1°alkylOR >> alkylO2CR. Tetrahedron Lett. 1985, 26, 1411.

Protecting groups in organic synthesis Hydroxyl Protecting Groups Acetals Tetrahydropyranyl Ether (THP) DHP

Stable to base, acid labile Formation: dihydropyran (DHP), pTSA, PhH (azeotropic water removing) Cleavage: AcOH, THF, H2O; Amberlyst H-15, MeOH

Ethoxyethyl ethers (EE) J. Am. Chem. Soc 1979, 101 , 7104; JACS 1974, 96 , 4745.

base stable, acid labile

Protecting groups in organic synthesis Hydroxyl Protecting Groups Silyl Ethers R-OH → R-O-SiR3 Synthesis 1985, 817; 1993, 11; 1996, 1031 formation: - R3Si-Cl, pyridine, DMAP; J. Am. Chem. Soc. 1972, 94, 6190 R3Si-Cl, CH2Cl2 (DMF, CH3CN), imidazole, DMAP R3Si-OTf, iPr2EtN, CH2Cl2 Tetrahedron Lett. 1981, 22, 3455 Trimethylsilyl ethers Me3Si-OR TMS-OR - very acid and water labile -useful for transiant protection Triethylsilyl ethers Et3Si-OR TES-OR -considerably more stable that TMS can be selectively removed in the presence of more robust silyl ethers with with For mild acid

Protecting groups in organic synthesis Silyl Ethers Triisopropylsilyl ethers iPr3Si-OR TIPS-OR - more stabile to hydrolysis than TMS Phenyldimethylsilyl ethers, J. Org. Chem. 1987, 52 , 165 t-Butyldimethylsilyl Ether tBuMe2Si-OR TBS-OR TBDMS-OR; JACS 1972, 94 , 6190 - Stable to base and mild acid - under controlled condition is selective for 1°alco hols t-butyldimethylsilyl triflate tBuMe2Si-OTf; TL 1981, 22 , 3455 - very reactive silylating reagent, will silylate 2°al cohols cleavage: acid; F- (HF, nBu4NF, CsF, KF) t-Butyldiphenylsilyl Ether tBuPh2Si-OR TBDPS-OR - stable to acid and base - selective for 1°alcohols - Me3Si- and iPr3Si groups can be selectively removed in the presence of TBS or TBDPS groups. - TBS can be selectively removed in the presence of TBDPS by acid hydrolysis. TL 1989, 30 , 19 Cleavage: F-, Fluoride sources: - nBu4NF (TBAF basic reagent), HF / H2O /CH3CN TL 1979, 3981. HF•pyridine Synthesis 1986, 453; other fluoride sources: Triethylamine trihydrofluoride, Et3N•3HF; Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF); H4N+F–

JOC 1981, 46 ,1506 TL 1989, 30 , 19.

JACS 1984, 106 , 3748

Protecting groups in organic synthesis Silyl Ethers: stability • In general, the stability of silyl ethers towards acidic media increases as indicated: TMS (1) < TES (64) < TBS (20,000) < TIPS (700,000) < TBDPS (5,000,000) • In general, stability towards basic media increases in the following order: TMS (1) < TES (10-100) < TBS ~ TBDPS (20,000) < TIPS (100,000)

J.Chem. Soc., Perkin Trans . 1 1992, 3043. J. Org. Chem. 1988, 53, 2602

Protecting groups in organic synthesis Silyl Ethers Monosilylation of symmetrical diols is possible, and useful J. Org. Chem. 1986, 51, 3388.

Tetrahedron Lett. 2000, 41, 4281

J. Org. Chem. 1983, 49, 4674

Selective deprotection of silyl ethers is also important, and is also subject to empirical determination

J. Am. Chem. Soc. 1995, 117, 8106

J. Am. Chem. Soc., 1994, 116, 1599.

Protecting groups in organic synthesis Esters and Carbonates:

Protecting groups in organic synthesis Ester formation with activated carboxylic functions

carbonyldimidazole

Carbonate formation

Protecting groups in organic synthesis Activated esters. These activated esters can be used as acyl transfer agents to alcohols or amines (Nu)

Mukaiyama's Reagent, Chem. Lett. 1975, 1045; 1159; 1976, 49; 1977, 575

Corey Reagent

The DMTC group is stable to a variety of reagents and reaction conditions (PCC oxidations, Swern oxidations, chromium reagents, Grignard and alkyllithium reagents, phosphorous ylides, LAH, HF, TBAF, and borane). The protecting group is introduced using imid2CS followed by treatment with dimethylamine, or by reaction with commercially available ClCSN(CH3)2.

Protecting groups in organic synthesis Esters are stable to acid and mild base, not compatible with strong base or strong nucleophiles such as organometallic reagents In general, the susceptibility of esters to base catalyzed hydrolysis increases with the acidity of the product acid.

Trifluoroacetates Formation: trifluoroacetic anhydride or trifluoroacetyl chloride Cleavage: - K2CO3, MeOH Pivaloate (t-butyl ester), Fairly selective for primary alcohols Formation: - tbutylacetyl chloride or t-butylacetic anhydride Cleavage: - removed with mild base Benzoate (Bz) more stable to hydrolysis than acetates. Formation: benzoyl chloride, benzoic anhydride, benzoyl cyanide (TL 1971, 185) , benzoyl tetrazole (TL 1997, 38, 8811) Cleavage: mild base; - KCN, MeOH, reflux

Protecting groups in organic synthesis Ester function cleavage Acetate Esters: Several methods cleaving acetate esters have been developed. K2CO3, MeOH, reflux; KCN, EtOH, reflux; NH3, MeOH; LiOH, THF, H2O and enzymatic hydrolysis. Lipases can often be used for the enantioselective hydrolysis of acetate esters (the same enzimes are emploied for forming acetates). The enantioselective hydrolysis of meso diesters is an important synthetic transformation and racemic esters have been kinetically resolved using lipases. Meso compounds

Tetrahedron Lett. 1986, 27, 1255.

Chloroacetate: can be selectively cleaved with Zn dust, thiourea or primary amines

NH H2N

SH

J. Chem. Soc. CC 1987, 1026 J. Am. Chem. Soc. 1998, 120, 5319

Protecting groups in organic synthesis Carbonate function cleavage Allyl Carbonate

Methyl Carbonate

Tetrahedron Lett. 1978, 19, 1375

9-Fuorenylmethyl Carbonate:

Synlett 1993, 680.

2-(Trimethylsilyl)ethyl Carbonate:

J. Chem. Soc., Chem. Comm. 1982, 672 Tetrahedron Lett. 1981, 22, 969.

Trichloroethyl Carbonate: Benzyl Carbonate:

Tetrahedron Lett. 1988, 29, 2227.

Dimethylthiocarbamate (DMTC) Carbamate

J. Am. Chem. Soc. 1939, 61, 3328

Org. Lett. 2003, 5, 4755

Protecting groups in organic synthesis Protection of 1,2- and 1,3- Diols acetals

Synthesis 1981, 501 Chem. Rev. 1974, 74, 581

Silylethers, cleaved with fluoride (HF, CH3CN -or- Bu4NF -or- HF•pyridine), will not fuctionalize a 3°-alcohol TL 1988, 29 , 1561 Formation iPr2Si(Cl)-O-Si(Cl)iPr2 pyridine

TL 1981, 22 , 4999 formation (t-Bu)2SiCl2, Et3N, CH3CN, HOBT

Protecting groups in organic synthesis General methods used to form acetals and ketals. Acetonides: in competition between 1,2- and 1,3-diols, 1,2-acetonide formation is usually favored - cleaved with mild aqueous acid

Synthesis 1981, 501 Chem. Rev. 1974, 74, 581 Cycloalkylidene Ketals - Cyclopentylidene are slightly easier to cleave than acetonides - Cyclohexylidenes are slightly harder to cleave than acetonides The relative rates of hydrolysis of 1,2-Oalkylidene-a-glucofuranoses have been studied.

Carbohydr. Res. 1977, 58, 337

Protecting groups in organic synthesis Examples of selectivity in acetal and ketal formation. In the case of a 1,2,3-triol, careful analysis must be performed to accurately predict the site of acetonide formation. The more substituted acetonide will be favored in cases where the substituents on the resultant five-membered ring will be trans. If the substituents on the five-membered ring would be oriented cis, then the alternative, less substituted acetonide may be favored.

J. Org. Chem. 1989, 54, 915.

J. Am. Chem. Soc. 1984, 108, 2949

J. Chem. Soc., Perkin Trans. 1 1997, 913 Selective Protection: thermodynamic control

Methods Carbohydr. Chem. 1963, 2, 318

Selective Protection: kinetic control

Carbohydr. Res. 1974, 35, 87

Protecting groups in organic synthesis General methods used to form Benzylidenes.

Benzylidene Acetals in competition between 1,2- and 1,3-diols, 1,3-benzylidene formation for is usually favored - benzylidenes can be removed by acid hydrolysis or hydrogenolysis - benzylidene are usually hydrogenolyzed more slowly than benzyl ethers or olefins

Selectivity in benzylidenes formation

Helv. Chim. Acta. 1995, 78, 1837.

Protecting groups in organic synthesis Examples of selectivity in benzylidenes formation. In general, cis-fused 5,6-systems are formed faster than trans-fused 5,6-systems

No cis

trans

Acta. Chem. Scand. 1972, 26, 518.

Note the preference for 1,3-diol protection with the benzylidene acetal. The phenyl group is oriented exclusively as shown, in an equatorial orientation.

Carbohydr. Res. 1972, 21, 473

Protecting groups in organic synthesis Special diol protection groups Formation of dispiroacetals as a protective group for vicinal trans diequatorial diols

Tetrahedron

Lett. 1992, 4767

A cheaper alternative has also been developed:

J. Org. Chem. 1996, 61, 3897

J. Chem. Soc., Perkins Trans. 1 1997, 2023.

Protecting groups in organic synthesis Generalities concerning the selective removal of acetals and ketals: Hydrolysis of the less substituted dioxane or dioxolane ring occurs preferentially in substrates bearing two such groups.

Tetrahedron Lett. 1996, 37, 8643

Methods Carbohydr. Chem. 1963, 2, 318.

Carbohydr. Res. 1978, 45, 181

Protecting groups in organic synthesis Generalities concerning the selective removal of benzylidenes: In general, substitution of the ring of a benzylidene acetal with a p-methoxy substituent increases the rate of hydrolysis by about an order of magnitude

J. Am. Chem. Soc. 1962, 84, 430.

Can be oxidatively removed with Ce(NH4)2(NO3)6 (CAN)

Benzylidene acetals can also be cleaved from the diol reductive

Protecting groups in organic synthesis Selective removal of benzylidenes Methods have also been developed to cleave only one carbon-oxygen bond resulting in the formation of a benzyl ether. This reaction has been extensively studied in the context of carbohydrate chemistry

Tetrahedron Lett. 1995, 5, 669. Tetrahedron Lett., 1998, 39, 355 Pure. Appl. Chem. 1984, 56, 845. J. Org. Chem. 1993, 58, 3480

Protecting groups in organic synthesis Other examples of selective removal of benzylidenes

Protecting groups in organic synthesis Selective removal of benzylidenes Oxidation of benzylidene and substituted benzylidene acetals:

J. Org. Chem. 1969, 34, 1035, 1045, and 1053. Org. Syn. 1987, 65, 243

mechanism

Protecting groups in organic synthesis Selective removal of benzylidenes Oxidation of benzylidene and substituted benzylidene acetals: Ozonolysis also cleaves acetals to hydroxy esters efficiently. This reaction has been reviewed: Can. J. Chem. 1974, 52, 3651.

J. Org. Chem. 1984, 49, 992

J. Org. Chem. 1996, 61, 2394

Protecting groups in organic synthesis 2- electron oxidation of 4-methoxybenzyl groups with DDQ is a general reaction.

J. Org. Chem. 1989, 54, 17.

A useful extension of this reaction has been developed to protect diols directly

Tetrahedron Lett. 1983, 24, 4037

Protecting groups in organic synthesis Carbonyl protective groups

General order of reactivity of carbonyl groups towards nucleophiles: aldehydes (aliphatic > aromatic) > acylic ketones ≈ cyclohexanones > cyclopentanones > α,β-unsaturated ketones ≈ α,α disubstituted ketones >> aromatic ketones.

Preparation of dimethyl acetals and ketals:

1. MeOH, dry HCl. J. Chem. Soc. 1953, 3864. 2. MeOH, LaCl3, (MeO)3CH. Acetals are formed efficiently, but ketalization is unpredictable. J. Org. Chem. 1979, 44, 4187. 3. Me3SiOCH3, Me3SiOTf, CH2Cl2, –78 °C. Tetrahedron Lett. 1993, 34, 995. 4. Sc(OTf)3, (MeO)3CH, toluene, 0 °C. Synlett 1996, 839

Other dialkyl acetals are formed similarly. Cleavage of dimethyl acetals and ketals: TFA, CHCl3, H2O. These conditions cleaved a dimethyl acetal in the presence of a 1,3-dithiane and a dioxolane acetal. Tetrahedron Lett. 1975, 499. 2. TsOH, acetone. J. Chem. Soc., Chem. Commun. 1971, 858. Trans-ketalization 3. 70% H2O2, Cl3CCO2H, CH2Cl2, t-BuOH; dimethyl sulfide. Tetrahedron Lett. 1988, 29, 5609.

Protecting groups in organic synthesis Cyclic acetals and ketals: Relative rates of ketalization with common diols:

In general, saturated ketones can be selectively protected in the presence of α,β-unsaturated ketones. Generally, methods used for formation of 1,3-dioxolanes are also useful for formation of 1,3-dioxanes J. Org. Chem. 1986, 51, 773

Tetrahedron Lett. 1980, 21, 1357.

In protecting α,ß-unsaturated ketones, olefin isomerization is common. Recl. Trav. Chim. Pays-Bas. 1973, 92, 1047.

Protecting groups in organic synthesis Cleavage of 1,3-dioxanes and 1,3-dioxolanes (Chem. Rev. 1967, 67 , 427)

1. PPTS, acetone, H2O, heat. J. Chem. Soc., Chem. Commun. 1987, 1351. 2. 1M HCl, THF. J. Am. Chem. Soc. 1977, 43, 4178. 3. Me2BBr, CH2Cl2, –78 °C. This reagent also cleaves MEM and MOM ethe rs. Tetrahedron Lett. 1983, 24, 3969. 4. NaI, CeCl3•7H2O, CH3CN. J. Org. Chem. 1997, 62, 4183. This method is selective for cleavage of ketals in the presence of acetals. It is also selective for ketals of α,ß-unsaturated ketones over ketals of saturated ketones.

Basic cleavage Using fluoride

Using organic bases

Protecting groups in organic synthesis Dithioacetals General methods of formation of S,S''-dialkyl acetals

1. RSH, HCl, 20 °C. Chem. Ber. 1950, 83, 275. 2. RSSi(CH3)3, ZnI2, Et2O. J. Am. Chem. Soc. 1977, 99, 5009. 3. RSH, BF3•Et2O, CH2Cl2. Marshall, J. A.; Belletire, J. L. Tetrahedron Lett. 1971, 871. See also J. Org. Chem. 1978, 43, 4172. α,β-Unsaturated ketones are reported not to isomerize under these conditions. However, with any of the above mentioned conditions conjugate addition is a concern. General methods of cleavage of S,S''-dialkyl acetals. A variety of methods has been developed for the cleavage of S,S''-dialkyl acetals, largelydue to the fact that these functional groups are often difficult to remove. 1. Hg(ClO4)2, MeOH, CHCl3. Tetrahedron Lett. 1989, 30,15. 2. CuCl2, CuO, acetone, reflux. Org. Synth. Collect. Vol. 1988, 6, 109. 3. m-CPBA; Et3N Ac2O, H2O.. J. Am. Chem. Soc. 1973,95, 6490. 4. (CF3CO2)2IPh, H2O, CH3CN. Tetrahedron Lett. 1989, 30, 287.

Protecting groups in organic synthesis Dithioacetals as useful synthons In addition to serving as a protective group, S, S'-dialkyl acetals serve as an umpolung synthon (acyl anion equivalent) in the construction the of carbon-carbon bonds.

Org. Lett. 2000, 2, 3127.

Protecting groups in organic synthesis Carboxylic Acid Protective Groups: Alkyl Esters

Formation: - Fisher esterification (RCOOH +R'OH + H+), or Acid Chloride + R-OH, pyridine t-butyl esters: Isobutylene, H2SO4, Et2O, 25 °C, Org. Synth., Collect. Vol. IV. 1963, 261. t-BuOH, EDC•HCl, DMAP, CH2Cl2, J. Org. Chem. 1982, 47, 1962. i-PrN=C(O-tBu)NH-i-Pr, toluene, 60 °C, Tetrahedron Lett. 1993, 34, 975.

Cleavage: CF3CO2H, CH2Cl2. J. Am. Chem. Soc. 1977, 99, 2353; Bromocatechol borane. Tetrahedron Lett. 1985, 26, 1411. methyl esters: MeOH, H2SO4, J. Am. Chem. Soc. 1978, 100, 6536. diazomethane; TMSCHN2, MeOH, benzene, Chem. Pharm. Bull. 1981, 29, 1475. This is considered a safe alternative to using diazomethane;

LiOH, MeOH, 5 °C. Tetrahedron Lett. 1977, 3529. Bu2SnO, PhH, reflux (Tetrahedron Lett. 1991, 32, 4239); Pig liver esterase. This enzyme is often effective for the enantioselective cleavage of a meso diester

Tetrahedron Lett. 1984, 25, 2557.

Tetrahedron Lett. 1989, 30, 2513

Protecting groups in organic synthesis Allyl esters, Formation: Allyl bromide, Cs2CO3, DMF. Int. J. Pept. Protein Res. 1985, 26, 493. Allyl alcohol, TsOH, benzene, (–H2O). Liebigs Ann. Chem., 1983, 1712

Cleavage: The use of allyl esters in synthesis has been reviewed: Tetrahedron, 1998, 54, 2967; Pd(Ph3P)4, RSO2Na, CH2Cl2. J. Org. Chem. 1997, 62, 8932.

Benzyl ester: benzyl esters are typically prepared by the methods outlined in the general methods section

The 1,1-dimethylallyl ester is removed under the same conditions as an allyl ester, but is less susceptible to nucleophilic attack at the acyl carbon. Org. Lett. 2005, 7, 1473.

cleavage: 1. H2, Pd–C. Org. React. 1953, 7, 263. 2. BCl3, CH2Cl2. Synthesis. 1991, 294. 3. Na, NH3

Phenyl esters: Phenyl esters typically prepared by the methods outlined in the general methods section. They have have the advantage of being cleaved under mild, basic conditions Cleavage: H2O2, H2O, DMF, pH = 10.5. J. Am. Chem. Soc. 1972, 94, 3259.

Protecting groups in organic synthesis Other carboxylic acid activation systems for mild esterification

Synthesis, 1980, 547.

2-(Trimethylsilyl)ethyl Esters J. Am. Chem. Soc. 1984, 106 , 3030 - cleaved with Fluoride ion; 2Trimethylsilyl)ethoxymethyl Ester (SEM), Helv. Chim. Acta 1977, 60 , 2711. Cleaved with Bu4NF in DMF; MgBr2•OEt2 Tetrahedron Lett. 1991, 32, 3099

SEM ester

Diphenylmethyl Esters, Cleavage: - mild H3O+; H2, Pd/C; BF3•OEt2

o-Nitrobenzyl Esters: selective removed by photolysis

Protecting groups in organic synthesis

Special protecting groups

Ortho Esters: The synthesis of simple ortho esters has been reviewed: Synthesis, 1974, 153; Chem. Soc. Rev. 1987, 75. Stable to base; cleaved with mild acid Tetrahedron Lett. 1983, 24, 5571

Alternatively, ortho esters can be prepared from a nitrile: Helv. Chim. Acta. 1983, 66, 2294.

Special Carboxylates, α-Hydroxy and ß-Hydroxy: Formation: 1. Ketone or aldehyde, Sc(NTf2)3, CH2Cl2, MgSO4. Synlett 1996, 839. Pivaldehyde, acid catalyst. Helv. Chim. Acta. 1986,70, 448,

Protecting groups in organic synthesis Protection of amines: Amides Removable alkyl groups

acetamides

formamides

Benzylamine

Allylamine

Tritylamine Trifluoroacetamide

Carbamates

Methyl Carbamate

Benzyl carbamate (Cbz)

Allyl Carbamate (Alloc)

2,2,2-Trichloroethyl Carbamate (Troc)

t-Butyl Carbamate (Boc)

2-(Trimethylsilyl)ethyl Carbamate (Teoc) 9-Fluorenylmethyl Carbamate (Fmoc) Acc. Chem. Res. 1987, 20 , 401

Protecting groups in organic synthesis Formation of benzylamines:

If primary amines are the starting materials, dibenzylamines are the products

Monobenzylated derivatives

Removal : Pd–C, ROH, HCO2NH4. Tetrahedron Lett. 1987, 28, 515; Na, NH3. Synth. Comm. 1990, 20, 1209.

Formation of allylamines: If primary amines are the starting materials, diallylamines are the products. J. Org. Chem. 1993, 58, 6109.

Removal: Pd(Ph3P)4, RSO2Na, CH2Cl2. Most allyl groups are cleaved by this method, including allyl ethers and esters. J. Org. Chem. 1997, 62, 8932.

Formation of tritylamines: Synthesis 1989, 198.

Cleavage: 0.2% TFA, 1% H2O, CH2Cl2. Tetrahedron Lett. 1996, 37, 4195.

Protecting groups in organic synthesis General preparation of carbamates:

Bases that are typically employed are tertiary amines or aqueous hydroxide.

Tetrahedron Lett. 1986, 27 , 3753 Tetrahedron Lett. 1985, 26 , 1411

Protecting groups in organic synthesis Cleavage of carbamates Methyl Carbamate:

TMSI, CH2Cl2. J. Am. Chem. Soc. 1987, 109, 442; MeLi, THF. J. Am. Chem. Soc. 1992, 114 , 5959

9-Fluorenylmethyl Carbamate:

Acc. Chem. Res. 1987, 20 , 401 Amine base. The half-lives for the deprotection of Fmoc-ValOH have been studied Atherton, E.; Sheppard R. C. in The Peptides, Udenfriend, S. and Meienhefer Eds., Academic Press: New York, 1987, Vol. 9, p. 1. Other removal methods: Bu4N+F–, DMF. Tetrahedron Lett. 1987, 28, 6617; Bu4N+F–, n-C8H17SH. Thiols can be used to scavenge liberated fulvene. Chem. Lett. 1993, 721.

Protecting groups in organic synthesis Cleavage of carbamates 2,2,2-Trichloroethyl Carbamate: Zn, H2O, THF, pH = 4.2. Synthesis, 1976, 457; Cd, AcOH. Tetrahedron Lett. 1982, 23, 249; electrochemically. Tetrahedron Lett. 1986, 27 , 4687

2-Trimethylsilylethyl Carbamate: Bu4N+F–, KF•H2O, CH3CN, 50 °C. J. Chem. Soc., Chem. Commun. 1979, 514; CF3COOH, 0 °C. J. Chem. Soc., Chem. Commun. 1978, 358; Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), DMF. J. Am. Chem. Soc. 1997, 49, 2325.

JACS 1979, 101, 7104

Protecting groups in organic synthesis Cleavage of carbamates t-Butyl carbamate

CF3COOH, PhSH. Thiophenol is used to scavenge t-butyl cations. TBS and TBDMS ethers are reported to be stable under these conditions. J . Org. Chem. 1996, 61, 2413; Bromocatecholborane. Tetrahedron Lett. 1985, 26, 1411and Tetrahedron Lett 1985, 26 , 1411; TMS-I

Allyl Carbamate

1. Pd(Ph3P)4, Bu3SnH, AcOH, 70 – 100% yield. J. Org. Chem. 1987, 52, 4984; Pd(Ph3P)4, (CH3)2NTMS, 89 – 100% yield. Tetrahedron Lett. 1992, 33, 477.

