Stereoselective Synthesis CHEM30411/31411/60101C Dr Nathan Owston Department of Chemistry nathan.owston@manchester.ac.uk Core 1 - Course Structure • Stereoselective Synthesis (Dr N. Owston) • Reactive Intermediates (Dr R. Whitehead) • Pericyclic Chemistry (Dr D. Leonori) CHEM30411/31411/60101C : Stereoselective Synthesis (Dr Nathan Owston) • Office 2.061 • Questions encouraged – I will address questions in subsequent lectures Course Textbooks • Organic Chemistry (Clayden, Greeves, Warren: OUP, 2012) Recap: Chapter 16 (Conformational Analysis) Chapter 32 Chapter 33 Chapter 41 • OUP Primer: Asymmetric Synthesis (G. Procter) – freely available through the library/bibliotech. Stereoselective Synthesis • Extends the fundamental concepts introduced in Y1 and Y2/previous lecture courses • Structure, Bonding and Reactivity • Conformational analysis • Stereochemistry • Steric Effects/Electronic Effects • Stereoelectronics (interplay between electronic structure and geometry) • Stereocontrol in Synthesis: Controlling the stereochemical outcome of reactions is of paramount importance when building complex molecular architectures. This course is primarily about the manipulation of molecules - often (but not always) by using reactions encountered previously and applying them to more complex molecular settings where stereochemical aspects need to be considered and addressed. In this course, we will primarily focus on the stereoselective synthesis of diastereoisomers and enantiomers. CHEM30411: Stereoselective Synthesis • Intended Learning Objectives - Apply knowledge of molecular structure, reactivity and stereochemistry to both rationalise and predict the stereochemical outcome of chemical reactions - Evaluate and propose strategies for the synthesis of complex molecules (diastereoisomers and enantiomers) which include stereoselective reactions. Recap: Stereochemistry • Stereoisomerism Enantiomers – stereoisomers that are mirror images of one another Diastereoisomers – stereoisomers that are not mirror images of one another • You should be familiar with the following concepts and terminology: - Chirality Stereogenic (chiral) centres Cahn-Ingold-Prelog (CIP) rules for describing configuration R and S E and Z cis and trans syn and anti* • Revision: CHEM20411 (Stereochemistry) * There is no single formal definition of syn and anti, but in this course these terms will be used to describe the stereochemical relationship of given substituents - 'anti' means 'on opposite sides' of a reference plane, in contrast to 'syn' which means 'on the same side' Convention: Representing/drawing single diastereoisomers • Starting material is racemic, therefore product must also be racemic. • Since the reaction is diastereoselective, we must show the relative stereochemistry • Chemist’s Convention: arbitrarily choose one enantiomer and draw that product 1. Stereoselective Reactions 1.1 - Stereospecific and Stereoselective Reactions Stereospecific reactions • Reactions which lead to the production of a single isomer as a direct result of the mechanism of the reaction and stereochemistry of the starting material • No “choice” of reaction pathways • Example – the SN2 reaction results in inversion of stereochemistry • E2 reactions are stereospecific (proceed through an antiperiplanar transition state) https://goldbook.iupac.org/terms/view/S05994 Stereospecific reactions • Different diastereoisomers lead to different products • Consider the E2 elimination reactions shown below: Stereospecific reactions • Different diastereoisomers lead to different products • Consider the E2 elimination reactions shown below: Stereospecific Reactions: Single diastereoisomers from alkenes • Electrophilic halogenation (CHEM10412) is stereospecific. • Provide a mechanism which accounts for the diastereoselectivity observed: Z • The stereochemistry of the starting material determines the relative stereochemistry of the product formed. Stereoselective reactions Stereoselective reactions • Reactions which give one predominant product stereoisomer because there is a “choice” of reaction pathways (and one is more favourable that the other(s)) - Pathway of lower ΔG‡ - kinetic control - More stable product is formed – thermodynamic control • Note: A stereospecific reaction is not simply a reaction that happens to be very stereoselective! Diastereoselectivity in bicyclic systems • Cyclic systems (by way of their defined conformational preferences) frequently undergo stereoselective reactions CHEM20412 • Fused and bridged bicyclic compounds often undergo stereoselective reactions (due to their (relative) conformational rigidity) Stereoselectivity in bridged bicyclic systems • Consider the reduction of the bridged bicyclic compounds below: • Make a model Diastereoselectivity in fused bicyclic systems • Predict the product of the epoxidation of the (rigid) cis-4,5-fused ring system below: • Predict the major product of the reaction shown above • Make a model of both the starting material and the product Diastereoselectivity in fused bicyclic systems • Predict the product of the epoxidation of the (rigid) cis-4,5-fused ring system below: 1.2 - Stereoselective Reactions: Cyclic Intermediates Stereochemical Control: Reactions with Cyclic Intermediates • Reaction of an alkene with iodine in the presence of a weak base (e.g. NaHCO3) • A useful reaction for the synthesis of cyclic molecules (note intramolecular nucleophile) I2, NaHCO3 • Reaction proceeds via a trans-iodonium ion cyclic intermediate, followed by stereospecific ring-opening to the anti- product • The stereochemistry of the alkene is reproduced in the product Stereochemical Control: Reactions with Cyclic Intermediates • Observed: reaction below yields only one diastereoisomer: Stereochemical Control: Reactions with Cyclic Intermediates • Observed: reaction below yields only one diastereoisomer: • The formation of the iodonium ion is reversible, but only the ion with I and the carboxylate trans- to each other can cyclize. • Key idea: Reactions with cyclic intermediates/transition states can (and often do) lead to high levels of stereochemical control 1.3 - Stereoselective Reactions: Cyclic Transition States Stereochemical Control: Cyclic Transition States • Consider the outcome of the two epoxidation reactions below: Stereochemical Control: Cyclic Transition States • Consider the outcome of the two epoxidation reactions below: • In the case of the acetate group, the anti- epoxide is formed (consider steric effects) Stereochemical Control: Cyclic Transition States • Consider the outcome