Tetrahedron Lett 1986, 27 , 3753

Protecting groups in organic synthesis Cleavage of carbamates Benzyl Carbamate:

H2/Pd–C. Chem. Ber. 1932, 65, 1192; H2/Pd–C, NH3. These conditions cleave the benzyl carbamate in the presence of a benzylether. Tetrahedron Lett. 1995, 36, 3465; BBr3, CH2Cl2. J. Org. Chem. 1974, 39, 1427; Bromocatecholborane. This reagent is reported to cleave benzyl carbamates in the presence of benzyl ethers and TBS ethers. Tetrahedron Lett. 1985, 26, 1411; hν (254 nm); Na/ NH3 removed by photolysis J. Org. Chem. 1974, 39 , 192

Cleavage of Amides Formamides or Ac2O/HCOOH

removed with strong acid

Acetamides removed with strong acid

Trifuoroacetamides base (K2CO3, MeOH, reflux, J. Org. Chem. 1988, 53, 3108); NH3, MeOH

Protecting groups in organic synthesis Sulfonamides p-Toluenesulfonyl (Ts) Cleavage: - Strong acid; sodium Naphthalide; Na(Hg)

J. Org. Chem. 1989, 54 , 2992

Trifluoromethanesulfonyl (introduced using (CF3SO2)2O)

J. Org. Chem. 1992, 33, 5505

Protecting groups in organic synthesis Other amine protecting groups Trimethylsilylethanesulfonamide (SES) Tetrahedron Lett. 1986, 54 , 2990; J. Org. Chem. 1988, 53, 4143;

removed with CsF, DMF, 95°C

tert-Butylsulfonyl (Bus) J. Org. Chem. 1997, 62, 8604

Alkyne protecting groups Typical silyl groups include TMS, TES, TBS, TIPS, and TBDMS. Many silyl acetylenes are commercially available, and are useful acetylene equivalents. General preparation of silyl acetylenes: Silyl chorides are suitable for smaller silyl groups, but the preparation of more hindered silylacetylenes may require the use of the more reactive silyl triflate.

Protecting groups in organic synthesis In general, a strong fluoride source such as TBAF is used to cleave silylalkynes. In the case of trimethylsilylalkynes, milder conditions can be used. Cleavage of trimethysilylalkynes: KF, MeOH, 50 °C. J. Am. Chem. Soc. 1991, 113, 694; AgNO3, 2,6-lutidine. J. Am. Chem Soc. 1995, 117, 8106; K2CO3, MeOH. Helv. Chim. Acta. 1995, 78, 732.

Angew. Chem., Int. Ed. Engl. 2000, 15, 2732.

Alternatively to trialkylsilyl groups, propargylic alcohol can be considered as alkyne protecting group. These are formed by reacting acetilides with ketones (acetone or benzophenones) and removed by treatment with NaOH in MeOH R O HO R

+

R1

R1

R1 = Me or Ph

Na OH R

R1

R1

MeOH

H

Strategies and Tactics in Organic Synthesis

Synthesis plan guide line 1. Write the synthetic sequence, including reagents. 2. Check for mutually incompatible FGs. 3. Check compatibility between FGs and reagents. 4. Take into account problems of regioselectivity and chemoselectivity. 5. Use protecting groups to resolve these problems. 6. Make sure you make the right TM: check for length of carbon chain, size of rings, position of substituents, nature and position of FGs, removal of protecting groups.

computer-assisted synthetic analysis The computer-assisted synthetic analysis designated OCSS (organic chemical simulation of synthesis) and LHASA (logic and heuristics applied to synthetic analysis) were designed to assist chemists in synthetic analysis by Corey et al. LHASA generates trees of synthetic intermediates from a target molecule by analysis in the retrosynthetic direction. Other programs: WODCA, EROS (Gasteiger), SYNGEN (Hendrickson) AIPHOS (Sasaki). www.infochem.de, www.spresi.de, [email protected] Corey, E. J., Wipke, W. T., Cramer, R. D., III and Howe,W. J., J. Am. Chem. Soc., 1972, 94, 421. Corey, E. J., Howe,W. J. and Pensak, D. A., J. Am. Chem. Soc., 1974, 96, 7724

Strategies and Tactics in Organic Synthesis Basic Concepts of Retrosynthetic Analysis There are some useful general strategies which do not depend on molecular complexity: Transform-based strategies rely on the application of powerfully simplifying transforms. Structure-based strategies rely on the recognition of possible starting materials or key intermediates for a synthesis. Functional group-based strategies identify functional groups as key structural subunits. Topological-based strategies depend on the identification of one or more individual bond disconnections or correlated bond-pair disconnections as strategic. Stereochemical-based strategies remove stereocenters and stereorelationships under control. Corey, E. J. The Logic of Chemical Synthesis

Strategies and Tactics in Organic Synthesis

Transform-based strategies

Transform-based strategies consist on the identification of a powerful simplifying transform leading to a TGT with certain keying features. The required retron may be not present in a complex TGT and a number of antithetic (retrosynthetic) steps may be needed to establish it. Such a strategy relies on synthetic and mechanistic knowledge, which can inspire the recognition of a hidden retron (partial retron)

Strategies and Tactics in Organic Synthesis Transform-based Strategies A case: six-membered cyclic motif

Is it possible to envisage any simple transform in these cyclic structures? The answer could be ... Yes.

Strategies and Tactics in Organic Synthesis Transform-based Strategies In the case of tetrahydropyran a straightforward disconnection, based on SN2 or SN1 processes, can be easily envisaged

Angew.Chem. Int. Ed. 2003, 1258 For a similar retrosynthetic analysis based on a SN2 process, see J. Org. Chem. 1997, 5672 and Synlett 2003, 1817

Strategies and Tactics in Organic Synthesis Transform-based Strategies It becomes more difficult to identify a similar transform in the cyclohexane case and often FGA transforms are required, in the sense that one or more functional gruop is added to individuate the retron

retron for Diels-Alder cycloaddition or Robinson annulation

retron for Diels-Alder cycloaddition or Birch reduction of a benzene ring with Li

1 x FGA

retron for Diels-Alder cycloaddition, Metathesis and Cationic ring formation

In all these case a Diels-Alder reaction can be envisage

Strategies and Tactics in Organic Synthesis Transform-based Strategies The venerable Diels-Alder reaction: a [4π + 2π] cycloaddition

Otto Diels

Remember that an alkyne can also partecipate in Diels- Alder process

Kurt Alder Otto Diels and Kurt Alder Justus Liebigs Annalen der Chemie 460, 98 (1928)

Strategies and Tactics in Organic Synthesis Transform-based Strategies It can be rationalized through Frontier Orbital analysis which permits to predict the regio-, siteand the relative stereochemistry

Strategies and Tactics in Organic Synthesis Transform-based Strategies Regioselectivity: orto-para rule

The coefficients of AO of the monosubstituted diene and of the mono-substituted dienophile are not equal at each end

Strategies and Tactics in Organic Synthesis Transform-based Strategies Site-selectivity

For a siteselectivity analysis in unsymmetrical quinones, see JACS 2004, 4800

Strategies and Tactics in Organic Synthesis Transform-based Strategies Relative stereochemistry: endo rule

Strategies and Tactics in Organic Synthesis Transform-based Strategies

Lewis acid catalysed DA reactions are faster and more stereo and regioselective. All these features can be explained by the effect the Lewis acid has on the LUMO of the dienophile. The Lewis acid coordination with the dienophile lowers the energy of the LUMO, which increases the rate, modifies the LUMO coefficient, increasing the regioselectivity and makes the secondary interaction greater that in the uncatalysed case which accounts for the greater endo selectivity

Fleming, I. Frontier Orbitals and Organic Chemical Reactions

Strategies and Tactics in Organic Synthesis Transform-based Strategies A classic example: the synthesis of reserpine by Woodward

Strategies and Tactics in Organic Synthesis

Other examples

Carpanone JACS 1971, 6696

Strategies and Tactics in Organic Synthesis Transform-based Strategies The power of tactic combinations: estrone by Vollhardt

J. Am. Chem. Soc. 1980, 5253

Strategies and Tactics in Organic Synthesis

An asymmetric Diels Alder reaction: colombiasin A synthesis by Nicolaou

Angew. Chem. Int. Eng. 2001, 2482

Strategies and Tactics in Organic Synthesis Olefinic Metathesis: an alternative to Diels-Alder cyclohexene retron Metathesis = Meta (change) & thesis (position)

AB Blechert, S. Angew. Chem. Int. Ed. 2003, 1900 Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2004, 4592. K. C. Nicolaou, Angew. Chem. Int. Ed. 2005, 44, 4490 – 4527

+ CD

AC + BD

Olefin metathesis has come to the fore in recent years owing to the wide range of transformations that are possible with commercially available and easily handled catalysts. Consequently, olefin metathesis is now widely considered as one of the most powerful synthetic tools in organic chemistry.... With the evolution of new catalysts, the selectivity, efficiency, and functional-group compatibility of this reaction have improved to a level that was unimaginable just a few years ago. These advances together with a better understanding of the mechanism have brought us to a stage where more and more researchers are employing cross-metathesis reactions in multistep procedures and in the synthesis of natural products. Olefin

metathesis can be formally described as the intermolecular mutual exchange of alkylidene fragments between two olefins promoted by metal-carbene complexes

Katz 1976

Tebbe 1978

Schrock 1990

Grubbs 1995

Grubbs 1999

Strategies and Tactics in Organic Synthesis Olefinic Metathesis: The perfect reaction: The process is catalytic (1–5 mol%) High yields under mild conditions High levels of chemo-, regio-,and stereoselectivity The reaction is reversible The starting materials are easily prepared The olefinic products are suitable for further structural elaboration Three main variations on the metathesis theme a) Cross–Metathesis

b) Ring-Closing & Ring-Opening Metathesis (RCM & ROM)

c) Enyne metathesis

Strategies and Tactics in Organic Synthesis Olefinic Metathesis Diels-Alder and Ring-Closing-Metathesis (RCM): two transforms for cyclohexene retron

(Catalytic) process Inter or intramolecular process Reversible Up to four new stereocenters Carbon- and hetero-Diels-Alder are possible

Catalytic process Intramolecular process Reversible No new stereocenters Carbon- and hetero-RCM are possible

Strategies and Tactics in Organic Synthesis Olefinic Metathesis The power of RCM: laulimalide by Ghosh and Mulzer

Laulimalide

Ghosh, A. K. J. Org. Chem. 2001, 8973 Mulzer, J. Adv. Synth. Catal. 2002, 573

Strategies and Tactics in Organic Synthesis Olefinic Metathesis Pioneering catalytic transforms: Sch38516 by Hoveyda

Sch38516 J. Am. Chem. Soc. 1997, 10302 Double bonds

Zirconium-Catalyzed Asymmetric Carbomagnesation Hoveyda, A. J. Am. Chem. Soc. 1993, 6997

Strategies and Tactics in Organic Synthesis Olefinic Metathesis The hidden retron: halosaline by Blechert

Expected metathesis disconnection

(–)-Halosaline Tetrahedron 1999, 817

>78%

Combined ROM & RCM metathesis

Strategies and Tactics in Organic Synthesis Olefinic Metathesis Domino cyclization mediated by metathesis: Grubbs

Grubbs, R. H. J. Org. Chem. 1998, 4291

Strategies and Tactics in Organic Synthesis Domino reactions A domino reaction is a process involving two or more bond-forming transformations (usually C–C bonds) which take place under the same reaction conditions without adding additional reagents and catalysts, and in which the subsequent reactions result as a consequence of the functionality formed in the previous step. Tietze, L. Chem. Rev. 1996, 115

With ever-increasing pressure to fashion diverse molecular architectures rapidly through efficient and atom-economical processes with high degrees of selectivity, cascade reactions are destined to become an integral design aspiration of most synthetic endeavors. In order to push the state-of the art of these sequences ...will require increasingly precise mechanistic and kinetic understanding of organic transformations combined with a large dose of intellectual flexibility and creativity. Nicolaou, K. C. Classics in Total Synthesis II

Strategies and Tactics in Organic Synthesis Domino reaction: Isolated rings The Baldwin rules often constitute a good starting point to analyze the synthetic possibilities .

Rule 1. Tetr a) 3,4,5,6,7-Exo allowed b) 5 i 6-Endo forbidden

Rule 2. Trig a) 3,4,5,6,7- Exo allowed b) 3,4,5-Endo forbidden c) 6,7-Endo allowed

Rule 2. Dig a) 3-4- Exo forbidden b) 5,6,7-Exo allowed c) 3,4,5,6,7-Endo allowed

Strategies and Tactics in Organic Synthesis

Cation π-cyclization. The retron for the cation π-cyclization transform can be defined as a carbocation with charge β to a ring bond which is to be cleaved.

Radical π-cyclization In a similar way, the retron for the radical π-cyclization transform can be defined as a radical with electron β to a ring bond which is to be cleaved, but ...

Strategies and Tactics in Organic Synthesis Domino reaction: a classic of cation π-cyclization: progesterone by Johnson

Progesterone, JACS 1971, 4332

K2CO3 72%

Stereochemical course of the process relies on stereoelectronic issues, according to the StorkEschenmoser hypothesis. Three rings and six contiguous stereocenters are created simultaneously

Strategies and Tactics in Organic Synthesis Domino reaction: a nice solution to a daunting problem: aspidophytine by Corey

Aspidophytine J. Am. Chem. Soc. 1999, 6771

Strategies and Tactics in Organic Synthesis Apparently similar radical π-cyclization

Strategies and Tactics in Organic Synthesis Just two classics of radical π-cyclization: hirsutene and ∆9(12)-capnellene by Curran

Hirsutene JACS 1985, 1448

∆9(12)-Capnellene TL 1985, 4991

Strategies and Tactics in Organic Synthesis Functional group-based Strategies Functional groups

The concept of functional group provides a valuable framework for understanding reactivity and an useful tool to go deeply into retrosynthetic analysis

Strategies and Tactics in Organic Synthesis Functional group-based Strategies Corey classifies the functional groups, FG, in three families: 1st Level: the most important FG

2nd Level: less important FG

3rd Level: peripheral, which are associated with useful reagents providing activation or control in chemical processes, or combination of more fundamental group

They can also be associated into super-set or super-families depending on their electronic behaviour EWG: CO, CN, SOR, NO2 or EDG: OR, NR

Strategies and Tactics in Organic Synthesis Functional group-based Strategies Furthermore, many retrons contain only a single FG, while others consist of a pair of FG's separated by a specific carbon chain path or connection

Strategies and Tactics in Organic Synthesis Functional group-based Strategies Functional group-based strategies The use of functional group to guide retrosynthetic reduction of molecular complexity. Single FG's or pairs of FG's, and the interconnecting atom path, can key directly the disconnection of a TGT skeleton to form simpler molecules or signal the application of transforms which replace functional by hydrogen. FGI is a commonly used tactic for generating from a TGT retrons which allow the application of simplifying transforms. FG's may key transforms which stereoselectively remove stereocenters, break strategic bonds or join proximate atoms to form rings. As mentioned early, taking into account that most common synthetic reactions are polar, a bond forming process (and the corresponding transform) can be viewed as a combination of donor, d, and acceptor, a, synthons. Then,obvious rules can apply to arrangement of functionality in the product. For a molecule containing n FG's there are n(n–1)/2 possible pairs …

Consonant relationschip

Strategies and Tactics in Organic Synthesis Functional group-based Strategies Remember!

Strategies and Tactics in Organic Synthesis 1,2-Difunctional systems: a1 + d1 combination

Moss, N. Synthesis 1997, 32

Strategies and Tactics in Organic Synthesis 1,3-Difunctional systems: a1 + d2 combination

d synthons: enol, enolate and synthetic equivalents 2

a1synthons: aldehydes, ketones and esters

Strategies and Tactics in Organic Synthesis

A benchmark: helminthosporal by Corey

Helminthosporal JACS 1965, 5728

Strategies and Tactics in Organic Synthesis

Experimental condition and final result

Attention: this 1,5-difunctional relationship can evolve through two different pathways

Strategies and Tactics in Organic Synthesis

Helminthosporal: synthetic protocol

Strategies and Tactics in Organic Synthesis

A polifunctional target: 18-epi-tricyclic core of garsubellin A by Shibasaki

Applying the n(n–1)/2

Org. Lett. 2002, 859

Strategies and Tactics in Organic Synthesis

Retrosynthesis garsubellin A core

Strategies and Tactics in Organic Synthesis Garsubellin A core: synthetic protocol Strategy leads the way, but tactics accounts for the success: regiocontrol of enolate formation

Kinetic trap of the resulting enolate avoids regioselective problems

OK

OTBS

more stagle but not formes by steric inderance

SiMe3

Me3Si N

KHDMS

K

More accessible site for derotonation with potassium hexamethyldisilylamide (KHDMS) a bulky base

Strategies and Tactics in Organic Synthesis Garsubellin A core: synthetic protocol

Strategies and Tactics in Organic Synthesis

Garsubellin A core: synthetic protocol Retrosynthetic strategy is based on the following disconnections

Strategies and Tactics in Organic Synthesis

Garsubellin A core: final steps

Strategies and Tactics in Organic Synthesis TRANSITION METAL-MEDIATED PROCESSES: Cross-Coupling reactions

Tsuji Palladium Reagents & Catalysts Wiley 2004 and van Leeuwen Homogenous Catalysis Kluwer 2004, K. C. Nicolaou, Angew. Chem. Int. Ed. 2005, 44, 4442 – 4489

Strategies and Tactics in Organic Synthesis TRANSITION METAL-MEDIATED PROCESSES LG:leaving group

LG Pd0 Nu

Pd

Tsuji: Palladium Reagents & Catalysts, ed. Wiley 2004; van Leeuwen: Homogenous Catalysis, ed. Kluwer 2004

Strategies and Tactics in Organic Synthesis

Palladium mediated cross coupling reaction mechamism

Reductive elimination

Oxidative addition

Boronic or other organometallic reagent

Strategies and Tactics in Organic Synthesis

What should be the analysis in the case of dissonant relationships? Remember of considering the opportunity of:

Seebach, D. Angew. Chem. Int. Ed. Eng 1979, 239 Johnson, J. S. Angew. Chem. Int. Ed. 2004, 1326.

Strategies and Tactics in Organic Synthesis

Remember, in a retrosynthetic sense, if a disconnection is identified as strategic but is not permitted by the particular core functional group present, the replacement of that group by an equivalent which allows or actuates becomes a subgoal objective. Obviously, such an operation requires a synthetic step that permits to invert (umpolung) the type of synthon, from acceptor to donor or from donor to acceptor

Strategies and Tactics in Organic Synthesis Carbonyl Umpolung: acylanion

Strategies and Tactics in Organic Synthesis Enolate Umpolung: α−carbonyl cation

Strategies and Tactics in Organic Synthesis Michael acceptor Umpolung: β−carbonyl anion

Strategies and Tactics in Organic Synthesis

The Spongistatins: architecturally Complex Natural Products through umpolung concept

ACIE 2001, 191,195; OL 2002, 783

Strategies and Tactics in Organic Synthesis

Fragment A–B

1,3-Consonant relationships: Aldol reaction could be the answer? It could be, but it was envisioned another disconnection

Strategies and Tactics in Organic Synthesis

Fragment C–D

Strategies and Tactics in Organic Synthesis

Fragment A–B

HMPA: hexamethylphosphorotriamide, strong lithium coordinating agent. It is used to disaggregate lithium organometallic reagents improving nucleophilicity and basicity.

Me2N Me2N P O Me2N

HMPA

Strategies and Tactics in Organic Synthesis Organometallic Compounds Organometallic compounds have at least one carbon to metal bond, according to most definitions. This bond can be either a direct carbon to metal bond ( σ bond or sigma bond) or a metal complex bond ( π bond or pi bond). Compounds containing metal to hydrogen bonds as well as some compounds containing nonmetallic ( metalloid ) elements bonded to carbon are sometimes included in this class of compounds. Some common properties of organometallic compounds are relatively low melting points, insolubility in water, solubility in ether and related solvents, toxicity, oxidizability, and high reactivity. An example of an organometallic compound of importance years ago is tetraethyllead (Et 4 4Pb) which is an antiknock agent for gasoline. It is presently banned from use in the United States. The first metal complex identified as an organometallic compound was a salt, K(C 2 H 4 )PtCl 3 , obtained from reaction of ethylene with platinum (II) chloride by William Zeise in 1825. It was not until much later (1951–1952) that the correct structure of Zeise's compound

was reported in connection with the structure of a metallocene compound known as ferrocene

Strategies and Tactics in Organic Synthesis Organometallic Compounds Nomenclature: Organometallic compounds are normally named as substituted metals, e.g. alkyl metal or alkyl metal halide. Organomagnesium compounds are generally referred to as Grignard reagents. Examples: CH3Li = methyl lithium, CH3MgBr = methyl magnesium bromide. Physical Properties: Organometallic are usually kept in solution in organic solvents due to their very high reactivity (especially with H2O, O2 etc.) Structure: Organosodium and organopotassium compounds are essentially ionic compounds. Organolithiums and organomagnesiums have a s bond between a C atom and the metal: C-M These are very polar, covalent bonds due to the electropositive character of the metals. Look at the electronegativities of the metals Li, Na, K and Mg compared to C and the other atoms we have seen so far (e.g. N, O, F, Cl etc). See how C is more electronegative than the metal. Partial Periodic Table with Pauling Electronegativities

H 2.1

He

Li1.0

Be1.5

B2.0

C2.5

N3.0

O3.5

F4.0

Ne

Na0.9

Mg1. 2

Al1. 5

Si1.8

P2.1

S2.5

Cl3.0

Ar

K0.8

Ca1.0

Ga

Ge

As

Se

Sc

methyl chloride

Ti

V

Cr

Mn

Fe

Co

methyl lithium

Ni

Cu

Zn

Br2.8 Kr

methyl magnesium bromide

The images show the electrostatic potentials for methyl chloride, methyl lithium and methyl magnesium bromide. The more red an area is, the higher the electron density and the more blue an area is, the lower the electron density

Strategies and Tactics in Organic Synthesis Organometallic Compounds In the alkyl halide, the methyl group has lower electron density (blue), and is an electrophile. In methyl lithium, the methyl group has higher electron density (red) and is a nucleophile. In methyl magnesium bromide, the methyl group is less electron rich that methyl lithium. Therefore, organometallic compounds react as electron rich or anionic carbon atoms i.e. as carbanions, which means they will function as either bases or nucleophiles. It is reasonable to think of these organometallic compounds as R- M+ Basicity: The following equation represents the loss of a proton from a generic hydrocarbon forming a carbanion:

Organolithium and organomagnesium compounds are strong bases since the negative charge is on carbon. Simple carbanions are strong bases, (see pKa's below) since the C is not very electronegative (compared to N or O). In the presence of weak acids, RLi and RMgX protonate giving the hydrocarbon.

Implications: RLi or RMgX CANNOT be used in the presence of acidic hydrogens such as -OH, NH or -SH units.

Strategies and Tactics in Organic Synthesis Organometallic Compounds

Compound

Structure

pKa

2methylpropane

71

ethane

62

methane

60

ethene

45

Benzene

43

ammonia

36

ethyne

25

Ethanol

16

water

15.7

The table shows the pKa's of a selection of representative systems. Note that the hydrocarbons are very weak acids, implying that the carbanions will be strong bases.

Strategies and Tactics in Organic Synthesis Organometallic Compounds Preparation of Organolithium Reagents

Reaction type: oxidation - reduction

Summary Organolithiums are formed by the reaction of alkyl halides with lithium metal. Typical solvents are normally anhydrous diethyl ether but pentane or hexane can also be used. The alkyl group can be primary, secondary or tertiary. Halide reactivity : I > Br > Cl R can be alkyl, vinyl or aryl Other Group I metals (Na, K) can be used instead of Li.

Strategies and Tactics in Organic Synthesis Organometallic Compounds Preparation of Organomagnesium Reagents

Reaction type: oxidation – reduction

Summary Organomagesiums are formed by the reaction of alkyl halides with magnesium metal. Typical solvents are normally anhydrous diethyl ether or tetrahydrofuran. The alkyl group can be primary, secondary or tertiary. Halide reactivity : I > Br > Cl R can be alkyl, vinyl or aryl.

Strategies and Tactics in Organic Synthesis Organometallic Compounds Preparation of Organocopper Reagents

Summary The most useful organocopper reagents are lithium dialkylcuprates, R2CuLi. Lithium dialkylcuprates are formed by the reaction of 2 equivalents of an organolithium with a copper (I) halide. Typical solvents are normally anhydrous diethyl ether or tetrahydrofuran. The alkyl group is usually primary. Secondary and tertiary are prone to decomposition. R can be alkyl, vinyl or aryl.

Strategies and Tactics in Organic Synthesis Organometallic Compounds Preparation of Organozinc Reagents

Reaction type: oxidation – reduction Summary Organozinc reagents, RZnX, are prepared in a fashion analogous to that of organomagnesium reagents RMgX. They are much less reactive than either RLi or RMgX to aldehydes and ketones. The most common application of organozinc reagents is in the Simmons Smith reaction

Strategies and Tactics in Organic Synthesis Organometallic Compounds Preparation of Acetylenic Reagents

Reaction type: acid-base Summary terminal acetylenes can be deprotonated using sodium amide, NaNH2

Acetylenic Grignard reagents, RC=CMgX, can also be prepared. Rather than starting from the acetylenic halides, they are prepared by an acid-base reaction of the terminal acetylene with a second Grignard reagent. Acetylenic Grignards react in a similar fashion to other Grignard reagents.

Strategies and Tactics in Organic Synthesis Organometallic Compounds Reactivity of Organometallics As previously said, the carbon attached to the metal is anionic in character, so it reacts as a carbanion, a nucleophilic carbon. In principle there are 3 important groups of reactions where nucleophiles attack electrophilic C atoms. For the organometallic reagents these types of reactions will result in the formation of new C-C bonds. 1. Nucleophilic Substitution: R2CuLi with alkyl halides or tosylates to give alkanes

2. Nucleophilic Addition: RLi or RMgX with aldehydes or ketones to give 2o or 3o alcohols

3. Nucleophilic Acyl Substitution: RLi or RMgX with esters to give 3o alcohols

Limitations: Organolithium, RLi, and organomagnesium, RMgX, reagents are typically too basic to be used in nucleophilic substitution reactions (1) with alkyl halides or tosylates where they tend to cause elimination reactions or other side reactions. Organocuprates, R2CuLi, reagents are less reactive and do not react with aldehydes, ketones or esters but can be reacted with alkyl halides or tosylates to give alkanes without elimination. Nucleophilic acyl substitution (3) reactions of organolithium, RLi, and organomagnesium, RMgX, reagents are most commonly used with esters.

Strategies and Tactics in Organic Synthesis Organometallic Compounds Overview of Grignard Reactions: Here is a preview of Grignard reactions. In each case the alkyl group, R', from the original Grignard reagent is indicated in blue and the electrophilic portion in black.

Strategies and Tactics in Organic Synthesis Organometallic Compounds Reactions of RLi and RMgX with Aldehydes and Ketones. Reactions performed usually in Et2O or THF followed by H3O+ work-ups

Reactions of RC=CM with Aldehydes and Ketones. Reaction usually in Et2O followed by H3O+ work-up

Reactions of RLi and RMgX with Esters. Reaction usually in Et2O followed by H3O+ work-up. First step Nucleophilic Acyl Substitution then Nucleophilic Addition

Strategies and Tactics in Organic Synthesis Organometallic Compounds Alkane synthesis using R2CuLi

Organolithium cuprates, R2CuLi, react with alkyl halides forming a new C-C, giving alkanes. Primary alkyl iodides make the best substrates otherwise elimination can be a problem. The R group of the cuprate can also be aryl or vinyl. The R' group in the halide can also be aryl or vinyl. Although the mechanism looks like a SN2, it is more complex and is currently not well understood.

Conjugate Addition with Organocopper reagents

Other organometallics reagents such as alkyl lithiums tend to undergo direct or 1,2-addition, while Grignard reagents may give mixtures of 1,2- and 1,4-addition depending on the system.

Strategies and Tactics in Organic Synthesis Organometallic Compounds Synthesis of Cyclopropanes using RZnX (The Simmons-Smith reaction)

The iodomethyl zinc iodide is usually prepared using Zn activated with Cu. The iodomethyl zinc iodide reacts with an alkene to give a cyclopropane. The reaction is stereospecific with respect to to the alkene (mechanism is concerted). Substituents that are trans in the alkene are trans in the cyclopropane

Strategies and Tactics in Organic Synthesis Organometallic Compounds Oxymercuration-Demercuration of Alkenes

Overall transformation C=C to H-C-C-OH This is an alternative method for hydrating alkenes to give alcohols Typical reagents are mercury acetate, Hg(OAc)2 in aqueous THF Unfortunately, mercury compounds are generally quite toxic Regioselectivity predicted by Markovnikov’s rule (most highly substituted alcohol) The reaction is not stereoselective Reaction proceeds via the formation of a cyclic mercurinium ion (compare with bromination of alkenes)

Nu

Nu

NaBH4

Nu

+ Hg HgOAc OAc

H

Strategies and Tactics in Organic Synthesis

Structure-goal strategies Structure-goal strategies are based on the identification of a potential starting material, building block, retron–containing element or initiating chiral element. In other words, the retrosynthetic analysis is guided by the use of a particular structure corresponding to a potentially available starting material or synthetic intermediate. In many synthetic problems the presence of a certain type of subunit in the target molecule coupled with information on the commercial availability of compounds containing that unit can suggest potential starting materials

Strategies and Tactics in Organic Synthesis Chiron approach: synthesis of enantiomerically pure compounds. The chiron approach to synthesis involves disconnection of strategic bonds in a target molecule with minimum pertubation of existing stereogenic centers. This generates chirons with a maximum overlap of functional groups, of stereochemical features, and of carbon framework with the target molecule (or a given substructure). Such molecules normally contain one to five or six stereogenic centers and can originate from Nature (terpenes, carbohydrates, α-amino acids, αhydroxy acids,...), from asymmetric reactions on achiral substrates, from resolution of racemates, and from enzymatic and related sources. By relating a TGT to chiral starting materials as the outset, the scenario for a synthesis plan is established In the chiron approach,it is the type of chiral substructure present in the molecules that will dictate the strategy. The main issue now deal with proceeding in the forward direction using the inherent or newly-created chirality and building from there. Hanessian, S. Total Synthesis of Natural Products: The Chiron Approach Pure & Appl. Chem. 1993, 1189

Sugars carbon framework

asymmetric centres

sense of chirality

Acyclic Cyclic combination 3–7 carbon atoms

1–5 (or 6 includes anomeric center)

2n permutations, generally D

sequential functionality α-hydroxy aldehyde, ... α-amino aldehyde, ... polyols, amino alcohols, …

Strategies and Tactics in Organic Synthesis Sugars as starting chiral materials: some example of retrosynthesis approach

Elaboration of glucose in the synthesis of thromboxane B2

Can. J. Chem. 1977, 562; Can. J. Chem. 1981, 870

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Tetrahedron Lett. 1984, 1853

D-Mannose

Strategies and Tactics in Organic Synthesis

(+)-Meroquinone by Hanessian

(+)-Meriquenone , Tetrahedron 1990, 231

D-Glucose

It is evident that all the hydroxyl groups in D-glucose must be destroyed en route to the construction of the carbon skeleton of (+)-meroquinone, which can be regarded as a stereochemically wasteful procedure. However, the D-glucose framework is efficiently used to install the two vicinal C-substituents by a sequential stereocontrolled one-step conjugate addition and enolate trapping protocol on a readily available enone Pure & Appl. Chem. 1993, 1189

Strategies and Tactics in Organic Synthesis

Other chiral starting materials: Amino acids, hydroxy acids, terpenes

Strategies and Tactics in Organic Synthesis Some examples of retrosynthesis individuating aminoacids, terpenes and hydroxyacids

Strategies and Tactics in Organic Synthesis A brilliant performance: cephalosporin C by Woodward

JACS 1966, 852

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis Topological-based strategies The existence of alternative bond paths through a molecular skeleton as a consequence of the presence of cyclic subunits gives rise to a topological complexity which is proportional to the degree of internal connectivity. Then, topological strategies are based on the use of a particular bond, pair of bonds, set of bonds, or subunit as eligible for disconnection to guide retrosynthetic analysis. Conversely, the designation of bonds or cyclic subunits as ineligible for disconnection. The disconnection of a strategic bond simplifies the topological complexity of a TGT Guidelines – It is not worth disconnecting aromatic or heteroaromatic systems. – Cycloalkyl subunits bound to the carbon skeleton should not be disconnected – Several options should be considered.

Strategies and Tactics in Organic Synthesis

Metathesis Cannon & Blechert. ACIE 2003, 1900

Pauson-Khand Gibson&Stevenazzi ACIE 2003, 1800

Strategies and Tactics in Organic Synthesis

Fused and Bridged systems Primary rings are those that can not be constructed by the sum of two or more smaller rings Secondary rings are those that are not primary rings Synthetically significant rings are 3-7 membered primary or secondary rings

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis Further readings Woodward, R. B. Art and Science in the Synthesis of Organic Compounds: Retrospect and Prospect. In Pointers and Pathways in Research, CIBA of India ,1963 Corey, E. J. Pure&Appl.Chem. 1967, 14, 19. Corey, E. J.; Wipke, W. T. Science 1969, 166, 178. Corey, E. J. Q. Rev. Chem. Soc. 1971, 25, 455. Seebach, D. Angew. Chem. Int. Ed. Engl. 1990, 29, 1320. Corey, E. J. Angew. Chem. Int. Ed. Engl. 1991, 30, 455. Hanessian, S.; Franco, J.; Larouche, B. Pure&Appl.Chem. 1990, 62, 1887. Tietze, L. F.; Beifuss, U. Angew. Chem. Int. Ed. Engl. 1993, 32, 131. Hanessian, S. Pure&Appl.Chem. 1993, 65, 1189. Trost, B. Angew. Chem. Int. Ed. Engl. 1995, 34, 259. Ihlenfeldt, W-D.; Gasteiger, J. Angew. Chem. Int. Ed. Engl. 1995, 34, 2613. Diverses autors. Frontiers in Organic Synthesis. Chem. Rev. 1996, 96, Vol. 1. Nicolaou, K. C.; Sorensen, E. J.; Winssinger, N. J. Chem. Ed. 1998, 75, 1226. Mukaiyama, T. Tetrahedron 1999, 55, 8609. Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. Angew. Chem. Int. Ed. 2000, 39, 44. Sierra, M. A.; de la Torre, M. C. Angew. Chem. Int. Ed. 2000, 39, 1538. Arya, P.; Chou, D. T. H.; Baek, M.-G- Angew. Chem. Int. Ed. 2001, 40 , 339. Schreiber, S. L. Science 2000, 287, 1964. Nicolaou, K. C.; Baran, P. S. Angew. Chem. Int. Ed. 2002, 41, 2678. Benfey, O. T.; Morris, P. J. T. Robert Burns Woodward. Architect and Artist in the World of Molecules. Chemical Heritage Foundation. Philadelphia, 2003. Burke, M. D.; Schreiber, S. L. Angew. Chem. Int. Ed. 2004, 43 , 46. de la Torre, M. C.; Sierra, M. A. Angew. Chem. Int. Ed. 2004, 43 , 160.

Strategies and Tactics in Organic Synthesis Stereochemical-based Strategies Why should we consider stereochemistry? For practical and aesthetic reasons, it is now common practice to plan synthesis in such a way so as to produce an enantiomerically pure (or enriched) TGT. This has become a virtual necessity in pharmaceuthical research laboratories since stereochemistry is the common denominator between chemistry and biology. Hanessian, S. Pure & Appl. Chem. 1993, 1189. About 80% of the active compounds that pharmaceutical companies have in the pipeline are chiral, and it is estimated that this fraction will increase, as the development of active compounds continues to be improved ... The authorities responsible for the registration of new active compounds increasingly demand the targeted synthesis of one stereoisomer... Enantiomerically pure compounds are also being used increasingly in the agrochemicals industry. The targeted synthesis of the active enantiomer can improve the economics of the process and lead to reduced quantities applied and thus to reduced environmental impact. Hauer, B. Angew. Chem. Int. Ed. 2004, 788

There are basically three main strategies to adopt when the synthesis of an enantiomerically pure molecule is considered: 1) resolution of a racemic final compound or an intermediate 2) use of an enantiomerically pure starting material, which can be obtained by resolution, an asymmetric process or by relying on the "chiral pool" 3) through an asymmetric synthesis

Strategies and Tactics in Organic Synthesis The chirality is a dimensional property in the sense that it is referred to the order of dimension. Object can be chiral in one, two and three dimensional system. A system chiral in a dimension is achiral or prochiral in a higher order dimension. mirror mirror

mirror

A

B

B

A

Chiral object in monodimensional system. Achiral in bi or tridimensional systems

A

B

B

A

A A B B Chiral object in bidimensional system. Achiral or prochiral in tridimensional systems

C D

C

D

Chiral object in tridimensional system. Achiral or

prochiral in higher dimensional systems

The importance of chirality

A

Nature yields an enormous variety of chiral compounds Each enantiomer often have very different effects , properties and uses We must control stereochemistry

Roughly 1/3 of pharmaceuticals are chiral; 90% of the top 10 selling drugs the active ingredient is chiral A. M. Rouhi, Chem. Eng. News. 2004, June 14, 47 and Sept. 6, 41

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Atrovastin or atorvastin

Olanzapine Simvastatin

stereocentre

Clopidogrel Lansoprazole

Amlodipine

Sertaline Flutucasone

Strategies and Tactics in Organic Synthesis The direct goal of stereochemical strategies is the reduction of stereochemical complexity by the retrosynthetic elimination of stereogenic elements in a TGT. Stereocomplexity depends on the number of stereogenic elements present in a molecule and their spatial and topological locations relative to one another. Stereogenic element is the origin of stereoisomerism (stereogenic center, axis, or plane) in a molecule such that interchange of two ligands (i.e. 1 and 2) attached to an atom in such a molecule leads to a different stereisomer.

Terminology

stereocentre

Stereoisomers - Isomers that differ only by the arrangement of substituents in space Stereogenic element - the origin of stereoisomerism, be it a stereogenic centre, axis or plane, within the molecule such that the change of two substituents about this element leads to different stereoisomers Chiral compound - simply a molecule (or object) that cannot be superimposed upon its mirror image. The chirality is a property of the whole object and not of a part of it. Most obvious example is our hands... Molecule with a single stereocentre or stereounit, it is tolerated the old definition of chiral centre. In a tetrahedral (Xabcd) or trigonal pyramidal (Xabc) structure, the atom X to which the four (or three, respectively) substituents abc(d) are attached. Lone pairs a re considered as sustituents with the lowest priority

Strategies and Tactics in Organic Synthesis Stereogenic units other than carbon: Nitrogen, Sulfur and Phosphorous Defining absolute configuration: Define priorities according to CIP Point lowest priority (4) away from viewer Draw line from 1 to 3 If the way from 1 to 3 is anti-clockwise, the descriptor is (S) (S)-(4methoxyphenyl)methyl phenyl-phosphine oxide Nitrogen / amines have the potential to be chiral, but due to the rapid pyramidal inversion normally prevents isolation of either enantiomer. If substituents are constrained in a ring then rigid structure prevents inversion as in the case of Troger’s base.

Strategies and Tactics in Organic Synthesis

Trigonal pyramidal phosphorus(III) is configurationally stable below 200°C Tetrahedral phosphorus (V) is configurationally stable

Sulfoxides thiosulfinic esters and sulfinamided have a tetrahedral sulfur atom which possesses a lone pair as substituent! Are configurationally stable at room temperature but, certain anions (chloride ), can cause racemisation (interconversion of the enantiomers)

Strategies and Tactics in Organic Synthesis Chiral molecules with only first order symmetry elements (simple rotation axis) Molecules with C2 symmetry, i.e. with only C2 symmetry axis

Spiro-compounds C2 axis

Chiral axis in CIP definitions

C2 axis

atropoisomerism

(S)-2-(diphenylphosphino)-1-(2-(diphenylphosphino)naphthalen-1-yl)naphthalene

Strategies and Tactics in Organic Synthesis Other chiral systems Helical system: twisted molecules (like a cork-screw) Right-handed helix is denoted P (clockwise as you travel away from viewer) and M for Left-handed

Helical chirality in CIP definitions

Chiral organometallics compounds: chirality resulting from the arrangement of out-of-plane groups with respect to a plane Planar chirality in CIP definitions

Strategies and Tactics in Organic Synthesis Enantiomers and optical rotation Each enantiomer has identical physical & chemical properties (in an achiral environment) Only differ by how they rotate plane polarised light (rotate in opposite directions) Enantiomers are said to be optically active

Enantiomeric excess: Optical purity - an outdated measurement of the enantiomeric excess (amount of two enantiomers) in a solution / mixture. If a solution contains only one enantiomer, the maximum rotation is observed. The observed rotation is proportional to the amount of each enantiomer present

Strategies and Tactics in Organic Synthesis Enantiomeric excess

Racemate (racemic mixture) - 1 to 1 mixture of enantiomers (50% of each) Racemisation converting 1 enantiomer to a 1:1 mixture of enantiomers Polarimeter measures difference in the amount of each enantiomer. New methods more reliable & purity measured in terms of enantiomeric excess (e.e.)

Strategies and Tactics in Organic Synthesis Molecules with more than one stereogenic unit A molecule with 1 stereogenic centre exists as 2 stereoisomers or enantiomers Enantiomers have identical physical properties in an achiral environment) A molecule with 2 or more stereogenic units can exist as 4 or 2 n stereoisomers Enantiomers (mirror images) still have identical physical properties Diastereoisomers (non-mirror images) have different properties

chiral solubility 0.1g/100ml EtOH

meso solubility 3.3g/100ml EtOH

Enantiomers differ only by their absolute stereochemistry (R or S etc) and Diastereoisomers differ by their relative stereochemistry. Relative stereochemistry - defines configuration with respect to any other stereogeneic element within the molecule but does NOT differentiate enantiomers A molecule can only have one enantiomer but any number of diastereoisomers. The different physical properties of diastereoisomers allow us to purify them

Strategies and Tactics in Organic Synthesis Meso Compounds The rule 2n gives the maximum number of stereoisomers but in special case as in the case of meso compounds the number of possible stereoisomers is lower A meso compound is - an achiral member of a set of diastereoisomers that also includes at least one chiral member. Simplistically - a molecule that contains at least one stereogenic unit but has a second order symmetry element (plane of symmetry) and is thus achiral • Meso compounds have a plane of symmetry which split up the molecule in two subunit (each ones are stereocentres) which are one the mirror image of the other with (R) configuration on one side and (S) on the other C2 axis mirror R

S

Tartaric acid chiral no plane of symmetry non-superimposable on mirror image but due to the presence of a C2 symmetry axis it is asymmetric molecule

achiral plane of symmetry superimposable on mirror image (meso)

Strategies and Tactics in Organic Synthesis Difference in diastereomers allows chiral derivatising agents to resolve enantiomers Remember a good chiral derivatising agent should: Be enantiomerically pure (or it is pointless or useless) Coupling reaction of both enantiomers must reach 100% (if you are measuring ee) Coupling conditions should not epimerize stereogenic centres Enantiomers must contain point of attachment Above list probably influenced depending whether you are measuring %ee or preparatively separating enantiomers

Strategies and Tactics in Organic Synthesis Chiral derivatising agent: Mosher’s acid Popular derivatising agent for alcohols and amines is α-methoxy-αtrifluoromethylphenylacetic acid (MTPA) or Mosher’s acid Typical difference in chemical shifts in 1H NMR 0.15 ppm and 19F NMR gives one signal for each diastereoisomer No α-hydrogen so configurationally stable Diastereoisomers can frequently be separated In many cases use of both enantiomers of MTPA can be used to determine the absolute configuration of a stereocentre (JACS, 1973, 512, JOC 1973, 2143 and JACS 1991, 4092)

Difference in NMR signals between diastereoisomers : 1H NMR ∆δ = 0.08 (Me), 19F NMR ∆δ = 0.17 (CF3)

Strategies and Tactics in Organic Synthesis Diastereoisomeric ionic salt formation No need to covalently attach chiral derivatising group Benefit - normally easier to recover and reuse reagent Use of non-covalent interactions allows other methods of resolving enantiomers

Strategies and Tactics in Organic Synthesis Resolution of enantiomers: chiral column chromatogaphy Resolution - the separation of enantiomers from either a racemic mixture or enantiomerically enriched mixture Chiral chromatography - Normally HPLC or GC A racemic solution is passed over a chiral stationary phase Compound has rapid and reversible diastereotopic interaction with stationary phase Hopefully, each complex has a different stability allowing separation

Strategies and Tactics in Organic Synthesis Resolution of enantiomers: chiral column chromatogaphy Measurements of ee by HPLC or GC are quick and accurate (±0.05%) Chiral stationary phase may only work for limited types of compounds Columns are expensive (>€1500) Need both enantiomers to set-up an accurate method

Strategies and Tactics in Organic Synthesis NMR spectroscopy: chiral shift reagents Chiral paramagnetic lanthanide complexes can bind reversibly to certain chiral molecules via the metal centre. Compound must contain Lewis basic lone pair (OH, NH2, C=O, CO2H etc). Coordination process faster than NMR timescale and normally observe a downfield shift (higher ppm) Two diastereomeric complexes are formed on coordination; these may have different NMR signal Problems - as complexes are paramagnetic, line broadening is observed (especially on high field machines). Accuracy is only ±2%

Strategies and Tactics in Organic Synthesis NMR spectroscopy: chiral shift reagents New reagents are being developed all that time that can overcome some y of these problems 1H NMR spectra (400 MHz) of valine (0.06 M, [D]/[L] = 1/2.85) in D O at pH 9.4 and in the 2 presence of samarium complex Signal show no paramagnitic broadening. Extimated ratio D/L: 1/ 3.02 vs 1/2.85 experimental

Strategies and Tactics in Organic Synthesis Desymmetrisation: process that transforms a symmetric or prochiral object into a non symmetric one or in a chiral one From a synthetic point of view, the introduction of new stereogenic centers into a TGT is normally achieved by means of two fundamentally distinct processes: most commonly through addition to one or other stereoheterotopic (enantio- or diastereotopic) faces of a double bond, but also by selective modification or replacement of stereoheterotopic ligands. Symmetric object containing II order symmetry element (plane containing 1, 2, 3 and carbon

Symmetric object containing II order symmetry element (plane containing 1,2 and carbon carbon

carbon

Chiral in a bidimentional system or prochiral in a tridimentional one

Chiral in tridimentional system

Chiral in a bidimentional system or prochiral in a tridimentional one

Strategies and Tactics in Organic Synthesis Substrate: stereocontrol due to a stereochemical bias in the substrate The stereochemical outcome of a wide range of reactions is not contolled by mechanistic issues. Otherwise, it depends on the structure of the substrate or reagent. The generation of a new stereocenter can be controlled by the steric bias of preexisting stereocenters. This kind of stereocontrol is frequent in cyclic structures, conformationally no flexibles. In acyclic systems, the situation is much more complicated Given that the new stereocenters are usually created by addition to a sp2 carbon, high stereocontrol can be achieved if the molecule adopts a definite reactive conformation in which one of the two diastereofaces is efficiently shielded by steric effects of the substituents: 1) Passively by steric shielding of one or two diastereotopic faces on the reactive center. 2) Actively by binding the reagent in form of non-covalent interactions and directing it towards one of the diastereotopic faces Steric and stereoelectronic effects play a crucial role to devise powerful retrosynthetic analysis.

Conformational issues must be considered Acyclic systems Cyclic systems

Strategies and Tactics in Organic Synthesis What conformation is the most stable? And the most reactive?

Lewis acid – Lewis base considerations, coordination (chelation), hydrogen-bonding, must be also considered

Stereoelectronic effect: is any effect determining the properties or reactivity of a species that depends on the orientation of filled or unfilled electron orbitals in space. Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry

O

O

O

O

O

weak lone pair repulsion More stable

O

medium lone pair repulsion

strong lone pair repulsion Less stable

Strategies and Tactics in Organic Synthesis Mechanism: intrinsically stereocontrolled transforms There are reactions which show stereoselectivity primarily because of mechanism: SN2 processes, hydroboration, epoxidation, OsO4 oxidation of alkenes ect.. Those disconnections involving C–C bonds are specially important The stereochemistry of bis-epoxide controls the final stereochemical outcome

Mulzer, J. ACIEE 1990, 1476

Ireland, R. E. JOC 1991, 4031

Strategies and Tactics in Organic Synthesis Stereoselectivity in Organic Synthesis Stereospecific reactions - a reaction where the mechanism and the stereochemistry of the starting material determine the stereochemistry of the product; there is no choice! e.g. SN2 reactions. Diastereospecific reaction permits only one diastereoisomer to be formed control relative stereochemistry not absolute stereochemistry for example Iodolactonisation Proceeds via an iodonium species followed by intramolecular ring-opening Geometry of alkene controls relative stereochemistry If there is a pre-existing stereogenic centre then reaction can be stereoselective. In such reactions two diastereoisomers could be formed but one is favoured

I2

Stereoselective reactions - a reaction where one stereoisomer of a product is formed preferentially over another. The mechanism does not prevent the formation of two or more stereoisomers but one predominates. Diastereoselective reactions - a stereogenic centre is introduced into a molecule in such a way that diastereoisomers are produced in unequal amounts

Enantioselective reactions - a reaction that produces two enantiomers of a product in unequal amounts

Strategies and Tactics in Organic Synthesis Stereoselective reactions Nucleophilic addition to C=O and Prochiral Nomenclature Trigonal carbons that are not stereogenic units but can be transformed into them are called prochiral, to each carbonyl face is assigned the label Si or Re based on the CIP rules. If the carbonyl function is in a chiral molecule is called prostereogenic unit and the faces are said to be diastereotopic In the case of achiral molecules the carbonyl faces are named enantiotopic and the addition of nucleophiles to the carbonyl function can occur with enantioselection or the reaction is enantioselective if one prochiral face is attached preferentially over the other.

Reaction of a nucleophile with a carbonyl in a substrate where other sterecentre are present, gives two possible diastereoisomers. Reaction is stereoselective if one diastereoisomer predominates

Strategies and Tactics in Organic Synthesis Possible models proposed along the time for nucleophile apprach to the carbonyl function with a stereocentre in α

Models proposed with a perpendicular approach of Nu to the carbonyl function

Nucleophiles attack the carbonyl group along the Bürghi-Dunitz angle of ~107°

the Bürghi-Dunitz (107°) angle is the compromise between electrostatic interaction and optimised orbital overlaps

Later on other models have been proposed with Bürghi-Dunitz trajectory of Nu to the carbonyl function

Strategies and Tactics in Organic Synthesis Importance of conformational analysis Newman projection: two substituents (C=O & Ph) are eclipsed - unfavoured

Other possible conformers: Two favoured as largest substituent (Ph) furthest from O and H

Re face One of the more stable conformer largest substituent (Ph) furthest from O&H

Explained using Felkin-Ahn model in most stable conformation the favoured approach is close to the smallest substituent (H) when molecule

Si face One of the more stable conformer largest substituent (Ph) furthest from O&H

Strategies and Tactics in Organic Synthesis General features for the addition to a carbonyl with a α stereocentre: Felkin-Ahn Model

To explain or predict the stereoselectivity of nuclophilic addition to a carbonyl group with an adjacent stereogenic centre, use the Felkin-Ahn model: Draw Newman projection with the largest substituent (L) perpendicular to the C=O; Nucleophile (Nu) will attack along the Bürghi-Dunitz trajectory passed the least sterically demanding (smallest, S) substituent, draw the Newman projection of the product, redraw the molecule in the normal representation. Whilst the Felkin-Ahn model predicts the orientation of attack, it does not give any information about the degree of selectivity but only whose will be the predominant stereoisomer The size of the nucleophile greatly effects the diastereoselectivity of addition: Larger nucleophiles generally give rise to greater diastereoselectivities. Choice of metal effects the selectivity as well, although this may just be a steric effect. The size of substituents on the substrate will also effect the diastereoselectivity. Again, larger groups result in greater selectivity. Should be noted that larger substituents normally result in a slower rate of reaction

Strategies and Tactics in Organic Synthesis The effect of electronegative atom in α to carbonyl function Steric hinderance is not the only factor that justify the high observed stereoselectivity and faster reaction in the addition of ester enolates to α-amino substituted aldehydes. Other factors, such as electronic factors, can play an important rule as in the case of αdibenzylamino substituted aldehydes. The Bn2N group must be perpendicular to C=O since in this way there is a better interaction between the C-N and the carbonyl double bond. Applying the Fenkin-Ahn model, the approach of enolate is favoured from the opposite site to Bn2N (electronic repulsion between two electron rich group namely enolate and Bn2N). Fenkin-Ahn approach

When an electronegative group is perpendicular to the C=O it is possible to get an overlap of the π* orbital and the σ* orbital which results in a new, lower energy orbital, more susceptible to nucleophilic attack, thus if electronegative group perpendicular, C=O is more reactive.

Strategies and Tactics in Organic Synthesis The effect of electronegative atom and chelation control

Other example of electronic effect control

If heteroatom (Z) is capable of coordination and a metal capable of chelating 2 heteroatoms is present we observe chelation control. Metal chelates carbonyl and heteroatom together fixing their conformation affording greater selectivity and faster reaction. The chelating metal acts as a Lewis acid and activates the carbonyl group to attack. Chelation can reverse selectivity. Chelation controlled additions are easy to predict and normally do not need to draw Newman projection!

Strategies and Tactics in Organic Synthesis Chelation control in the nucleophilc addition to α carbonyl: other examples

The following example shows normal Felkin-Ahn selectivity gives one diastereoisomer Electronegative and bulky phosphorus group in perpendicular position, Chelation control gives opposite diastereoisomer and occurs through 6-membered ring. Lower reaction temperatures are typical in activated chelated carbonyl systems

Strategies and Tactics in Organic Synthesis Application of Fenkin-Ahn model in total synthesis An example of the Sakurai reaction (addition of allylsilane to carbonyl) from the synthesis of preswinholide A which is effectively the monomer of swinholide A (the dimmer, isolated from a Red Sea sponge), a compound displaying potent cytotoxic activity Total synthesis by Ian Paterson, Tetrahedron, 1995, 51, 9437

Strategies and Tactics in Organic Synthesis

The synthesis of canadensolide, a fungicidal agent is another example of the Mukaiyama aldol reaction (addition of ester silylenolether to carbonyls • Yung-Son Hon & Cheng-Han Hsieh, Tetrahderon, 2006, 62, 9713

Strategies and Tactics in Organic Synthesis Stereoselctive reaction of enolates The stereoselectivity of reactions of enolates is dependent on: Presence of stereogenic centres on R1, R2 and frequently on the geometry of the enolate (but not always)

Geometry of the enolate: The terms cis and trans in relation of the disposition group with highest priority on the α-carbon atom to O–M bond C-α si face

C-α re face

MO

R2 α

R1

H

C-α si face

MO

H α

R1

R2

C-α re face

Strategies and Tactics in Organic Synthesis Enolate formation and geometry Enolate normally formed by deprotonation, this is favoured when the C–H bond is perpendicular to C=O bond as this allows σ orbital to overlap π orbital. σ C–H orbital ultimately becomes p orbital at C-α of the enolate π bond

Deprotonation process and geometry of the enolate Two possible conformations which allow this: Little steric interaction between R1 and R2 Initial conformation (Newman projection) similar to transition state results in the formation of cis enolate

Strategies and Tactics in Organic Synthesis Enolate formation and geometry

Deprotonation process and geometry of the enolate Second conformation: C–H perpendicular to C=O which differs by relative position of R1 and R2 and gives trans-enolate The steric interaction of R1 and R2 results in the cis-enolate normally predominating but the stereoselectivity is influenced by the size of R

Strategies and Tactics in Organic Synthesis Enolate formation and geometry The selectivity observed can be explained via chair-like transition state of deprotonation step In ketones cis-enolate favoured if R is large but trans-enolate favoured if R is small

With esters the R vs OMe interaction is alleviated and 1,3-diaxial interaction controls the geometry of the enolate, hence trans-enolate predominates

Strategies and Tactics in Organic Synthesis Enolate formation and geometry Amides invariably give the cis-enolate; remember restricted rotation of C–N bond. The previous arguments are good generalisations, many factors effect geometry. Use of the additive HMPA (hexamethylphosphoric triamide) reduces coordination and favours the thermodynamically more stable enolate

In ester the reverse is observed

Strategies and Tactics in Organic Synthesis Addition electrophile to an enolate: Alkylation

It is important to know the trajectory of approach of the enolate and electrophile Reaction is the overlap of the enolate HOMO and electrophile LUMO Therefore, new bond is formed more or less perpendicular to carbonyl group The example shows a simple SN2 reaction with X = leaving group

Strategies and Tactics in Organic Synthesis Stereoselective (diastereoselective) alkylation of prochiral enolates. The alkylation of prochiral enolates of acid is normally preformed using chiral derivatives such as chiral amides (Meyer approach, enantiopure aminoalcohol) or imides (Evans approach enantiopure oxazolidinones) Evans approach

From phenylalanine Chelation is important for enolate geometry and for the approach of the electrophile. M= Li (JACS 1982, 104, 1737 ) or TiCl3 (JACS 1990, 112, 8215) d.e.>95 to 100%. After removing the chiral auxiliary the final acid is obatin with high e.e.

Cis- enolate

Myers approach

d.e. >94%, yields >80% JACS 1994, 116, 9361; 1995, 117, 8488

Cis-enolate

Strategies and Tactics in Organic Synthesis Stereoselective (diastereoselective) alkylation of chiral enolates Simple alkylation of a chiral enolate usually occurs with very high diastereoselectivity Since the cis-enolate is usually formed with high diastereoselectivity the reactive conformer considering the alkenes A(1,3) strain. Larger the substituent, R, greater the selectivity

The geometry of enolate is not important

Cis-enolate

minor diastereoisomer probably arises from electrophile approaching from R group site and not reacting with the trans enolate. So its dimension play and important role in determining diastereoselectivity. It is possible to change the diastereoselectivity simply using the proton as electrophile in quenching the enolate of the alkylated final product

Strategies and Tactics in Organic Synthesis Stereoselective (diastereoselective) aldol reaction The aldol reaction is a valuable C–C forming reaction. In addition it can form two new stereogenic centres in a diastereoselective manner. Most aldol reactions take place via a highly order transition state know as the Zimmerman–Traxler transition state which is a 6-membered, chair-like transition state. Contrary to alkylation, the enolate geometry effects diastereoselectivity

syn aldol

Strategies and Tactics in Organic Synthesis Stereoselective (diastereoselective) aldol reaction: Zimmerman–Traxler transition state

Zimmerman–Traxler transition state for cis-enolate Enolate substituents are fixed due to the double bond thus the orientation of the aldehyde in relation to the enolate is crucial in determining the final stereoselectivity (diatereo and enantio selectivity) in the aldol reaction Bulky aldehyde substituent should be arranged in pseudoequatorial position in the Zimmerman–Traxler transition state in order to avoid 1,3-diaxial interactions

Enantiomeric TS Me and OH point towards the observer

si face of enolate attacks re face of aldehyde

re face of enolate attacks si face of aldehyde

to ‘see’ relative stereochemistry consider the blue carbon sequence on a plane and see which groups are above and which below. Thus in this case Me and OH are farer from observer

Attack via the enantiomeric transition state (re face of aldehyde) gives the enantiomeric aldol product. This differs only by the absolute stereochemistry but the relative stereochemistry is the same Me and OH on the same site

Strategies and Tactics in Organic Synthesis Stereoselective (diastereoselective) aldol reaction: Zimmerman–Traxler transition state Trans-enolate: The opposite stereochemistry of enolate gives opposite relative stereochemistry

In this case the two hydrogens must axial

Strategies and Tactics in Organic Synthesis Stereoselective (diastereoselective) aldol reaction: enolate geometry In the lithium enolates of ketones the size of the non-enolised substituent, R, is important Geometry of the enol in ketones is determined by the dimension of R

With boron enolates we can select the geometry by altering the boron reagent used

The bulky groups on boron force enolate to adopt trans geometry

9-BBN (9-borabicyclononane) looks bulky, but most of it is ‘tied-back’ behind boron thus allowing formation of the cis-enolate

Strategies and Tactics in Organic Synthesis Substrate control in the total synthesis of oleandomycin aglycon

Cram chelation control

Strategies and Tactics in Organic Synthesis Aldon reaction: Substrate control in the total synthesis of oleandomycin aglycon

the opportunities offered by the aldol reaction. It creates 1 C–C bond and 2 stereogenic centres per reaction. Ian Paterson,, J. Am. Chem.Soc., 1994,116, 11287

Strategies and Tactics in Organic Synthesis Aldon reaction: Substrate control in the total synthesis of swinholide A by Paterson Tetrahedron 1995, 9393–9467

fragment A

fragment B

Strategies and Tactics in Organic Synthesis

fragment A

fragment B

Strategies and Tactics in Organic Synthesis Stereoselective Synthesis; Chiral auxiliary Chiral auxiliary - allows enantioselective synthesis via diastereoselective reaction Add chiral unit to substrate to control stereoselective reaction. Can act as a built in resolving agent (if reaction not diastereoselective). Problems - need point of attachment, adds additional steps (atom economy),.cleavage conditions must not damage product!

An ideal chiral auxiliary has to fulfil several criteria: i) it should be cheap, and both enantiomers should be readily available; ii) attachment of the substrate to the auxiliary should proceed in high yield by simple methods, applicable to a broad variety of substrates; iii) there should be many different types of reactions to be carried out; iv) the auxiliary must be stable under the conditions of the diastereoselective reaction; v) there must be a high degree of diastereoselection vi) the derivatives of the chiral auxiliary should preferably be crystalline, allowing easier purification, and removal of diastereoisomeric ans other impurities by simple crystallization; vii) the cleavage of the auxiliary must be possible with high yield under mild conditions, and the procedures should be generally applicable viii) the auxiliary should not be destroyed under the conditions applied for cleavage, thus allowing for recycling ix) isolation of the enantiomerically pure product and recovery of the auxiliary should be possible by simple methods. Seebach, D. Helvetica Chimica Acta 1998, 2093

Strategies and Tactics in Organic Synthesis Chiral auxiliary and addition to the carbonyl group We have seen many examples of substrate control in nucleophilic addition to the carbonyl group (Felkin-Ahn & chelation control). If molecule does not contain a stereogenic centre then we can use a chiral auxiliary. The chiral auxiliary can be removed at a later stage

Opposite diastereoisomer can be obtained from reduction of the ketone with lower diastereoselectivity...‘H–’ is smaller

Strategies and Tactics in Organic Synthesis

Chiral auxiliary in synthesis The chiral auxiliary, 8-phenylmenthol, has been utilised to form the pheromone, frontalin Aggregation pheromone of the Southern Pine Beetle - the most destructive beetle to pine forests in southeastern united states

Strategies and Tactics in Organic Synthesis Stereoselective synthesis: chiral reagents Chiral reagents Chiral reagent - stereochemistry initially resides on the reagent • Advantages - No coupling / cleavage steps required ....................... .Often override substrate control ....................... .Can be far milder than chiral auxiliaries • Disadvantages - Need a stoichiometric quantity (not atom economic) .............................Frequently expensive .............................Problematic work-ups

Strategies and Tactics in Organic Synthesis Chiral reagents Clearly, chiral reagents are preferable to chiral auxiliaries in that they function independent of the substrate’s chirality or on prochiral substrates A large number have been developed for the reduction of carbonyls Most involve the addition of a chiral element to one of our standard reagents

selectivity governed by 1,3-diaxial interactions

Strategies and Tactics in Organic Synthesis

Binol derivative of LiAlH4 Reducing reagent based on BINOL and lithium aluminium hydride • Selectivity is thought to arise from a 6-membered transition state (surprise!!) • Largest substituent (RL) adopts the pseudo-equatorial position and the small substituent (RS) is axial to minimise 1,3-diaxial interactions

Transition state

Strategies and Tactics in Organic Synthesis Chiral reagent in total synthesis (+)-Ipc2BCl is a more reactive, Lewis acidic version of Alpine-borane • Might want to revise the Mitsunobu reaction (step 2)

• M. Srebnik, P.V. Ramachandran & H.C. Brown, J. Org. Chem., 1988, 53, 2916

Strategies and Tactics in Organic Synthesis Chiral allyl boron reagents Allyl boron reagents have been used extensively in the synthesis of homoallylic alcohols • Reaction always proceeds via coordination of Lewis basic carbonyl and Lewis acidic boron

• This activates carbonyl as it is more electrophilic and weakens B–C bond, making the reagent more nucleophilic • Funnily enough, reaction proceeds by a 6-membered transition state

Aldehyde will place substituent in pseudo-equatorial position (1,3-diaxail strain) • Therefore alkene geometry controls the relative stereochemistry (like aldol rct)

Strategies and Tactics in Organic Synthesis Chiral allyl boron reagents II

Reagent is synthesized from pinene in two steps • Gives excellent selectivity but can be hard to handle (make prior to reaction)

• Remember pinene controls absolute configuration Geometry of alkene controls relative stereochemistry

Strategies and Tactics in Organic Synthesis Other boron reagents A number of alternative boron reagents have been developed for the synthesis of homoallylic alcohols • These either give improved enantiomeric excess, diastereoselectivity or ease of handling / practicality • Ultimately, chiral reagents are wasteful - they need at least one mole of reagent for each mole of substrate • End by looking at chiral catalysts

Strategies and Tactics in Organic Synthesis Chiral reagent in total synthesis Silicon reagent developed by J. Leighton • Used in the synthesis of (+)-SCH 351448, a reagent for the activation of low-density lipoprotein receptor (LDLR) promoter. L. Leighton, Org. Lett., 2005, 7, 3809

Strategies and Tactics in Organic Synthesis Stereoselective synthesis: chiral catalysis Chiral catalysis - ideally a reagent that accelerates a reaction (without being destroyed) in a chiral environment thus permitting one chiral molecule to generate millions of new chiral molecule The reaction is often perfomed on achiral substrates or prochiral ones (as for example carbonyl functions).

Strategies and Tactics in Organic Synthesis Catalytic enantioselective reduction An efficient catalyst for the reduction of ketones is Corey-Bakshi-Shibata catalyst (CBS): The reagent is prepared from a proline derivative: diphenylprolinol. Enantioselection is deternated by the nature of chiral reagent and occurs by the formation of diastereoisomeric transition states with different energies. The reaction utilises ~10% heterocycle and a stoichiometric amount of borane and works most effectively if there is a big difference between each of the substituents on the ketone.

Prochiral carbonyl function

The mechanism is quite elegant: This catalyst brings a ketone and borane together in a chiral environment

Boron Lewis acidic center that coordinates carbonyl oxygen

Strategies and Tactics in Organic Synthesis Catalytic enantioselective nucleophilic addition There are now many different methods for catalytic enantioselective reactions. Some few examples. Simple amino alcohols are known to catalyse the addition of dialkylzinc reagents to aldehydes with a mechanism involving a bifunctional zinc species where one zinc becomes the Lewis acidic centre and activates the aldehyde and the second equivalent of the zinc reagent actually attacks the aldehyde. Once again a 6-membered ring is involved and 1,3-diaxial interactions govern the observed selectivity

1,3-diaxial interaction

Strategies and Tactics in Organic Synthesis Lewis acid catalysed allylation / crotylation Chiral Lewis acids can be used to activate carbonyl group with impressive results and in the case of allylation works very well with high e.e. However the control of diastereoselectivity is often difficult to achieve. In this reaction the reaction proceeds via an open transition state and this partially explain the relative difficulty in controlling the diastereoselection. C-Sn Bond is enough polarized and this makes the gamma position particularly nucleophilic

nucleophilc site

RE

Rz δ− Sn δ+

The E or Z nature of stannyl derivative has no influence on diatereoselection but are important the dimention of the group in gamma position to the Sn i.e the differences between the dimention RE and RZ.

Strategies and Tactics in Organic Synthesis Catalytic chiral Lewis base mediated allylation with allyl silicon reagents Alternatively allylsilyl reagents are emploied in allylation of carbonyls. In this case the use of chiral Lewis bases, which activate the crotyl reagent, higher diatereoselection are obeserved. The reaction proceeds via the activation of the allylsilicon reagent by coordination of chiral base and with the generation a hypervalent silicon species This species coordinates and activate the carbonyl function allowing the reaction to proceed by a highly ordered by a closed transition state. As a result good diastereoselectivities are observed and the geometry of nucleophile controls the relative stereochemistry.

RE and RZ = Me or H Example of base catalysts used in this reaction

Strategies and Tactics in Organic Synthesis

Reactions of alkenes: Stereospecific reactions Alkenes are versatile functional groups that present plenty of opportunity for the introduction of stereocenters. One possibility is by Hydroboration (the reaction that allows to transform alkenes in alcohols) that permits the stereo-selective introduction of boron. The corresponding borane can undergo a wide-range of stereospecific reactions

The two compounds formed previously, mono& diisopinocampheylborane are common reagents for the stereoselective hydroboration of alkenes. Ipc2BH is very effective for cisalkenes but less effective for trans. IpcBH2 gives higher enantiomeric excess with trans and trisubstituted alkenes

Strategies and Tactics in Organic Synthesis Hydrogenation: is another important reaction that can be carried out enantioselectively under metal catalysis condition. One well known example for its huge importance from industrial point of view, is the catalytic hydrogenation of dehydroaminoacid derivatives (prepared by Knovenagel like reaction on glycine). Diphosphines are used as Rutenium ligand and it is essential that there is a second coordinating group (the amide in the dehydroaminoacid).

On coordination, two diastereoisomeric complexes are formed. The stability / ratio of each of these complexes is unimportant in determining the final stereoselection but the rate of hydrogen coordination.

Si face Re face

Strategies and Tactics in Organic Synthesis Mechanism proposed for catalytic hydrogenation

Hydrogen oxidative addition

Hydrogen transfer

Strategies and Tactics in Organic Synthesis Other systems can be hydrogenated with the same chiral catalyst: industrial synthesis of candoxatril

Used in the synthesis of candoxatril, a potent atrial natriuretic factor (ANF) potentiator (cardiovascular drug developed by Pfizer). Process used on ton-scale Org.Process Res. Dev., 2001, 5, 438

Strategies and Tactics in Organic Synthesis Reactions of alkenes: epoxidation diastereospecific reaction Diastereospecific - reaction permits only one diastereoisomer to be formed control relative stereochemistry not absolute stereochemistry Electrophilic epoxidation via a concerted process is a good example

Concerted oxygen transfer

Epoxidation is irreversible and the reaction is under kinetic control.

Strategies and Tactics in Organic Synthesis Conformation are important in determining the observed stereoselection: the lowest energy conformations have greatest separation of bulky substituents. The control of conformation in allyl systems is called allylic strain or A(1,3) strain

allylic strain or A(1,3) strain

Strategies and Tactics in Organic Synthesis

In the trans alkene the differences in energy between the two conformers is sensibly lower and the d.e. is minor (61/39)

Strategies and Tactics in Organic Synthesis Hydroxyl group can direct epoxidation in acyclic compounds as well • Once again, major product formed from the most stable conformation

• Thus the cis methyl group is very important • The minor product is formed either via non-directed attack or via the less favoured

...conformation

Strategies and Tactics in Organic Synthesis Directed epoxidation: effect of C-2 substituent The presence of a substituent in the C-2 position (Me) facilitates a highly diastereoselective reaction • The preferred conformation minimises the interaction between the two Me (& Me) groups • With C-2 substituent (H) there is little energy difference between conformations • Therefore, get low selectivity

Strategies and Tactics in Organic Synthesis Substrate control in total synthesis Directed epoxidation from the synthesis of oleandomycin aglcon • Glycosylated version (R=sugar) is a potent antibiotic from streptomyces antibioticus

• David A. Evans and Annette S. Kim, J. Am. Chem. Soc. 1996, 118, 11323

Strategies and Tactics in Organic Synthesis

A hydroxyl group can reverse normal selectivity and direct epoxidation • Epoxidation with a peracid, such as m-CPBA, is directed by hydrogen bonding and favours attack from the same face as hydroxyl group • The reaction with a vanadyl reagent results in higher stereoselectivity as it bonds / chelates to the oxygen

Strategies and Tactics in Organic Synthesis Sharpless Asymmetric Epoxidation (SAE) of allylic alcohols Sharpless, K. B. JACS 1980, 5974 • Sharpless asymmetric epoxidation was the first general asymmetric catalyst. There are a large number of practical considerations that we will not discuss. Suffice to say it works for a wide range of compounds in a very predictable manner. Compounds must be allylic alcohols as shown by epoxidation of the diolefin SAE is highly predictable . To understand where this comes from we must look at the mechanism

Strategies and Tactics in Organic Synthesis Mechanism of SAE

Active species thought to be 2 x Ti bridged by 2 x tartrate Reagents normally left to ‘age’ before addition of substrate thus allowing clean formation of dimer

Strategies and Tactics in Organic Synthesis SAE works for a wide range of allylic alcohols. Only cis di-substituted alkenes show lesser enantioselection

SAE can over-ride (have the priority) the inherent selectivity of a substrate. Furthermore, it demonstrates the concept of matched & mismatched. When the catalyst & substrate reinforce each other spectacular (or matched) results are achieved

Strategies and Tactics in Organic Synthesis Use of SAE in synthesis Fluoxetine is a commercial anti-depressant (better known as Sarafem® or Prozac®). Can be synthesized in a number of methods • One involves the use of the SAE reaction... Y. Gao and K. B. Sharpless, J. Org. Chem., 1988, 53, 4081. Yun Gao, Robert M. Hanson, Janice M. Klunder, Soo Y. Ko, Hiroko Masamune, and K. Barry Sharpless, J. Am. Chem. Soc., 1987, 109, 5165

Strategies and Tactics in Organic Synthesis

Kinetic resolution as racemic mixture

if allylic alcohol is desired: use 0.6eq TBHP if epoxy alcohol is desired: use 0.45eq TBHP Using the same diethyltartrate, both enantiomers should be epoxidised from same face, but rate of epoxidation is different and the differences are sufficient to epoxidise only one enantiomer if the reaction is stopped at 50% conversion. if reaction goes to 100% completion a 1:1 mixture of diastereoisomers is obtained

Strategies and Tactics in Organic Synthesis

Kinetic resolution Kinetic resolution normally works efficiently, but the problem with kinetic resolution is that is can only give a maximum yield of 50% in epoxide. Desymmetrisation of a meso compound allows 100% yield. Effectively, the same as two kinetic resolutions, first desymmetrises compound second removes unwanted enantiomer. E.e. of desired product increases with the reaction time (84% ee 3hrs ➔ >97% 140hrs)

Desymmetrisation has been used in many elegant syntheses. As an example in the synthesis of KDO, a key component of the cell wall lipopolysaccharide (LPS) of Gramnegative bacteria forming the necessary linkage between the polysaccharide and lipid A regions. Tetrahedron, 1990, 46, 4793. and J. Am. Chem. Soc.,1987, 109, 1525

Strategies and Tactics in Organic Synthesis

Jacobsen-Katsuki epoxidation SAE is a marvelous reaction but suffers certain limitations: substrate must be an allylic alcohol and cisdisubstituted alkenes are poor substrates. Alternatively (salen)Mn catalysts with bleach (NaOCl) are good in the epoxidation of many olefins.

The Industrial Syntheses of the Central Core Molecules of Indinavir, an HIV protease inhibitor marketed by Merck as Crixivan®, represent an example that demonstrates the industrial potential of such catalytic systems. Chem. Rev., 2006, 106, 2811

Strategies and Tactics in Organic Synthesis Sharpless Asymmetric Dihydroxylations (SAD)

The active, catalytic, oxidant is K2OsO2(OH)4 . OsO4 is too volatile & toxic, K3Fe(CN)6 is the stoichiometric oxidant K2CO3 & MeSO2NH2 accelerate the reaction Normally use a biphasic solvent system And the two ligands are

Ligands are pseudo-enantiomers (only blue centres are inverted; red are not). Coordinate to the metal via the green nitrogen...

Strategies and Tactics in Organic Synthesis Sharpless Asymmetric Dihydroxylation Reaction works on virtually all alkenes • Exact mechanism not known but it is relatively predictable (but not as predictable as the SAE)

The example shows the power of the SAD reaction in synthesis: exo-Brevicomin is the aggregation pheromone of several timber beetles. Interestingly, endo-brevicomin inhibits the aggregation of the southern pine beetle. Tetrahedron Lett., 1993, 34, 5031

Strategies and Tactics in Organic Synthesis

The Sharpless aminohydroxylation reaction A variant has now been developed that permits aminohydrodroxylation. It has been employed in the semi-synthesis of paclitaxel (Taxol®), an anti-carcinogen. Acta Chem. Scand., 1996, 50, 649

Strategies and Tactics in Organic Synthesis

Stereoselective Conjugate (1,4-) addition Nucleophilic attack on C=C bond normally requires electron deficient alkene as in the case of α−β unsaturated carbonyl derivaties. The reaction is known as 1,4-addition or conjugate Michael addition. After the addition of the nucleophile an enolate is formed this open to the possibility of forming two stereogenic centres. Substrate control - initial nucleophile addition to the least hindered face of enone, the electrophile addition normally occurs from opposite face

Second stereocentre First stereocentre

Application to the synthesis of PGE2

Prostaglandins are technically hormones with very strong physiological effects, for example have been utilised to prevent and treat peptic ulcers, as a vasodilator, to treat pulmonary hypertension and induce childbirth / abortion R. Noyori, J. Am. Chem. Soc. 1988, 110, 4718

This stereocentre control the addition to the double bond

Strategies and Tactics in Organic Synthesis

Diastereoselective conjugate additions Possible to use chiral auxiliary to control 1,4-nucleophilic addition. The chelation of amide and sultam oxygens to Mg restricts rotation and favours cis conformation, the nucleophile (Et) addition occurs from most sterically accessible side. Chiral auxiliary readily cleaved (& reused) to give enantiomerically pure compound via diastereoselective reaction

Strategies and Tactics in Organic Synthesis

Chiral auxiliary to control two stereocentres It possible to utilise 1,4-addition to introduce two stereogenic centres. The first addition (BuMgBr) occurs as before to generate an enolate. The enolate can then be trapped by an appropriate electrophile. Once again the sultam chiral auxiliary controls the face of addition (of Me)

Strategies and Tactics in Organic Synthesis

Alternative chiral auxiliaries A second chiral auxiliary is the oxazoline (5-membered ring) of Meyers. It can be prepared from carboxylic acids (normally in 3 steps) or from condensation of the amino alcohol and a nitrile. As can be seen excellent enantiomeric excesses can be achieved via a highly diastereoselective reaction

Strategies and Tactics in Organic Synthesis

Chiral auxiliary and radical conjugate addition Radicals once thought to be too reactive to allow diastereoselective reactions. But this is not always true - oxazolidinone auxiliary. Rare-earth Lewis acids give superior results. Use of Et3B & O2 as radical initiator allows the use of low temperatures

Strategies and Tactics in Organic Synthesis

Sulfoxide-based chiral auxiliary (& total synthesis) Sulfoxide is a good chiral auxiliary; not only does it introduce a stereocentre but it activates the alkene by addition of an extra electron-withdrawing group. Sulfoxide substituent blocks the bottom face & is readily removed. Simple substrate control instals aryl group on opposite face to substituent (–)-Podorhizon is a member of the anticancer podophyllotoxin family of compounds. Tetrahedron Lett. 1984, 25, 2627

Strategies and Tactics in Organic Synthesis

Chiral auxiliaries and total synthesis L-CCG-I (L-carboxycyclopropylglycine-I) is a conformationally restrained analogue of L-glutamic acid (there are four possible stereoisomers of L-CCG). L-Glutamic acid is the most abundant excitatory neurotransmitter in our bodies; it is thought to be involved in cognitive functions like learning and memory in the brain and possibly with umami, one of the five basic human tastes. J. Org. Chem. 2003, 68, 6817

Strategies and Tactics in Organic Synthesis

Enantioselective catalytic conjugate addition Much effort has been expended trying to develop enantioselective catalysts for conjugate addition. Whilst many are very successful for certain substrates, few are capable of acting on a wide range of compounds. The system above gives excellent enantioselectivities for cyclohexenone but no selectivity for cyclopentenone

Strategies and Tactics in Organic Synthesis

Enantioselective radical conjugate addition Once stereoselective conjugate radical additions with auxiliaries had been developed, the enantioselective catalytic variant rapidly has been proposed. The following chiral Lewis acid catalysed reaction. Most work in this area has been pioneered by Sibi

C2 symmetry axis

Strategies and Tactics in Organic Synthesis

[3,3]-Sigmatropic rearrangements

A class of pericyclic reactions whose stereochemical outcome is governed by the geometric requirements of the cyclic transition state. Reactions generally proceed via a chair-like transition state in which 1,3-diaxial interactions are minimised. The type of activation (thermal or photochemical) and the stereochemistry can often be predicted by the Woodward-Hoffmann rules which are based on the total number of electrons (those in the π-system + those of single bonds) involved in the rearrangement process: 4n electrons, is photochemically allowed from excited state; 4n + 2 electrons, the migration thermally allowed. Many similarities to the aldol reaction. Absolute stereochemistry - controlled by existing stereocentre (destroyed in rct).Relative stereochemistry - controlled by alkene / enolate geometry

Both are potential stereogenic unit or prochiral, depend on the nature of a,b,c,d

Strategies and Tactics in Organic Synthesis

Cope rearrangement A very simple example of a substrate controlled [3,3]-sigmatropic rearrangement is the Cope rearrangement. To minimise 1,3-diaxial interactions phenyl group is pseudo-equatorial. Note: the original stereocentre is destroyed as the new centre is formed. This process is often called ‘chirality transfer’

Strategies and Tactics in Organic Synthesis

Claisen rearrangements One of the most useful sigmatropic rearrangements is the Claisen rearrangement and all it’s variants. In blue the new formed C-C bond.

Strategies and Tactics in Organic Synthesis

Enantioconvergent’ synthesis Both enantiomers of initial alcohol can be converted into the same enantiomer of product. This process (Eschenmoser-Claisen) shows the importance of alkene geometry in [3+3] sigmatropic rearrangement

Same configuration

Strategies and Tactics in Organic Synthesis

Ireland-Claisen reaction Enolate geometry controls relative stereochemistry, therefore, the enolisation step controls the stereochemistry of the final product. As we have seen it is relatively easy to control enolate geometry and consequently the final stereochemistry

Strategies and Tactics in Organic Synthesis

Substrate control in Ireland-Claisen rearrangement In a similar fashion to the Cope rearrangement, the Ireland-Claisen rearrangement occurs with ‘chirality transfer’. Initial stereogenic centre governs the conformation of the chair-like transition state: Largest substituent will adopt the pseudo-equatorial position. Once again, the relative stereochemistry between the two new stereocentres is governed by the geometry of the enolate

Strategies and Tactics in Organic Synthesis

Auxiliary controlled rearrangement in total synthesis The use of chiral and enantiopure auxiliaries it is possible to perform the rearrangement in enantioselective manner. An application in the synthesis of (–)-Malyngolide is an antibiotic isolated from the blue-green marine algae Lyngbya majuscule. This synthesis utilises Enders' RAMP hydrazone as a chiral auxiliary to set up the quarternary centre. Tetrahedron 1996, 52, 5805 Ender’s hydrazine

Strategies and Tactics in Organic Synthesis

Chiral reagent control in the Ireland-Claisen rearrangement It is possible to carry the reaction out under “reagent” control as in the case of chiral boroenolates. Although, it could be argued that this is just a form of temporary auxiliary control! Enolate formation (enolate geometry) governs relative stereochemistry

Strategies and Tactics in Organic Synthesis

The use of a chiral reagent in total synthesis Dolabellatrienone is a marine diterpenoid isolated from gorgonian octocorals such as Eunicea calyculata and other marine organisms His enantioselective synthesis relies on boron enolate chemistry to establish the stereochemistry of the final molecule J. Am. Chem. Soc. 1996, 118, 1229

Via cis boroenolate

Strategies and Tactics in Organic Synthesis

Chiral catalyst control in the Ireland-Claisen rearrangement It is also possible to perform the reactions under chiral catalyst control using for example chiral Lewis acids. In this case it is reasonable that the Lewis acid coordinates to the oxygen influencing the reactive conformation thus controlling enantioselectivity

Coordination by Lewis acid

Strategies and Tactics in Organic Synthesis

2,3-Wittig rearrangement The 2,3 Wittig rearrangement is useful for good 'chirality transfer'. Requires the formation of anion and, in turn, acidic proton (Z=electron withdrawing group) or metal-functional group exchange Driving force is stability of alkoxide (although other elements can be used...). Transition state is under debate but it is reasonable the invoke a based on 'envelope' chair model

Largest substituents adopt pseudo-equatorial position

Strategies and Tactics in Organic Synthesis

Enantioselectivity in the 2,3-Wittig rearrangement Reagent control utilising chiral boron reagent similarly to that seen in Ireland-Claisen rearrangement reactions.

Enammine can be used as anion and the use of chiral amine the reaction show significant enantioselection

Strategies and Tactics in Organic Synthesis

[2,3]-aza-Wittig reaction in total synthesis Aza-Wittig rearrangement is less common. The relief of ring-strain accelerates reaction. AzaWittig rearrangement has been use in the total synthesis of indolizidine 209B from Dendrobates pumilio or the strawberry poison dart frog. Tetrahedron, 1995, 51, 9741

Strained aziridine ring

Strategies and Tactics in Organic Synthesis

Stereoselective Diels-Alder reaction Diels-Alder (DA) reaction is incredibly valuable method for the synthesis of 6-rings and is highly regioselective. It is controlled by the ‘relative sizes’ of the π-orbitals in the LUMO & HOMO involved or on the value of their orbital coefficients. In the presence of a Lewis acid dienophile is polarised giving higher regioselectivity and a faster reaction

Strategies and Tactics in Organic Synthesis

Endo vs exo selectivity Endo transition state and adduct is more sterically congested thus thermodynamically less stable but it is normally the predominant product. The reason is endo transition state is stabilised by π orbital overlap of the group on C or D with the diene HOMO; an effect called ‘secondary orbital overlap’. The reaction is suprafacial and the geometry of the diene and dienophile is preserved. Finally, remember that the dienophile invariably reacts from the less hindered face

The ‘cube’ method is a nice way to visualise the relative stereochemistry

Strategies and Tactics in Organic Synthesis

Chiral auxiliaries on the dienophile One diastereoisomer is formed - the endo product, but mixture of enantiomers, If we add a chiral auxiliary then there are two possible endo diastereoisomers, but one predominates, thus we can prepare a single enantiomer No enantioselection

Enantioselective version using a chiral auxilary

Strategies and Tactics in Organic Synthesis

Origin of diastereoselectivity Coordination dienophile by the Lewis acid and its activation, The rigidity of the chelate governs reactive conformationc (s-cis) and s-trans (s is referred to the double bond position in relation to carbonyl double bond). For steric reason the s-trans is disfavoured. >The iso-Propyl group blocks bottom face of the double bond so the diene’s approaches from less hindered face and maximises secondary orbital overlap favouring the endo product

Strategies and Tactics in Organic Synthesis

Other auxiliaries can be utilised and most give good diastereoselectivities

Camphor-derived auxiliary

Strategies and Tactics in Organic Synthesis

It is possible to attach the chiral auxiliary to the diene as well

Use of a chiral auxiliary in an intramolecular Diels-Alder reaction (IMDA). An example in the total synthesis of (–)-stenine.• (–)-Stenine is isolated from Stemona family of sub-shrubs (bush) is a constituent of a variety of Eastern folk medicines. Angew. Chem. Int. Ed. Engl., 1996, 35, 904

Strategies and Tactics in Organic Synthesis

Chiral catalysis and the Diels-Alder reaction The fact the Diels-Alder reaction is mediated or catalysed by Lewis acids means enantioselective variants are readily carried out. The aluminium catalyst, utilised in enolate chemistry (aldol) reaction, is very effective also in this Diels-Alder reaction.

Bis(oxazoline) ligands (Box) are amongst the most versatile and well used ligands known. Simply prepared from amino alcohols (and hence amino acids). Can be used in both DA and the equally useful HDA

Strategies and Tactics in Organic Synthesis

Catalytic enantioselective HDA in total synthesis

(+)-Ambruticin is an antifungal agent extracted from the myxobacterium Polyangium Cellulsoum, it has shown activity against Coccidioides immitis the cause of coccidioimycosis Synthesis of (+)-ambruticin J. Am.Chem. Soc. 2001, 123, 10772

Strategies and Tactics in Organic Synthesis

Stereoselective metal mediated reaction: The Heck reaction is a versatile method for the coupling sp2 hybridised centres

Strategies and Tactics in Organic Synthesis

Alkene isomerisation β-Hydride elimination is reversible, thus the double bond can ‘walk’ or migrate to give the most stable alkene. Only restriction is every step must be syn

Strategies and Tactics in Organic Synthesis

Enantioselective Heck reaction With the use of chiral ligands the Heck reaction can be enantioselective Intramolecular variant allows the construction of ring systems. The silver salt accelerates the reaction and prevents alkene isomerisation

Strategies and Tactics in Organic Synthesis

Enantioselective Heck reaction in total synthesis (+)-Xestoquinone was isolated from the Pacific sponge Xestospongia sapra and is a potent irreversible inhibitor of both the oncogenic protein tyrosine kinase pp60V-src encoded by the Rous sarcoma virus & the human epidermal growth factor kinase (EGF). The first total synthesis involved two Heck reactions; the first is enantioselective to give a quaternary centre and the second gives a second 6-ring. J. Am.Chem. Soc. 1996, 118, 10766 Review of asymmetric Heck: Chem. Rev. 2003, 103, 2945

Strategies and Tactics in Organic Synthesis

Suzuki-Miyuara reaction The Suzuki-Miyuara reaction is (normally) the palladium catalysed coupling of an alkenyl or aryl halide with an alkenyl or aryl boronic acid. Normally the components should be sp2 hybridised to avoid β-eliminations.

Strategies and Tactics in Organic Synthesis

Enantioselective biaryl formation Non only molecules that contain stereogenic units such stereocentres can be chiral, also hindered rotation, as in biphenyls, can be in a chiral situation. Two examples of chiral bisaryl compounds. Both ligands are thought to be mono-dentate (in the active species at least, although they may be bidentate in ‘resting state’) via the phosphine

Strategies and Tactics in Organic Synthesis

Enantioselective Pd catalysed allylic substitution Displacement of good leaving group (OAc, OCO2R, halide, epoxide etc.) normally using soft nucleophile. The reaction does not occur by direct displacement but via a palladium η3 complex

Strategies and Tactics in Organic Synthesis

Pd catalysed allylic substitution: Regio- and stereoselectivity Palladium initially adds to the opposite face to the leaving group (although possible equilibrium). Soft nucleophiles (large, diffuse charge) usually attack from opposite face to PdLn. Normally the nucleophile will add to the least hindered end of the allyl system.

Strategies and Tactics in Organic Synthesis

Enantioselectivity Problem with inducing selectivity is that ligand is on opposite side to nucleophile. Bulky ligands can overcome this problem and to have stereogenic centre on the substrate or on the nucleophile.

Stereocentre on the substrate

Stereocentre on the nucloephile

Strategies and Tactics in Organic Synthesis

. Allylic substitution in total synthesis (–)-Swainsonine can be isolated from locoweeds; in cattle it causes symptons similar to mad cow disease (BSE) and hence plants named after the Spanish for crazy. In humans it shows anticancer, antiviral, and immunoregulatory properties. J. Org.Chem. 2002, 67, 4325. On the desymmetrisation see also J. Org. Chem. 1998, 63, 1339

desymmetrisation process

Strategies and Tactics in Organic Synthesis

Other catalytic enantioselective reactions There are now a huge number of enantioselective reactions with more being invented / developed all the time. It is highly unlikely that this research in this vast, fascinating field will slow in the foreseeable future. It should be possible to develop enantioselective variants of most reactions – even those that do not initially look set-up for such chemistry. An example of a chiral variant of the Schrock metathesis catalyst. The reaction involves desymmetrisation by selective reaction if one disubstituted alkene

Strategies and Tactics in Organic Synthesis

Summary of methods for stereoselective synthesis

Organocatalysis

Strategies and Tactics in Organic Synthesis

In organic chemistry, the term Organocatalysis (a concatenation of the terms "organic" and "catalyst") refers to a form of catalysis, whereby the rate of a chemical reaction is increased by an organic catalyst referred to as an "organocatalyst" consisting of carbon, hydrogen, sulfur and other nonmetal elements found in organic compounds. Because of their similarity in composition and description, they are often mistaken as a misnomer for enzymes due to their comparable effects on reaction rates and forms of catalysis involved. Organocatalysts which display secondary amine functionality can be described as performing either enamine catalysis (by forming catalytic quantities of an active enamine nucleophile) or iminium catalysis (by forming catalytic quantities of an activated iminium electrophile). This mechanism is typical for covalent organocatalysis. Covalent binding of substrate normally requires high catalyst loading (for proline-catalysis typically 20-30 mol%). Noncovalent interactions such as hydrogenbonding facilitates low catalyst loadings (down to 0.001 mol%). Organocatalysis offers several advantages. There is no need for metal-based catalysis thus making a contribution to green chemistry. In this context, simple organic acids have been used as catalyst for the modification of cellulose in water on multi-ton scale. When the organocatalyst is chiral an avenue is opened to asymmetric catalysis, for example the use of proline in aldol reactions, Berkessel, A., Groeger, H. (2005). Asymmetric Organocatalysis. Weinheim: Wiley-VCH. List, B. (2007). "Organocatalysis". Chem. Rev. 107 (12): 5413–5883. P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed . 2001, 40, 3726 -3748 and Angew. Chem. Int. Ed. 2004, 43, 5138–5175. M.J. Gaunt, C. C.C. Johansson, A. McNally, N.T. Vo, "Enantioselective organocatalysis" Drug Discovery Today, 2007, 12(1/2), 8-27. D. Enders, C. Grondal, M. R. M. Hüttl, review: "Asymmetric Organocatalytic Domino Reactions", Angew. Chem. Int. Ed. 2007, 46, 1570–1581.

Justus von Liebig's synthesis of oxamide from dicyan and water represents the first organocatalytic reaction, with acetaldehyde further identified as the first discovered pure "organocatalyst", which act similarly to the then-named "ferments", now known as enzymes. Justus von Liebig, Annalen der Chemie und Pharmacie 1860, 113 , 246–247

Strategies and Tactics in Organic Synthesis CHIRAL ORGANOCATALYSIS Organocatalysts for asymmetric synthesis can be grouped in several classes: Biomolecules: notably proline, phenylalanine. Secondary amines in general. The cinchona alkaloids, certain oligopeptides. Synthetic catalysts derived from biomolecules. Hydrogen bonding catalysts, including TADDOLS, derivatives of BINOL such as NOBIN, and organocatalysts based on thioureas S. Bertelsen, K. A. Jørgensen, Chem. Soc. Rev., 2009, 38, 2178–2189 A certain class of imidazolidinone compounds (also called MacMillan organocatalysts) are suitable catalysts for many asymmetric reactions such as asymmetric DA reactions. The original such compound was derived from the biomolecule phenylalanine in two chemical steps (amidation with methylamine followed by condensation reaction with acetone) which leave the chirality intact

Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. Soc 2000; 122; 4243-4244

Strategies and Tactics in Organic Synthesis Regular achiral organocatalysts are based on nitrogen such as piperidine used in the Knoevenagel condensation, DMAP used in esterfications and DABCO used in the Baylis-Hillman reaction. Thiazolium salts are employed in the Stetter reaction. These catalysts and reactions have a long history but current interest in organocatalysis is focused on asymmetric catalysis with chiral catalysts and this particular branch is called asymmetric organocatalysis or enantioselective organocatalysis . A pioneering reaction developed in the 1970s is called the Hajos-Parrish reaction: Z. G. Hajos, D.R. Parrish J. Org. Chem.; 1974; 39, 1615-1621

Baylis–Hillman reaction

Strategies and Tactics in Organic Synthesis This catalyst works by forming a iminium ion with carbonyl groups of α,β-unsaturated aldehydes (enals) and enones in a rapid chemical equilibrium. This iminium activation is similar to activation of carbonyl groups by a Lewis acid and both catalysts lower the substrates LUMO. G. Lelais and D. W. C. MacMillan Aldrichimica Acta . 2006, 39, 3, 79

Angew. Chem. Int. Ed. 2003,42, 4955-4957

J. Am. Chem. Soc. 2007, 129, 15438-15439

Strategies and Tactics in Organic Synthesis Organocatalytic hydrogenation A recent development is the use of small organic molecules to achieve hydrogenation • Inspire by nature

• Based on the formation of a highly reactive iminium ion (this is the basis of many organocatalytic reactions)

Strategies and Tactics in Organic Synthesis Organocatalytic epoxidations As with most chemical reactions, epoxidation has seen a move towards ‘greener’ chemistry and the use of catalytic systems that do not involve transition metals A number of systems exist, notably the catalysts of Shi & Armstrong. Most are based on the in situ conversion of ketones to the active, dioxirane species, that actually performs the epoxidation

Dioxirane, epoxidation reagent

Tanabe Seiyaku Co. utilise organocatalysis in the synthesis of diltiazem-L®, a blood pressure reducing agent. J. Org. Chem. 2002, 67, 4599

Strategies and Tactics in Organic Synthesis Organocatalytic epoxidations in the industrial synthesis of Diltiazen-L® by Tanabe Seiyaku Co. a blood pressure reducing agent. T. Furutani, R. Imashiro, M. Hatsuda and M. Seki, J. Org. Chem. 2002, 67, 4599

Cat.

Strategies and Tactics in Organic Synthesis Lewis acid organocatalysis

Intermolecular hydrogen bond acts as a Lewis acid and activates carbonyl, intramolecular hydrogen bond organises Catalyst. Catalyst derived from simple nature product, tartaric acid. Clean, green and effective

Strategies and Tactics in Organic Synthesis

Organocatalysis in Michael addition New small molecule organic catalysts are now achieving remarkable results. Enone is activated by formation of the charged iminium species The catalyst also blocks one face of the enone allowing selective attack

Strategies and Tactics in Organic Synthesis

Organocatalysis in Michael addition: electronrich aromatic ring can be emploied in Michael addition

Strategies and Tactics in Organic Synthesis

Organocatalysis in Michael addition An interesting reaction is the Stetter reaction - this is the conjugate addition of an acyl group onto an activated alkene and proceeds via Umpolung chemistry (the reversal of polarity of the carbonyl group)

Strategies and Tactics in Organic Synthesis

Organocatalysis in Michael addition

The thio(urea) moiety acts as a Lewis acid via two hydrogen bonds The amine both activates the nucleophile and positions it to allow good selectivity

Strategies and Tactics in Organic Synthesis

Organocatalysis in Michael addition Beautiful example of enantioselective conjugate addition in total synthesis. From the synthesis of a marine alkaloid from the Bryozoa, Flustra foliacea by Joel F. Austin, Sung-Gon Kim, Christopher J. Sinz, Wen-Jing Xiao, and David W. C. MacMillan, PNAS 2004, 101, 5482

Strategies and Tactics in Organic Synthesis

Catalysis in total synthesis (R)-Muscone is the primary contributor to the odour of musk, a glandular secretion of the musk deer. •A racemic, synthetic version is used in perfumes. J. Am. Chem. Soc.,1993, 115, 1593

(R)-Muscone

Strategies and Tactics in Organic Synthesis

Organocatalysis and the Diels-Alder reaction Organic secondary amines can catalyse certain Diels-Alder reactions. The reaction proceeds via the formation of an iminium species. This charged species lowers the energy of the LUMO thus catalysing the reaction In addition one face of dienophile is blocked thus allowing the high selectivity

Application tio the total synthesis of the marine metabolite solanapyrone D, a phytotoxic polyketide isolated from thefungus Altenaria solani

Strategies and Tactics in Organic Synthesis

An example of a hetero-Diels-Alder reaction The aldehyde is the dienophile and the counterpart is a very electron rich diene. The amine catalyst acts as a Lewis acid via two hydrogen bonds

Tf= CF3SO2

Another hetero-Diels-Alder reaction. It looks very similar to the previous reaction but...It is believed that only one hydrogen bond coordinates the aldehyde and the other is used to form a rigid chiral environment for the reaction

Organic Photochemistry Introduction: Photophysics, interaction of light with the matter and photostimulated processes. Interaction with atoms and with molecules Photophysical processes Photochemistry: Photochemical processes Organic photostimulated reactions: Dissociation into radicals Dissociation into ions or “internal” electron transfer Intramolecular rearrangement Photoisomerization Hydrogen atom abstraction Photodimerization or photoaddition Photosensitized reactions Photoionisation reactions Miscellaneous reactions Photoreactivity of aromatic compounds Photochemistry of diazo- and azido compounds Photocleavable protecting groups Photopolimerization Chemoluminescence 4. Technical and experimental aspects.

Organic Photochemistry

Thermally stimulated reactions A

+

B

∆ heat

A B ‡ transition state

products

Photochemically stimulated reactions products A

+

hν

( A )* exited state

B

products

Differences between thermally and photochemically stimulated reactions: 1) Excited state has usually higher energy than transition state. 2) Electrons in the excited state are in high energy molecular orbitals, so they are more prone to react in comparison to that in bounding orbitals 3) Different type of excited states are possible with different chemical behavior 4) Electrons of different finctionalities can be excited by simple selecting the light energy, thus specific reactions for specific functionalities are possible

Organic Photochemistry

Organic Photochemistry

Organic Photochemistry The energy of light does not match with the difference in energy between occupied and unoccupied atomic orbitals or occupied bonding and unoccupied antibonding molecular orbitals, i.e. there is no absorption of light by the matter. The light is reflected or refracted by the matter and these phenomena are governed by the laws of classic optical physics.

. sen i = c1/c2 sen r c1/c2=n21 refraction index

Organic Photochemistry

Irf/I0=(n21-1/ n21+1)

2

Organic Photochemistry: photophysics processes Interaction of light with atoms

3s, 3p, 3d 2s and 2p

The energy of light matches with the energy gap between bonding and antibonding molecular orbital or atomic orbitals. In this case the energy is called resonant with the frequencies at which electrons oscillate in bonds and around nuclei. Typically these frequencies fall in the range of 10 15-1016 s-1 i.e. 200-700nm (visible and ultraviolet region). The interaction in such a case forces the electron to oscillate resonantly with the electromagnetic radiation and its motion describes an orbital at higher energy. This process is pictured for a hydrogen atom for a transition of an electron from a 1s orbital to a 2p orbital, which occurs at 121.6 nm

Prerequisites for absorption and emission

1s

1) The electronic transition between orbitals must generate (absorption) or destroy (emission) a node 2) The transition moment must a determined value i.e.

different from 0 or ∞ 0 means no interaction of light with electrons, ∞ means ionization process and not transition between orbitals.

Organic Photochemistry Interaction with molecules direction of light propagation parallel to molecular axis

σ molecular hydrogen orbital

E

no node light

hν: 121.2nm

H bond axis

π -like molecular orbital one node

σ molecular hydrogen orbital bond axis no node hν: 110.9nm

σ∗ molecular orbital one node

E

direction of light propagation perpendicular to molecular axis

light

H photophysics

Organic Photochemistry

spin allowed absorption

k RS

singlet (spins paired) ψ*

singlet (spins paired)

ψ

triplet (spins parallel)

electron jump

hν, fluorescence

hν, phosphorescence

and spin flip

Energy level description of absorption and emission. The arrows indicate electrons and the spin orientation; wavy arrows indicate photons

T1 ψ S0

S1

kIC

kF

S0

T1

kP

ψ* ψ

electron jump

ψ*

S0

State energy diagram

intersystem crossing

spin forbidden absorption

and spin flip

kRT

phosphorescence

electron jump

kST

internal conversion

hν

S1

singlet-singlet absorption fluorescence

singlet (spins paired)

triplet reaction

electron jump

singlet-triplet absorption

hν

excited state

intersystem crossing

ground state

Possible processes singlet reaction

Possible transition

photophysics

Organic Photochemistry Vibrational level Differently from single atoms, in molecules atoms in a bond vibrate from their equilibrium position, thus the ground electronic state is splitted into vibrational modes Bonds are usually described as spring connection atoms. Under this description, the bond energy is related to spring force k by Hooke law E= 1/2kr2

photophysics

Organic Photochemistry Vibrational level

Lennard-Jones curve for real molecule

Eυ = hν (ν +1/2)

photophysics

Organic Photochemistry

Absorption bands

Intensity of absorption band follows the Franck-Condon principle which states: The electronic transition starts from the lowest ν0 vibration state and the intensity is related to the sign and value of the function describing the vibrational state in the ground state and the arriving vibrational mode in the excited state. The transitions are describe by vertical lines and this because during the transition, which is very fast, negligible movement of atoms from their equilibrium position is observed

Ground and excited state Lennard-Jones curve

photophysics

Organic Photochemistry Radiative relaxing processes From the excited state: Fluorescence and phosphorescence Radiative processes occur from The lowest vibrational state of the excite state: Kasha rule

Vibrational modes

photophysics

Organic Photochemistry Absorption and emission band structure and energy In atoms absorption and emission bands have the same energy since only atomic orbital are involved. In molecules due to the presence of vibrational modes and to Kasha rule, the emission is at lower energy with respect to absorption E

E emission

absorption

a

Atoms hν λ

λ

E

distint vibrational states in molecules b

absorption

emission

hν absorption

λ emission

E absorption

emission

unresolted vibrational states in molecules c

hν absorption

emission

λ

a: sharp line absorption and emission spectrum typical of atoms at low pressure vapor phase b:broad-band absorption and emission spectrum typical of certain rigid molecule at low pressure vapor phase with resolted vibrational bands c:broad-band absorption and emission spectrum typical of molecule in solution with unresolted vibrational bands

photophysics

Organic Photochemistry

Time scale of photophysical processes

photophysics

Organic Photochemistry

More important Photophysical processes

photophysics

Organic Photochemistry

Exctited states and photophysical transitions between these states in a "typical" organic molecule 2nd excited singlet state 1st excited singlet state S2ν IC2

S2 state

S1ν

gle t

stat

ISC1

exc ited

sin

T1ν

S1

to 1 s t

S0ν

tion

T1 es or

abs orp

flu

ISC2

n ce

quantized r rotational level

S0ν'

IC1

ce en e sc or ph os ph ce

absorp tion to

Jablonski Diagram

e

2 n d ex cited s inglet

1st excited triplet state

quantized ν vibrational level S0

ground state

S0

Jablonski Diagram: solid lines are radiative transition; wave lines are radiationless processes: vertical are vibratioan and rotational relaxation processes; horizontal IC: internal conversion, ISC: intersystem crossing

photophysics

Organic Photochemistry: photochemical processes

Photophysical radiative process (fluorescence and phosphorescence) rates span from 10-15 to 1 sec, so only ultrafast reactions can be observed from singlet states. Fast chemical reaction can be competitive with radiative process from triplet states

Organic Photochemistry: photochemical processes The first law of photochemistry formulated by Grotthus (1817) and Draper (1843) in the early nineteenth century: Only the light which is absorbed by a molecule can be effective in producing photochemical change in the molecule. This law was then reformulated by Stark (1908-1912) and Einstein (1912-1913):The absorption of light by a molecule is a one-quantum process, so that the sum of all primary process quantum yields φ must be unity, that is ∑φi= 1, where φi is the quantum yield of the ith primary process.

A + hν → B Φ = Molecules of B formed x unit of volume x unit time/quanta absorbed by A x unit of volume x unit time

Under the validity of photochemistry law proposed by Stark-Bodenstain it is possible to correlate the absorption of light to the characteristics of any absorbing material. This is well expressed by the BeerLambert law

T= I/I0 = 10-εεcl

A= -log I/I0 = εcl

Secondary chemical processes are all those started by the intermediates produced in the primary process. As an example in radical halogenation of alkane the primary process is the halogen-halogen bond fission and the subsequent radical halogenation of alkane occurs without light so in the dark. One halogen molecule bond fission produce many halogenated alkane molecules. In this case the quantum yield is>1

photochemistry

Organic Photochemistry: photochemical processes ENERGETIC CONSIDERATIONS kcal/mol S1

T1

110

bond energy

ultraviolet

O-H 300nm 90

ketones

80

C-H 80 75

UV Lamps

C-C C-Cl

70 60

400nm

visible

C-H streching C=O streching photochemistry

700nm O-O

vibrational excitation

Sun Light

C-I

40

electronic excitation

violet

C-Br

infrared 10

3000 nm

5

6000 nm

red

Organic Photochemistry PRIMARY PHOTOCHEMICAL PROCESSES

AB + C

Dissociation into radicals

ACB

Intramolecular rearrangement

ABC' (S1) or ABC' (T1)

ABC (S1) or ABC (T1)

ABC' (S0)

R-H

(ABCH) + R

Hydrogen abstraction

ABC

(ABC)2

Photodimerization (photoaddition)

D

D

ABC + products

Photosensitized reactions

ABC+ + e-

Photoionization

ABC+ or -+

D- or +

AB+ or - + C- or + photochemistry

Photoisomerization

"External" electron transfer

"Internal" electron transfer

Organic Photochemistry Dissociation into radicals ABC (S1 or T1) → AB. .C

[X-X]* → X. + X.; X =Cl or Br [NO2]* → NO. + O. [NOCl]* → NO. + Cl. chloro-chloro or bromo-bromo bond can be homolitically broken by irradiation with mercury or tungsten lamps and the generated halogen radicals are exploited in the halogenation of alkanes, while the nitrosil and chloro radicals photogenerated from excited NOCl are industrially used for transforming cyclohexane into cyclohenanoneoxima, a precursor of e-caprolactam

NO-Cl

H

hν

NO

+ Cl

H - HCl

N-OH

ON

H

NO H

Organic Photochemistry

Dissociation into radicals

Photochemical behavior of carbonyl compounds Ketones and aldehydes show two principal electronic transitions n→π* (excitation of an electron from oxygen nonbonding orbitals to antibonding π* orbital) in the 280-330 nm range and π→π* transition (excitation of an electron from π bonding orbital to antibonding π* orbital) usually below 250 nm. The n→π* transitions (~300 nm) are the more convenient to stimulate a photochemical reaction. Singlet excited state photochemistry is generally observed in aliphatic aldehydes or ketones, while in aromatic ketones, such as benzophenone or acetophenone, triplet states are involved. Aromatic ketones are often used as excellent triplet sensitizers.

There are two main photochemical pathways from an excited carbonyl function: 1) α-cleavage reaction, known as Norrish Type I cleavage reaction 2) Norrish Type II photoelimination reaction The Norrish Type I reaction dominates gas phase photochemistry of many aldehydes and ketones and is an homolitic carbon-carbonyl bond scission affording acyl radical and alkyl radical. The acyl radical collapses into carbon monoxide and alkyl radical; this latter reacts with another alkyl radical (generated in the first step) to give hydrocarbons. This process is less common in solution chemistry where hydrogen atom abstraction is usually the predominant process. Ph

Ph

R-CHO + hν ν→ → + C=O + →R-H . . R-CO-R’ + hν ν→ R CO-R’ or R’. .CO-R → R-R’ + C=O R. .CO-H

H.

R.

O

Ph diphenylindanone

Enanthioselective Norrish I, solid state reaction O Me

R

Ph MeO2C

O S

Ph

enantiopure

CN

1) hν 2) α-cleav. 3) -CO

Me Me Ph MeO2C

C

CN

Ph

hν -C=O

R Ph MeO2C

R

CN

Ph

e.e. ca 100% d.e.>95%

Ph

Organic Photochemistry

Dissociation into radicals

Norrish Type II photoelimination reaction :

formation of aldehydes and alkenes

ν → R2C=CR2 + CR2=CH-OH→ → CR2H-CHO R2CH-CR2CR2-CHO + hν R2CH-CR2CR2-CO-R + hν ν → R2C=CR2 + CR2=CR-OH→ → CR2H-CO-R Examples in cyclic ketones

O

O

O hν

H

O H

O Si(Me)3

hν MeOH

H

Si(Me)3

Organic Photochemistry

Dissociation into radicals

The a-cleavage reaction occurs also in other carbonyl compounds such as carboxylic acids, anhydrides and esters by irradiation around 220nm. In the case of carboxylic acids the main products are hydrocarbons, CO and CO2; anhydrides give carboxylic acids, ketenes and CO2 while esters afford alcohols, hydrocarbons, CO and CO2. It must be made clear that these processes occur employing high energy radiation so that normally they are absent or negligible in almost all photochemical reactions.

Photochemistry of Carboxylic acids

R CO-O-H

. .

hν

CO2 + R-H

R + CO-O-H

hν

R CO-O

.

.

+ H

CO2 + R-H

Photochemistry of Esters

R CO-O-R'

hν hν

. .

CO2 + R-R', R-R, R'-R'

R + CO-O-R' R CO-O

.

.

+ R'

CO2 + R-R', R-R, R'-R'

Photochemistry of Anhydrides hν

R2CH-CO-O-CO-R' hν

.

R2CHCO2 +

.

CO-R'

R2C=C=O + R2CHCO2H

CO2 + R2CH-R' + CO

Organic Photochemistry

Dissociation into radicals

More attention must be devoted to molecules containing particular functional groups: E.g. diazo compounds decompose when irradiated at 320nm into carbenes loosing nitrogen (shown later). Alkylnitro compounds decompose into alkyl radical and nitrosyl radical (.NO2) or nitrous acid and alkenes. To avoid the use of nitromethane or nitroethane as photoreaction solvent, differently aromatic nitro derivatives are transformed into nitroso compounds loosing an atom of oxygen (oxene) when irradiated at 350-400 nm. When benzylic hydrogens are present in substituents in the ortho position to the nitro group, the photogenerated oxene inserts itself into the C-H benzylic bond. This latter photochemical process has been exploited in developing a new photolabile protecting group for carbonyl compounds and alcohols (shown later) and to measure (actinometry) the intensity of incident light on the photochemical system. For example, the 2nitro-benzaldehyde (NBA) is transformed into 2-nitrosobenzoyc acid by irradiation at 350-400nm with 0.5 quantum yield. If the concentration of NBA (called actinometric compound) and the optical pathway of the exposed sample cell are sufficiently high to make the reaction rate approximately of zero order, the intensity of incident light is inversely proportional to the quantum yield (I0 = k0/φ). By plotting [NBA] against time a straight line is usually obtained with k0 slope and therefore it is possible to evaluate the intensity of incident light .(in the range of 350-400nm)

O H NBA

-

d[Act] dt

= I0 φ f

I0= light intensity φ=quantum yield f=fraction of absorbed light [Act]= concentration of NBA

NO2 f= (I0-I)/I0 or =1-I/I0 where I=absorbed light

hν

O

f = 1-10-εl[Act], thus Io= -

O-H NO

from Lambert-Beer Law log(I0/I)=εl[Act]

d[Act] dt

x 1/φ x 1/(1-10-εl[Act])

under the zero order condition Io=ko/φ, thus plotting [Act] vs a line is usually obtained with ko slope. If φ is known the intensity of incident light Io can be evaluated

Organic Photochemistry Dissociation into ions or “internal” electron transfer

ABC (S1 or T1) → AB+ .CTwo possible pathways can be active: 1) heterolitic bond scission with production of cations and anions: Any possible reaction is related to the electrophilic or nucleophilic nature of photogenerated ions

2) Internal electron transfer without bond scission. A typical example of the first type is observed in photolysis of leucocynides (triphenylacetonitriles such as Malachite Green or Crystal violet) in polar solvent where this scission produces triphenylmethyl carbocations and cyanide. Generally, variation of absorbing properties is observed in these processes. This phenomenon is called Photochromism

1) heterolitic bond scission with production of cations and anions: Other photochromic systems: spiropyran–merocyanine dyes

R R

hν1 R'

CN

O

hν

CN

N

polar solvents

hν2

O N

R'

colorless colored R" R" Malachite green leucocianide, R=H, R'=R"=N(Me)2 Crystal violet leucocianide, R= R'=R"=N(Me)2

Used in photochromatic lenses or optical memories

Organic Photochemistry Dissociation into ions or “internal” electron transfer

2) Internal electron transfer without bond scission. This process is observed in olefins. In detail, from the excited S1 state of an olefin two possible pathways can be followed namely a true internal electron transfer giving a zwitterionic excited state (indicated by Z) or the expulsion of an electron affording a radical cation (termed as D±). The zwitterionic excited state can subsequently collapse into a radical cation by expulsion of an electron. Both these excited states, called Rydberg states, can react with nucleophiles or electrophiles eventually present in the reaction medium zwitterionic excited state

Z

hν

S1

Rydberg States + eD± radical cation excited state

D± state needs the presence of electron accepting molecules.

Organic Photochemistry 2) Internal electron transfer without bond scission.

R

R

R

hν

R

strained trans cycloalkenes

R Z

R ROH R'O

R carbonium ion

-H

+

R + R'O

-

addition product

R H

R H

R" Ar

hν CH

R

CH

CH

Ar

CH 2

R'OH R'O

R H

products from alkyl and hydride migration

hν R'OH

skeleton rearrangement

Ar

CH

CH

R

More stable zwitteronic excited state

R

Organic Photochemistry 2) Internal electron transfer without bond scission.

Ph

Ph hν

Ph

Ph ROH

Ph

Ph

OR RO

Ph H 30%

Ph

Ph OR hν, ROH

via zwitterionic excited state Z

Ph-CO-Me

Ph Ph hν, ROH Ph-CO-Me

no addition product is formed

H

-

Ph Ph H

RO-

Ph

Ph Ph

H

H 50%

OR

Organic Photochemistry Intramolecular rearrangement:

ABC (S1 or T1) → ACB.

In this process, the excited state evolves by bond formation or breaking followed by internal rearrangement of the molecular skeleton. Electrocyclic reactions and sigmatropic rearrangements represent typical examples of this process. This process is generally observed in conjugated polyunsaturated systems and regulated by Woodward-Hoffman rules. In conjugated polyenes a photochemically stimulated electrocyclic reaction starts from their excited states. The process occurs stereospecifically and determines the observed stereochemistry in the final cycloadducts. When the electrocyclic reaction represents the primary photochemical process, the following selection rules generally hold: Rule1: The stereochemical pathway of photochemical electrocyclic ring opening is the same as for ring closure. Rule 2: photochemical electrocyclic reactions proceed via disrotatory pathways when the number of interacting electrons in the cyclic array is 4q, where q is an integer. Rule 3: photochemical electrocyclic reactions proceed via conrotatory pathways when the number of interacting electrons in the cyclic array is 4q+2 (q is an integer). Conjugated dienes give cyclobutanes (4 electrons involved = 4q, i.e. q=1) by a disrotatory process while conjugated hexatrienes (6 electrons involved 4q+2, q=1) give cyclohexadienes by a conrotatory process

excited diene π*orbital hν

trans-trans

disrotatory ring closure photochemically allowed

trans cyclobutene

excited triene π*orbital hν

trans-cis-trans

conrotatory ring closure photochemically allowed

trans cyclohexadiene

Organic Photochemistry Intramolecular rearrangement: Electrocyclic reactions Disrotatory ring closure: synthesis of Dewar benzene

O

O

O

O

O

Pb(OAc)4

Dewar Benzene

O

hν

Provitamine D3

HO

HO

∆

HO

Vitamine D3

Conrotatory ring opening: synthesis of provitamine D3

Organic Photochemistry Intramolecular rearrangement: sigmatropic rearrangements These rearrangements or sigmatropic shifts involve a migration of a group or p-bond across an adjacent p-system. The type of activation (thermal or photochemical) and the stereochemistry can often be predicted by the Woodward-Hoffmann rules which are based on the total number of electrons (those in the p-system + those of single bonds) involved in the rearrangement process: 4n electrons, the migration via supra-supra with retention is photochemically allowed from excited state (supra-antara, thermally allowed); 4n + 2 electrons, the migration via supra-antara with inversion is allowed from the excited state (supra-supra , thermally allowed). [1,3] supra-supra hydrogen or alkyl migration with retention retention

4 electrons supra 1,3 shift

H

CN H1

H

H

H

hν

R

H1

H

CN hν

R

H

[1,5] hydrogen sigmatropic shift

[1,7] hydrogen sigmatropic shift

H H

hν

H

H

hν

C 6 electrons supra-antara

8 electrons supra-supra

Organic Photochemistry Intramolecular rearrangement: sigmatropic rearrangements Other examples: [1,2]-sigmatropic rearrangement [1,2] sigmatropic rearrangement (also known as di-π-methane rearrangement or Aza-di-π-methane rearrangements discovered by H. Zimmermann in the late sixties) where the migration of different groups from hydrogen is observed. This rearrangement is observed in 4,4-disubstituted cyclohexenones or related derivatives and generally occurs with high stereospecificity.

O

O

X

mechamism of migration

migration mechamism

X

1 2

5

3

4

R

O

hν antara with inversion

5

R

3

R

X

Ar

4

R

R

Ar

hν

2

Ar

R

R=alkyl

Ar

Ar R

X= O, C(Ph)2

[1,2]-sigmatropic rearrangement in alicyclic compounds

Ph

Ph Ph

Ph H

hν

Ph

CO2Me Ph

Ph

CO2Me

Ph

CO2Me Ph CO2Me

COOMe COOMe

Ph

Ph

mechamism of migration

Ph Ph

N Ph

hν, CH2Cl2

O-COPh

PhCO-Me

N Ph

Ph

O-COPh

Organic Photochemistry Photoisomerization:

ABC (S1 or T1) → ABC’ (S1 or T1) → ABC’

Excited molecules undergo internal rearrangements without any bond scission and produce a new spatial disposition of molecular constituting units. A classical photoisomeration reaction occurs in the photochemical cis-trans interconversion of alkenes. The formation of the lowest excited singlet state of simple alkenes arises from the allowed π-π* transition. This generally requires short wavelength irradiation extending to about 200 –210 nm. On irradiation, a photochemical steady state is established between the cis and trans isomers and this is usually more enriched in the cis isomer than that in the ground state. The composition of this photostationary state is correlated to the absorption properties of the two isomers, i.e. cis→trans and trans→cis quantum yields and the εcis and εtrans extinction coefficients, by the equation

[trans]s

=

[cis]s

εcis Φ cis εtrans Φtrans

trans cis

Generally εtrans > εcis and, assuming the quantum yield of cis→trans ≈ trans→cis, the concentration [cis]s > [trans]s. The double bond isomerization is believed to involve an excited state where the two sp2 carbons are twisted 90° with respect to their position in the ground state. This state is referred to as p (perpendicular) geometry and its energy is settled at a minimum between that for singlet and triplet excited states

b

b

a

hν

b

b

a

a

a

cis

H Ph

hν

b

a

a

b trans

p geometry

Ph hν H

trans stilbene

H

Ph

Ph

H p geometry

hν

H Ph

Ph H cis stilbene

Organic Photochemistry Photoisomerization: The cis → trans isomerization plays an important role in vision processes where light promotes the transformation of cis retinal into trans retinal bonded to a lysine residue of opsine by an imine function. The adduct retinal-opsine is called rodopsine and three different rodopsines are present in the rods of the retina which absorb the blue, green and red components of white light enabling color vision

H3C

CH3

CH3 hν

H3C

CH3

CH3 H

H N

CH3 11-cis retinal

CH3

11-trans retinal

N opsine hν opsine RODOPSINE visual signal

11-cis retinal + opsine

11-trans retinal + opsine isomerasi

Organic Photochemistry Photoisomerization: enantioselective process H

hν

+

chiral sensitizer R*OOC

H

H

H

COOR*

e.e up to 53% *

*

R OOC

COOR

chiral sensitizer

Photoisomerization in azo derivatives Azo group is another unsaturated system that undergoes photochemically induced trans-cis isomerization. Dramatic changes in absorption properties occurs during this isomerization, for example trans diarylazo compounds absorb in the visible region (coloured compounds) while the cis in the UV (white compounds). By thermal treatments, the cis isomer can be reconverted to the trans isomer or undergoes fragmentation with production of radicals which further evolve, losing nitrogen, into hydrocarbons. R hν

R N

N

N

R trans azo derivative

∆

N

∆

N

R R cis azo derivative -N2

N

N

R

R

R N2 + R2

+

via singlet excited state

hν N N

Ph2CO ∆

N

N

N

via triplet excited state

Organic Photochemistry Photoisomerization: hν or ∆ R X Dewar like structure

electrocyclic process [4e]

[1,3] shift

X R electrocyclic process [4e]

hν X

R [1 ,3]

R

overall process hν R

sh ift

h

r∆ νo

3 [1,

Aromatic heterocycles undergo electrocyclic photorearrangements that may be unified under two common primary processes that convert the excited singlet states into: bicyclic isomers via 4q electrocyclic reaction or a cyclopropene derivative via a [1,3] shift. Their subsequent thermal or photochemical rearrangements afford rearranged isomers of the starting heterocycle

X

t hif s ]

H

X cyclopropenylcarbonyl derivative R hν For example 2-substituted thiophenes isomerize to 3-substituted ones, while isoxazoles to oxazoles under irradiation

R

S R

H R

hν N O

or

R

S

N O

R

N

S R

S N

or

H

O

O

R

Organic Photochemistry Photoisomerization: Photoisomerizations followed by oxidation: Synthesis of Helicenes.

trans/cis

HH

cis stilbene

isomerization

trans stilbene electrocyclic reaction

oxidation

H

dihydro-phenantrene

O2/J2 phenantrene

H

-H2

Application to the synthesis of hexaelicene hν O2/J2

hexaelicene

Organic Photochemistry ABC (S1 o T1) + R-H→ → ABC-H + R.

Hydrogen atom abstraction

From molecular singlet or triplet excited states hydrogen atom abstraction reaction can be observed. This reaction is quite common with carbonyl compounds where both singlet and triplet excited states show diradical character and are able to abstract hydrogen atoms either intramolecularly or intermolecularly from molecules possessing weak R-H bonds (called hydrogen donors). After the hydrogen abstraction step, the generated radical species are responsible for the observed chemical reactions. Intramolecular hydrogen abstraction with the formation of cyclocarbinols (Yang reaction) The intramolecular hydrogen abstraction is very common when hydrogens are present at the g position to form a diradical intermediate which evolves into cyclobutanols via intramolecular coupling of radical centres. Depending on the multiplicity of the excited state (singlet or triplet) and on the efficiency of intersystem crossing (from singlet to triplet), the diradical intermediate can be singlet or triplet in nature and this reflects on the timing of cyclobutane ring formation: very fast from singlet, slow from triplet singlet or triplet carbonyl excited state

H

O

H

O H

R H

H

hydrogen migration from γ position

hν

H R

R

R H

H

cyclobutanols

O

H hν

R

HO

hydrogen migration from γ position

H

O

OH R

singlet or triplet carbonyl excited state

1,4-diradical intermediate

radical coupling

H

H

R

OH

OH

OH R

R

R OH

cyclobutanols cyclohexanols

Organic Photochemistry Intramolecular hydrogen atom abstraction An interesting example of this reaction is reported in stereoid chemistry where a angular methyl is involved in the hydrogen abstraction process which becomes included in a cyclobutane ring. The carbonyl group of ester function can be involved in hydrogen abstraction. In the following example the migration of the double bond is observed after hydrogen abstraction affording β,γ-unsaturared esters. The structure of carbonyl compounds strongly influence the course of reaction. In special cases the fragmentation of the molecule represents the main process as in the formation of α-cyclopropyloxyacephenone or decaline derivatives R OEt OEt OEt OEt R

HO

O

O

CH2

CH3

OH

OH

H

hν

hν diradical intermediate

diradical intermediate

R

pregnan-11-one

HO

unstable enol

H2C O

H

unstable enol OH

OH

hν

O

O Ph

+

Ph

Ph

O

diradical intemediate O Ph

Ph

Ph

OH

O H

O hν

+ diradical intemediate

Ph

O

Organic Photochemistry Intramolecular hydrogen atom abstraction: other examples

O

OH

In cyclic ketones, the hydrogens in the γ position are physically inaccessible to the carbonyl oxygen thus the abstraction occurs across the ring from a carbon which results in close proximity to the excited carbonyl function. For example the irradiation of cyclodecalone at 254nm affords the isomeric decanols, respectively in 42 and 10% yields

OH

hν

+

H H H 42%

H 10%

O O S

O O H S O N

The hydrogen abstraction can occur also at 4 and more carbon atoms far from the carbonyl oxygen atom. In this latter case fused polycyclic derivatives and macrocycles (up to 14membered rings) can be obtained. Significant examples of these type are reported in the field of steroid, ftalimido and β-lactam derivatives

hν

OH

COOMe

O

OH

N

N COOMe O

O

COOMe

penicillin derivative (β-lactam)

diradical

O

O O S

O

N

hν

O H S CH2

O 80%

N O diradical

S CH2

N HO

CH2S

9-membered ring R

O CO(CH2)5

H O

R

R

hν

O CO(CH2)5

OH

diradical

O CO(CH2)5

OH

14-membered ring

Organic Photochemistry H

Stereoselective intramolecular hydrogen atom abstraction

Ph OH R

S

N

HN HO

HO

Ph

+

H HO Ph N

HN

Ph

O

O

hν

S

R

exo adduct

N HN toluene N HN Hydrogen abstraction can also be H HO Ph performed a stereoselective manner. For H HO Ph O O S example the enantioselective hydrogen yields up to 80% S S S + abstraction at the δ in cyclic urea affords e.e up to 60% N HN N HN exo/endo up to 4:1 via a Norrish-Yang cyclization bicyclic derivatives in good enantio and diastereo O O selection. The strong hydrogen bonding endo adduct between the substrate and a chiral origin of stereoselection template forces the ring closure at the endo with respect to exo with respect to diradical species to occur from the Re Ph Ph face of carbonyl function and cyclic urea exo adduct endo adduct OH ring. The Si face of carbonyl is less HO Si face favoured by steric interaction with N benzoisoxazole moiety of the chiral N Re face Re face template O O steric intraction N H N H H H O N N

O

O hν

N

OH H N

COOMe O

N

O

OH N COOMe

O

O

COOMe O

N

If the Norrish type II and Yang reaction are not allowed for structural reasons, as in the case of phtalimmido derivative of valine, a photoreduction of the carbonyl function can be observed.

Organic Photochemistry Intramolecular hydrogen atom abstraction, particular cases In some particular (substituted compounds) for example ortho-methyl benzophenones, the intramolecular hydrogen abstraction can involve the methyl group producing a diene intermediate (via photogenerated diradical) which can be involved in Diels-Alder [4+2]-cycloaddition reaction acetilenic dienophiles to produce dihydronaphtalene derivatives

CH2

H

CH2

O Ph

CH2 OH

OH Ph

unstable enol diene trapped by Diels-Alder reaction

Ph EtOOC

COOEt

diradical

COOEt COOEt HO

Ph

Organic Photochemistry Intermolecular hydrogen atom abstraction Hydrogen abstraction occurs also intermolecularly. In this case the presence of good hydrogen donor molecules is needed or molecules with X-H bond energy lower than the energy of carbonyl excited states (exothermic reaction). A n→π* electronic transition is of about 70-75 kcal/mole thus suitable hydrogen donors are tertiary C-H in the isopropanol, O-H bond of phenols and Sn-H bond in tin hydrides. The energy of aliphatic C-H, aromatic C-H bonds and O-H of aliphatic alcohols is too high to be used as hydrogen donors

triplet state O π*

OH H

X

+X

RCH2O endothermic reaction

n

π*

∆H>0 ∆H90%) and with high stereoselection (controlled by crystalline packing forces)

H

H

F

F

perfluoroarene-arene H π−π interaction

F H F

H F

90%

N O H

+

H a 2.6 equiv.

n

hν, -60° C toluene

n

N H

H N

N

O

O H hν, -60° C toluene n = 2, 87%, e.e.>90%

O H N H

O

Organic Photochemistry Photodimerization or photoaddition

The formation of cyclobutane is a reversible reaction. This is extremely important in biological systems. It is known that damage of DNA occurring where dimerization of two thymine residues stimulated by UV light produces a thymine cyclobutane dimer. Photolyases an enzimatic system containing redox cofactor flavin (reduced photochemically at radical anion state), is able to promote stepwise cyclobutane ring opening repairing in this way the damaged DNA

O

thymine

O

N

CH2OH O

O

O

O P O-

O P O-

O

O

N

O

cyclobutane

O

HN

NH

HN O CH2OH O

O

O O

HOH2C

NH N

CH2OH O

UV-damage Photolyase

O

O

O P O-

O P O-

O

O

N

O

Organic Photochemistry Photodimerization or photoaddition The photochemical outcome can be different in the presence of triplet sensitizers. Indeed, under this condition, [2+2] or/and [4+2] cycloaddition reactions are observed

hν +

triplet sensitizer [2+2] adducts cis/trans mixture

hν

[4+2] adducts

+

triplet sensitizer [2+2] adducts cis/trans mixture

2

hν

[4+2] adducts

diantracene

Organic Photochemistry Photodimerization or photoaddition Paternó Büchi reaction In this reaction the excited state of the carbonyl function is involved. Two different mechanisms can be followed: 1) the formation of an exciplex (i.e. a complex between the excited carbonyl function and the alkene) which collapses directly into oxetane or via the formation of a diradical species; 2) abstraction of an electron from the alkene with the formation of a radical anion and radical cation which collapse into oxetane via the formation of a diradical species

O*

O*

exciplex

+

carbonyl excited state

O

O

diradical species

O

Organic Photochemistry Photodimerization or photoaddition

Paternó Büchi reaction

The Paternò-Büchi reaction shows a certain level of regioselectivity. In fact, in the case of reaction of benzophenone with isobutene the isomer with vicinal quaternary carbon atoms is formed in a 9:1 ratio compared to that where the carbon atoms are separated by a CH2. This ratio can be explained considering the major stability of tertiary radicals in the diradical intermediate. Enolethers can be used as alkenes. Cistrans isomerization goes with the [2+2] photocyclization and a mixture of oxetanes are formed as in the case of the reaction of acetone with a cis-1,2,dialkoxyalkene Me Ph

Me O +

Ph

Me

Φ= 0.5 Ph

Me Ph

Me Ph 90%

Ph 10%

Me Me

O diradical more stable than Me

Ph

Ph Ph

Me

OR

Me

hν O

Me

+

diradical intermediate

O Ph

O

Me

O

hν

+ RO

OR

O +

OR

Me

Me

RO

OR

mixture of cis and trans oxetane

trans isomer

Organic Photochemistry Photodimerization or photoaddition

Paternó Büchi reaction: other examples

O O

O

O MeOOC

H

+

Furanes can be used as enolethers. In this latter case bicyclic derivatives are obtained with high regioselectivity (i.e. only the regioisomer with geminal oxygen is formed)

H

MeOOC hν

+ O

benzene O

MeOOC

H

O The Paternò-Büchi reaction can also occur intramolecularly affording polycyclic derivatives

hν

Ph O O

(CH2)9

O

(CH2)9

Ph

83% O O

Organic Photochemistry Photodimerization or photoaddition

Paternó Büchi reaction: enantio and diastereoselective reactions

Chiral phenylglioxilic esters or reversible binding of alkene derivative to chiral template allow to perform diastereo and enanthioselective Paternò-Büchi reactions

O O

O

hν

+ OR*

O

O

O N

H

O

O

R*= O

*RO H O

O

H

N

+

O

OR* major diastreoisomer

O

O

O

O

H

O O

O H H N

+

N H

O

O

hν, -10° C toluene

O O

56%, e.e.>90%

N H

OH H N

O

H

O O

Organic Photochemistry Photodimerization or photoaddition

Paternó Büchi reaction of thioketones Thioketones undergo photoreaction analogous to ketones e.g. photoreduction and cycloaddition. A special feature of thioketones is that the reaction can also involve the S2 excited state. The photoreaction can be initiated both from S2 (π→π*) or T1 (n→π*). In absence of reacting substrates the thioketone dimerizes to 1,4-dithietane derivatives, while in the presence of alkenes [2+2] cycloaddition reaction occurs. The cycloaddition is stereospecific but not regiospecific from S2 and regiospecific but not stereospecific from T1. Because of the reactivity of S2 the reaction involving thioketones are wavelength dependent. Electron poor olefins seem more reactive with the S2 excited state affording thietanes, while T1 affords thietanes and 1,4-dithianes R R

S

R

R

hν

S

R

S

R

R

hν S

C=C

thietane

1,4-dithietane

Ph S Ph

hν

*

Ph

*

Ph S

S Ph

Ph

T1

S2 C=C

C=C

C=C

S

Ph Ph

S

Ph Ph

Ph S

Ph

1,4-dithiane

R

Organic Photochemistry Photosensitized reactions: ABC (S1 o T1) + D→ → ABC + products from excited state of the molecule D This reaction is promoted by energy transfer from an excited molecule (sensitizer) to another which undergoes chemical transformation. Examples of sensitized reactions have been analysed in the photodimerization or photoaddition and photoisomerization sections; here, attention is focused on photosensitized reactions involving the oxygen as reagent. Oxygen exists in nature in a triplet ground state. In this state, the oxygen is not particularly reactive as oxidazing agent or its reaction with molecules occurs with very slow reaction rates. Reactions are faster if oxygen is excited to its singlet state. Two singlet states are possible for oxygen: S1 or 1∆ state as commonly designated spectroscopically, the oxygen molecule is described O=O, while in its S2 or 1Σ state is described as a diradical species with paired electrons on two different π* molecular orbitals (termed πx* and πy* i.e. antibonding π* orbital along x and y axis). The two different singlet oxygen states show different chemical behaviour

S2 πx*

1

Σ

O

O

πy*

diradical character paramagnetic state

x y

πx

*

πy

*

πx

S1 *

πy

πy *

O

O

Σ

O

O

* O O πx

*

To πx*

∆

1

electronic state

3

spectroscopic designation

Lewis structure

z

diradical character paramagnetic state

O O πy*

Organic Photochemistry Photosensitized reactions: singlet oxygen reactions Singlet oxygen can be generated from triplet oxygen in many solvents by a broad variety of sensitizers and the more common are porphorhyns (usually tetraphenylporphyrine), Bengal rose and 1-cianonaphthalene. Typical organic reactions of singlet oxygen (both in its 1Σ and 1∆ excited state) are: 1) [2+2] cycloaddition reactions with alkenes giving 1,2-dioxetanes or [4+2] oxygen: 1O Diels-Alder like reaction, with conjugated 1 dienes such as for example ∆ excited state cyclopentadiene, furane, thiophene, pyrrole O O or 9,10-diphenyl-antracene affording endoperoxides respectively typically from 1∆ singlet excited state (O=O behavior). 1,2-dioxetane derivatives decompose under irradiation or by heating into carbonyl derivatives by C-C scission; one of the carbonyl derivatives is in its excited state

[2+2] cycloaddition O

O

O

O2

O O

[4+2] cycloaddition O2

X = CR2, O, S, N-R ;

O O

Cl Cl

Cl

COO Na

J

J

Na+ -O

O J

O

CN

N H

+

N

N

Oxygen sensitizers

H N

J

1-cianonaphtalene

Rosa Bengala sodium salt tetraphenylporphyrine

Ph 1

Ph

-

+

Ph

X

Cl

O*

excited carbonyl derivative

1,2 dioxetane

X 1

hν or ∆

Ph

Organic Photochemistry Photosensitized reactions: singlet oxygen reactions 2) allylic hydroperoxidation to give hydroperoxides; typically from O2 in its 1Σ excited state (diradicaloid nature). The mechanism can be described as an ene-type reaction. In general, the reactivity of an alkene in this reaction increases with alkyl substitution. Terminal alkenes usually do not react. If several allyl positions are present the hydrogen abstraction occurs from the side of the double bond that is more substituted (i.e bearing more alkyl substituents since statistically more allylic hydrogens are present) OH OH OH

O2, TPP, hν

HOO

HOO +

oxygen singlet 1Σ diradicaloid character

OH O O H

Oxygen singlet is also involved in oxygen atom transfer photoreactions as for example in the oxidation of sulfide to sulfoxides or phosphines to phosphinoxides. The presence of 1-ciano-naphtalene as oxygen sensitizer is required

S

S

O2, hν 1-cianonaphtalene

S

S

O 80%

If singlet oxygen is deleterious for an organic reaction, oxygen must be excluded from the reaction mixture or its production inhibited using singlet oxygen quenchers. Suitable candidates for this aim are tertiary aliphatic amines and in particular 1,4-diazabicyclo[2,2,2]-octane (DABCO). In some cases phenols can be used.

N

DABCO N

Organic Photochemistry Photosensitized reactions: triplet oxygen reactions Oxygen can also react in its natural triplet state. In this case the sensitizer must transfer its excitation to the substrate by a photoelectron transfer process (PET) into a radical cation. This latter is more prone to react with triplet oxygen (diradical nature). The oxidation potential of the substrate must be lower than that of the sensitizer.

+ hν → 1Sens* sensitizer excitation 1Sens* + A → Sens. +A + photoelectron transfer process A + + 3O2 → A-O-O+ reaction of radical cation of substrate with oxygen A-O-O+. + Sens. → Sens +AO2 (oxidized substrate) 1Sens

In some reactions the radical anion of the sensitizer reacts with the triplet oxygen producing superoxide radical anion, which, in turn, reacts with the radical cation of the substrate.

Sens. + 3O2 → Sens + O2.- superoxide radical anion production O2.- + A + → AO2 reaction of radical cation of substrate with superoxide radical anion In other cases the triplet state of the sensitizer abstracts hydrogen from the substrate and the resulting radical of the substrate reacts with triplet oxygen affording a radical peroxide which can initiate a radical chain reaction.

+ hν → 1Sens* sensitizer excitation 1Sens → 3Sens* intersystem crossing process: evolution of singlet to triplet 3Sens* + A-H → H-Sens. +A. Starting radical chain process (primary photochemical process) A. + 3O2 → A-O-O. reaction of radical cation of substrate with oxygen to give peroxiradical. A-O-O. A-H → A-O-O-H +A. reaction of peroxiradical with substrate with propagation of the radical chain. 1Sens

Organic Photochemistry Photosensitized reactions: triplet oxygen reactions

An example of the latter process is the transformation of benzaldehyde into perbenzoic acid by photolysis in presence of oxygen and benzophenone as triplet sensitizer

radical chain initiation Ph2C=O

hν

H

Ph2C O triplet state

radical chain propagation Ph

C=O + O2

+

Ph

O-O Ph

C=O

Ph2C

C=O

H Ph

OH

+

Ph

C=O + Ph2C +

Ph

C=O

C=O

O-OH OH

Ph

C=O

C=O

O-OH

radical chain termination O-O

Ph

+

perbenzoic acid

Ph2C=O

+

Ph

C=O

Organic Photochemistry Photoionisation reactions:

ABC (S1 o T1)→ → ABC+ + e-

Process where an electron is removed from the molecule. This process is more common in metal or metal oxides and it is the basis of the photoelectric effect. In molecules this process is less common and requires light of high energy in the range of X or γ-ray. Ionization processes can occur in the stratosphere and it is responsible for the generation of radical chlorofluorohydrocarbons (freons) which are highly effective in removing ozone (triplet oxygen) from the atmosphere. In very electron rich aromatic substrates such as 1,2-dimethoxybenzene the abstraction of an electron is possible by irradiation with formation of an aromatic radical cation. This latter undergoes nucleophilic aromatic substitution in the presence of nucleophiles such as cyanide anion OMe

hν ,

-e -

OMe

OMe

OMe OMe

hν, CN-

CN

t-ButOH, H2O Processes where an electron jumps from an excited molecule to another in its ground state are more common. This process can produce both radical cation and a radical anion couple or cation or anion species and are called external electron transfer:

ABC (S1 o T1) + D→ → ABC.(+, -) + D.(-, +) radical species ABC (S1 o T1) + D→ → ABC(+, -) + D(-, +) The external electron transfer between benzophenone and a triarylamine is a typical example. In this reaction the triplet state of the carbonyl compound removes an electron from the lone pair of nitrogen

Ph2C=O +Ar3N → Ph2C .-O - + Ar3N.+ λmax 620nm λmax 670nm

Organic Photochemistry Photoionisation reactions: OH

O CH3

hν, (CH3CH2)3N

When tertiary aliphatic amine are used, the ketyl radical anion further evolves by extracting a hν proton transfer hydrogen from an alkyl electron transfer process substituent of the amine radical process H cation affording an α-hydroxy N(CH2CH3)3 O O H C CH-NEt benzyl radical, which evolves into 3 2 pinacols, and an amino radical CH3 CH3 and the whole process is the photoreduction of a carbonyl carbonyl excited compound like that observed in Ketyl radical anion triplet state presence of hydrogen donor

CH3 2 pinacol radical dimerization OH CH3

the photoinduced electron transfer from sacrificial triethylamine can be exploited in other photoreductive process such as cyclopropane and epoxide reduction

O O

hν N(Et)3/EtOH 8:2

OMe

O

OMe

CH3CN

O 79%

O

hν, N(Et)3

O

O

OH

Organic Photochemistry oxidation process

Photoionisation reactions:

- e-

Photoinduced electron transfer reactions can be used to initiate radical reactions of alkenes. Two pathways are possible: oxidative leading to a radical cation, and reductive, leading to a radical anion. More common are oxidative processes (induced by the presence of 1,9dicianoanthracene as electron acceptor) since alkenes are more easy to oxidize than to reduce

CN

+ e-

CN

CN

electron acceptor

SiMe3

O

O

- e-

An example of this type is the photooxidation of enol silyl ether of cyclopentanone bearing a dimethylbutenyl substituent in a position. The photogenerated radical of 9,10-diciano-anthracene is intercepted intramolecularly by the double bond affording a bicyclic derivative

hν COOEt

COOEt

COOEt

CN

CN

+e

CN

+ e-

CN

O SiMe3

reduction process

-

CN

Ph

electron acceptor

Aromatic nitriles are generally employed to intercept the zwitterionic S1 excited state of an olefin. The removal of an electron generates a radical cation able to react with nucleophiles such as alcohols affording the corresponding addition product. THis latter is different from that obtained from the photolysis in absence of nitrile and involving the D± Rydberg state ionic pair of an excited alkene

+ R-CN * olefin excited state

Ph

electron transfer

+ [R-CN] D ROH

H

Ph

Ph

- RCN

Ph

H O

O

O

R

R

R

H

+ [R-CN]

Organic Photochemistry Miscellaneous Photoreactivity of aromatic compounds Aromatic compounds are usually unreactive under photochemical conditions and normally used as reaction solvent (e.g. toluene or benzene). However for prolonged irradiation in the UV spectrum (200÷254nm where the aromatic compounds show strong absorption bands) certain reactivity can be observed. The reactivity of aromatic compounds arises from changes in the electron distribution in the excited state. For example, if benzene is irradiated with light of 254 nm small amounts of benzvalene and fulvene are formed, while if the irradiation is performed at 203 nm, the formation of Dewar benzene is observed

hν 203 nm

hν 254 nm

+ Dewar benzene

benzvalene

fulvalene

Some functionalized benzene derivatives show a more prone photoreactivity. For example the 1,4-dimethoxybenzene gives [2+2] cycloaddition in reaction with acrylonitrile affording the corresponding cyclobutane derivatives in high yield

OMe + MeO

OMe

CN hν, 254nm low pressure Hg lamps MeO 95%

CN

Organic Photochemistry Photoreactivity of aromatic compounds

Photoinduced aromatic substitution reactions OH

The reactivity of aromatic compounds changes dramatically under photochemical conditions. The nucleophilic aromatic substitution follows a different pathway from that occurring under thermal conditions. For example, 3,4-dimethoxy, 1-nitro benzene undergoes, as expected, thermal nucleophilic substitution of the para-methoxy group with OH-, while the methoxy group in meta position is substituted under photochemical condition. This is one of differentiating aspects of photochemical reactivity from thermal reactivity

∆, OH-

thermal: para-orientation OMe

OMe OMe

NO2 OMe

NO2

OH

hν, OH-

Photochemical: meta-orientation

electron withdrawing group NO2

resonant structures describing the aromatic π∗ excited state The explanation of this different behavior can be found in the

W electron withdrawing group

W

W

zwitterionic nature of the excited state of aromatic compounds when an electron withdrawing group is present. This foresees the localization of the negative charge on the carbon bearing the electron withdrawing group and the positive one localised in meta position as described by cyclopropane containing structures generated by a redistribution of π-electrons. In addition, in 3,4dimethoxy 1-nitro benzene the positive charge in the meta position is stabilized by the electron donating methoxy group. Thus under photochemical conditions the charge distribution on the aromatic ring is the reverse of that of the ground state (where the meta position is less electron rich). The reverse is also observed in the chemical behaviour to nucleophilic substitution

Organic Photochemistry Photoreactivity of aromatic compounds

Photoinduced nucleophilic aromatic substitution reactions

electron releasing group OMe

Under photochemical conditions it is possible to carry out nucleophilic substitution even on electron rich halogen aromatic compounds. In some cases the reaction occurs by homolitic scission of the C-halogen bond generating an aryl radical which reacts with the nucleophile

OMe hν, CN-

Cl

hν

OMe

CN CN-

Cl

X

X + Nu-

hν -X-

X = Br, I Nuhν, Nu-

Ph-X Nu

Nu

In other cases the nucleophilic substitution follows a different mechanism especially when negative charged nucleophiles are employed. In a first step, the nucloephilic substitution is promoted by the photostimulated transfer of an electron from the nucleophile to the aromatic with the + Nu- formation of an aromatic radical anion. This undergoes Chalogen bond scission with formation of an aryl radical which reacts with the starting nucleophile affording a new aromatic radical anion. The latter subsequently transfers an electron to the starting aromatic substrate propagating the aromatic nucleophilc substitution. This type of aromatic substitution is called monomolecular radical nucleophilc aromatic substitution or SRN1. Bromo and iodo arenes are the suitable substrates and the reaction tolerates alkoxy and acyl substituents. Good nucleophiles in this type of reactions are: ketone enolates, β-diketone enolates, dialkylphosphite anions and thiolates.

Organic Photochemistry Photoreactivity of aromatic compounds

Photoinduced nucleophilic aromatic substitution reactions In naphtalenic substrates only the nucleophilic substitution at the α-position is observed independently of the nature of substituents present on the aromatic nucleus

NO2

OH hν, OH-

O2N

100% α-substitution O2N

H

CN OMe

hν, CN-

OMe

Organic Photochemistry Miscellaneous The photolysis of esters of phenols and amides of anilines produces the cleavage of C-O or C-N bond followed by a [1,3] or [1,5] acyl shift, called photo-Fries reaction, affording ortho or para acylated derivatives

O

R

hν

X

XH

XH

+

photo-Fries

R

O

X= O, NH

R

O tautomerization

hν α-cleavage O

R X

recombination

X

H

R

R

+

X O H

O

If the ortho position is blocked by substituents only the [1,6] acyl rearrangement can be observed. An interesting application of an intramolecular photo-Fries has been devised to generate paracyclophanes

Me O

Me

O

hν

N (CH2)11

Me

Me N Me

(CH2)11

O [1,6] shift

NH Me (CH2)11 paracyclophane derivative

Organic Photochemistry Miscellaneous Photochemistry of diazo- and azido compounds The most characteristic photoreaction of diazo and azido compounds is photoelimination of a molecule of N2 followed by reaction of the resulting carbene and nitrene. Using the Wigner spin rule, i.e spin conservation in a elemental chemical step: from a singlet excited state singlet carbene or nitrenes are generated while triplet carbene or nitrene from triplet exited states. Singlet carbene or nitrene show a zwitterionic nature and diradicaloid in their triplet states. The reactivity reflects the singlet or triplet nature of these species. Typical reactions of singlet states are: 1,2 sigmatropic shift with formation of a double bond; stereospecific insertion into σ-bonds; stereospecific insertion into π-bonds; addition of a nucleophile or (less commonly) an electrophile. Typical reaction of triplet states are: atom abstraction reaction with production of radicals; nonstereospecific addition to insertion into π-bonds; addition of radicals or radical-like substrates. The presence of sensitizers (benzophenone) is needed in the photochemical production of triplet excited states of diazo or azido compounds

diazo compound R N

N

R

hν

R

R

- N2

R

N

N

R R

C

R

R

C

R

R diradicaloid character

triplet

R

R

singlet

R

C

zwitterionic character

azide R N N

N hν

R N N

N

R

N

- N2 triplet

R

N

diradicaloid character

R

N

singlet

R N zwitterionic character

Organic Photochemistry Photochemistry of diazo- and azido compounds As an example, the reaction of diphenylcarbene (photogenerated from diphenyldiazomethane) in the presence of isopropanol affords different products in relation to its electronic state: diphenyl-isopropylether from singlet state (reaction as zwitterionic character) and diphenyl-methane and acetone from triplet state (diradicaloid state)

Ph

Ph C

Ph

Ph N N

Me C

Ph C

+ HO

Ph

Me

singlet zwitterionic nature

H O

Ph CH Ph

Me Me

Ph

Me O Me

Ph Ph C Ph

Me H Me

Ph OH

Ph

Me CH

+

CH2 +

OH Me

Ph

Me

Ph

O Me

triplet diradicaloid nature

Difference in chemical behaviour is also observed in reactions of carbenes with double bonds. For example singlet photogenerated carbene from diazomethane adds in a stereospecific manner to cis 2-butene affording a single cyclopropane derivative, while triplet carbene (photoproduced from diazomethane in the presence of benzophenone as triplet sensitiser) affords a mixture of two possible stereoisomers

hν via singlet carbene CH2N2

hν, Ph2CO

+

via triplet carbene

Organic Photochemistry Photochemistry of diazo- and azido compounds Diazoketones are photodecomposed to singlet ketocarbene which, in turn, undergoes Wolff [1,2] rearrangement to ketenes captured by nucleophiles such as alcohols to give esters, while triplet ketocarbene cannot undergo Wolff rearrangement without violation of Wigner spin rule thus normally evolves to methylketone by hydrogen abstraction

singlet O

hν

CH

Ph PhCO CHN2

hν, Ph2CO

[1,2] Wolff rearr.

PhCH=C=O ketene

(Me)2CH-OH

PhCO-O-CH(Me)2

O Ph

CH

(Me)2CH-OH

PhCOCH3

via hydrogen abstraction

triplet diradicaloid behavior OMe

OMe H3C

H3C

OMe HN CH2

hν

CO

insertion

Acylazides are photodecomposed to acylnitrenes which do not undergo Curtius rearrangement to isocianate as occurs under thermal conditions, but give insertion reactions in C-H or in double bonds

CO-N acylnitrene

CO-N3 Ph N3

hν

Ph

N

Organic Photochemistry Photocleavable protecting groups Protecting groups are often a necessity in organic synthesis along with all the drawbacks associated with their use as for example the fact that their introduction and cleavage require two synthetic steps and introduce complications to the synthetic plan by their incompatibility with some organic reagents. The complication increases rapidly with the number of different protecting groups on the same molecule. The conditions necessary for their cleavage have to be very specific for a given group in order to leave intact all the others (the so-called “orthogonality”). Photolabile protecting groups bring an interesting feature: they do not require any reagent for their cleavage, just light. This category of protecting groups opens the possibility of dealing with extremely sensitive molecules, otherwise incompatible with acids or bases. o-nitrobenzylic derivatives The most popular photolabile protecting groups are based on o-nitrobenzyl derivatives which undergo a photochemically-induced photoisomerisation into o-nitrosobenzaldehyde. The mechanism is: the excited triplet state of the nitro function abstracts a hydrogen from the ortho benzylic carbon atom, subsequently the so formed diradical species evolves into a cyclic acetal derivative whose hydrolysis yields o-nitrosobenzaldehyde liberating the moiety X bounded (bonded) to the benzylic carbon atom in high or quantitative yields

OH

O N OH O NO2 X

hν

N O

X

N O hydrogen X abstraction

N O

X

+

O N OH

N O OH

X X

acetalic function hydrolysis

CHO

X-H

Organic Photochemistry Photocleavable protecting groups Different functionalities can be protected by this group such as for example nitrogen of heterocycles or hydroxy functionalities. The N-(o-nitrobenzyl) protecting group of the imidazole side-chain of histidine is removed quantitative yields giving back histidine without any racemisation: The tertButhoxycarbamoyl (BOC) nitrogen protection is stable under photolysis conditions N O

NO2

H

OH N

N

100%

hν

N N

N

COOH

COOH

N

NH-Boc imidazole protected histidine

NO

+

CHO

COOH NH-Boc

NH-Boc

NO2

NO2

PCl5

O

O P 2 OH

O O 2

HO

O

Thy

+

P Cl

OAc

phosphate protected motiety The ortho-Nitrobenzyl alcohol derivatives were used for the protection of the phosphate group in nucleotide synthesis. Both protection and deprotection occur very efficiently

O HO

hν

P

HO

O

O OAc

Thy

>305 nm 70%

NO2 O O

P 2

O

O OAc

Thy

Organic Photochemistry Photocleavable protecting groups Orthogonal photolabile groups i.e. group which can be removed using light of different wavelength.

Organic Photochemistry Photocleavable protecting groups The 6-nitroveratroyloxycarbonyl group (NVOC) is undisputedly the most popular and used photolabile protecting group for the amino function in amino-acids. The two methoxy groups were introduced to increase the absorbance at wavelengths longer than 320 nm. Under these conditions, even the tryptophan, one of the most light-sensitive compounds, is not affected The simpler ortho-nitro-benzyloxycarbonyl group (NBOC) is normally used with less light sensitive substrates

MeO

NO2 hν, 350nm

MeO

H N

O O

COOH

- CO2

MeO

COOH

H2N

NO2

+

H

MeO

R

O

R NO2

Nitroveratroyloxycarbonyl protecting group (NVOC)

H N

O

COOH

hν, 260nm

R

O

Nitrobenzyloxycarbonyl protecting group (NBOC)

Both NVOC and NBOC groups can be OH used for the protection of the hydroxy groups in carbohydrate chemistry. For example, the hemiacetalic form of glucose HO can be protected as a mixed acetal. HO Photolysis gives quantitative yields of glucose, with both types of photolabile groups

OH O R

O OH

O2N

R

R= H, OMe

hν quant.

O HO HO

OH OH

Organic Photochemistry Photocleavable protecting groups The 1-(2-nitrophenyl)ethylenglicole can be effectively used in the protection of the carbonyl function of ketones.

NO2 OH

O + R1

NO2

TsOH/PhH R2

O

- H2O 70-97%

OH

O

O + R1

R2

R2

O 31-90%

NO

R1

hν, 350 nm PhH OH N O O

OH

R1 O

R2

Organic Photochemistry Photocleavable protecting groups Benzophenone as photooxidant The N-(2-acetoxyethyl) group (introduced by alkylation of an amine with 2-acetoxyethyl bromide) can be used as amine protecting photolabile group. The deprotection requires a stoichiometric amount of 4,4 -dimethoxybenzophenone (the electron acceptor), and irradiation at 350 nm. The deprotection follows an external electron transfer process

O R1 N

+

R2

O-Ac

MeO

MeCN/H2O

OMe

hν, 350 nm external electron transfer process O

R1 N R2

O-Ac

MeO

OMe

OH R1 NH R2

+ MeO

OMe

Organic Photochemistry Photocleavable protecting groups Benzyl alcohol derivatives The N-benzyloxycarbonyl (Cbz) amino protecting group is usually removed by hydrogenolysis but it is found that its cleavage can be performed in significant chemical yields (~ 70%) by a photosolvolysis process upon irradiation at 254 nm. A heterolytic mechanism of C-O bond scission has been proposed with formation of benzylic carbocation and carbammic acid anion. In the presence of water both these intermediates evolve into benzylic alcohol and amine with evolution of CO2. The presence of electron-releasing groups on the aromatic ring or of water in the reaction medium increases the quantum yield of the deprotection reaction

R R

hν H N

O O

-

COO- 254 nm

+

R1 H2O - CO2 R

+ OH

COO-

H3N R1

H N

O O

COOR1

Organic Photochemistry Photocleavable protecting groups Thiohydroxamate derivatives Thiohydroxamate derivatives of carboxylic acids can be regarded as protecting groups of a C-H bond. The deprotection reaction requires the use of an external hydrogen donor agent such as Bu3SnH, TMS3SiH or t-BuSH. Thiohydroxamate derivatives are also used as traceless linkers in solid state synthesis

S S

N

OH +

OH

R

Coupling reagent

O

Me thiohydroxamic acid

S S

N

O

Me

hν

O R

SH

hydrogen donor X-H

S

N

+ CO2 + R-H

Me

O

O

S S

N

O

Me

NMe

hν, 350 nm

Me

NMe

O SH

hydrogen donor

+ S

N Me

Organic Photochemistry Photopolimerization The generation of radicals by homolitic bond scission or molecular excited states with radical character can be exploited to initiate polymerization. Under irradiation benzophenone is excited to a triplet state with diradical nature and, as already seen in the previous sections, can stimulate many photochemical processes as well as be exploited as radical photoinitiator of polymerization processes. A recent application of this possibility is the surface modification of polypropylene microporous membranes by means of a polymeric layer with the aim of improving its hydrophilicity, permeation, hemocompatibilty and anti-fouling properties. This has been realized by photopolymerization of suitable methylacrylate induced by catalytic amounts of benzophenone as photoinitiator

photoinitiators Me O X

methaacrylate derivative

Me

hν

n

photoinitiator

O Ph

Ph

benzophenone

O X

polymethylmethacrylate

O Ph MeO

Ph OMe

2,2-dimethoxy-2-phenyl-acetophenone DMPA

Organic Photochemistry Chemoluminescence

Chemoluminescence is a phenomenon that occurs when a sizeable amount of exothermicity (∆G) of a chemical reaction is converted into electronic excitation energy of a reaction product which then relaxes emitting light (hν). The most significant examples of chemoluminescence are: oxidation of luminol by oxygen under alkaline conditions. The treatment of luminal by NaOH transforms it into the corresponding dianion which reacts with oxygen producing an endoperoxide whose decomposition produces N2 and the triplet state of 3-aminopthalate. The light is emitted after intersystem crossing from the triplet state to the singlet

NH3

O

NH2

O

2 OH-

N

O2

N

NH

N

O luminol

NH2

NH2

O

O

Light + O

NH2

O O

N

O

N

O

1

O

O

O

O

O O 3-amino-phtalate singlet excited state

endoperoxide

- N2

NH2

3

O

intersystem crossing

O O O 3-amino-phtalate triplet excited state

Organic Photochemistry Chemoluminescence

Bioluminescence observed in fireflies (Photinus pyralis) represents a particular and well know aspect of chemoluminescence. Bioluminescence requires a lumophore and an enzime system that acts as mediator of chemoluminescence step. The enzyme system (termed luciferase) associated with lumophore is called luciferin. Commonly a molecule of oxygen is also required and aquantum yield of 1 for chemoluminescence process has been measured. The decarboxylation of a peroxolactone is believed to be a key step in producing the excited intermediate whose relaxation occurs radiatively

N HO

H

N

S

CO-OH luciferase

N

CO-AMP + P2O7-2

ATP

S

H

N

HO

S

S

lumophore H O

O2 O

HO

N

N

S

S

O O HO

N

N

S

S

O AMP O

endoperoxide - CO2

HO

N

N

S

S

excited lumophore

O

*

N

N

O + Light

HO

S

S

Organic Photochemistry Chemoluminescence One of the most efficient “synthetic” chemoluminescent systems (quantum yield Φ~0.25) involves the reaction of H2O2 with diphenylester of oxalic acid. A peroxydione intermediate (peranhydride of oxalic acid) decomposes into two CO2 molecules, one of which is in the excited state is believed to be at the basis of the chemoluminescence process. The excitation of CO2 is transferred to a suitable energy acceptor as for example Rubrene which, in turn, emits in the visible region (yellow green)

excited carbondioxyde molecule

O PhO

O OPh

O

O

+ H2O2 O O peroxydione

Ph

O * Rubrene

C

O +

O

O energy transfer to Rubrene

Ph

Ph

Ph

Ph

Ph

Light + Ph Ph Rubrene

C

excited Rubrene

*

Organic Photochemistry Technical and experimental aspects In order to perform photochemical reactions correctly, safely, and with success, technical and experimental protocols and indications should be followed. 1) Purity of starting materials. This is a prerequisite valid in general for any procedure in organic synthesis, but plays a particular and important role in photochemical reactions since the reactive species are photogenerated at very low concentration and can be captured or quenched by the presence of impurities. 2) Before starting a photochemical reaction a UV/vis spectrum of the “photoactive” compound should be recorded. The “photoactive” compound is the electronically excited molecule which undergoes or initiates a primary photochemical process from its excited singlet or triplet state. From UV spectra recorded with different compound concentrations, allows to evaluate the extinction coefficients in the whole range of interest. The extinction coefficient gives an idea of the power of light source to be used: low extinction coefficient need high intense radiation to produce enough excited molecules. UV spectra of all reagents should be recorded to be sure that there is no or little interference in absorption with the “photoactive” compound. If available, a UV spectrum of the product should also be recorded. UV spectra from the reaction mixture may help to identify ground state interactions between the reagents or CT complexes, which can be useful as a guide to individuate the best reaction conditions. 3) In principle, photochemical reactions can be performed in the gas phase, in solid state or in solution. For practical reasons most photochemical reactions are performed in solution, therefore the choice of the right solvent is critical. The solvent must be transparent or at least it must show a very low extinction coefficient in comparison with the “photoactive” compound. In fact, if the extinction coefficient of the “photoactive” compound is only 10 times higher than that of the solvent at the irradiation wavelength, a significant solvent filter effect can be observed with the consequence that the reaction is much slower than it could be. The solvent must be free of impurities (ethylendiamine tetracetic acid EDTA can be useful to remove, by complexation, trace metal ions). The solvent must, of course, dissolve the reactants. The polarity of the solvent plays an important role in stabilizing or destabilizing the ground and excited states of a molecule and consequently this reflects on their reactivity and on the energy needed for performing a photochemical reaction. In Table 2 the optical characteristics of some utilized solvents for photochemical reactions are reported, expressed by the cut off wavelength (lcutoff) together with the parameter normally used for valuating the solvent polarity (dielectric constant e and the Dimroth-Reichardt value). At longer wavelength than lcutoff the solvent can be considered completely transparent

Organic Photochemistry Technical and experimental aspects Cut-off wavelength nm

εT

ET(30)

Water

185

78.30

63.1

acetonitrile

190

35.94

45.6

n-hexane

195

1.88

31.0

Ethanol

204

24.5

51.9

Methanol

205

32.66

55.4

Cyclohexane

215

2.02

30.9

Diethylether

215

4.20

34.5

1,4-dioxane

230

2.21

36.0

Methylene chloride

230

8.93

40.7

Chloroform

245

4.81

39.1

Tetrhydrofurane

245

7.58

37.5

Ethyl acetate

255

6.02

38.1

Acetic acid

250

6.17

51.7

Dimethylsulfoxide

277

46.45

45.1

Benzene

280

2.27

34.3

Toluene

285

2.38

33.9

Pyridine

305

12.91

40.5

Acetone

330

20.56

42.2

Solvent

Table 3: Sensitizer and Quencher in non-polar solvents ET (kJ/mol)a

Es (kJ/mol)b

ΦISC c

Benzene

353

459

0.25

Toluene

346

445

0.53

Methyl benzoate

326

428

-

Acetone

332d

372

0.90/1.00d

Acetophenone

310

330

1.00

Xanthone

310

324

-

Benzaldehyde

301

323

1.00

Triphenylamine

291d

362

0.88

Benzophenone

287

316

1.00

Fluorine

282

397

0.22

Triphenylene

280

349

0.86

Biphenyl

274

418

0.84

Phenanthrene

260

346

0.73

Styrene

258

415

0.40

Naphtalene

253

385

0.75

2-acetylnaphtalene

249

325d

0.85d

biacetyl

236d

267d

1.00

benzil

223

247

0.92

Anthracene

178

318

0.71

Eosine

177

209

0.33

Rose bengala

164

213

0.61

Methylene blue

138

180

0.52

Solvent

Organic Photochemistry Technical and experimental aspects Different light sources can be used for photochemical reactions: 1a) the sun, useful wavelenghts 300÷1400 nm, 1) low-pressure mercury lamp (Hg approx. 10-5 atm), useful wavelenghts: 185, 254 (the most intense), 577÷579 nm. 2) medium pressure Hg lamps (Hg vapor pressure 5 atm), useful wavelengths: 365 (the most intense), 436, 546 and 577÷579 nm, 3) high pressure Hg lamps (Hg vapor pressure approx. 100 atm;), useful wavelenghts from 360÷600 nm, (broad emission), 4) low- and high pressure sodium lamps, useful wavelenghts 589 nm. Among the different typologies of photoreactors commercialized or homemade, the more used are: 1) Apparatus for external irradiation (the simplest case is an irradiated flask) or Raynet a or Immersion-well reactor b in which the lamp is surrounded by the reactions electric supply motor water outlet acqua

water inlet acqua

reflecting walls UV lamps photoreactors

Hg medium pressure bulb

cooling fan cooling walls

a

b

In all cases the lamp usually needs cooling to avoid its overheating and heating of the reaction solution. Low pressure mercury lamps are commercialized from 1 W to tens of Watts, medium and high pressure mercury lamps are commercialized from 125 up to 500W. Most lamps operate at high temperature (400÷700°C) and at high vapor pressure. Never move or touch lamps during operation. Never switch off the cooling system immediately after switching off the lamp.

Organic Photochemistry Technical and experimental aspects The material of the reactor depends on the necessary irradiation energy. For irradiation at 254 nm quartz glass (expensive apparatus) is needed. For irradiation at 300 nm pyrex glass is needed, and for irradiation > 350 nm normal lab glass (window glass) is sufficient. The glass acts as a solid filter. Additional solid or liquid optical filters may be used to restrict the irradiation wavelength.

Quartz and Pyrex transmittance, sample thickness 2mm

quartz

60

40 20 200

250

300 λ nm

350

400

trasmittance %

80

pyrex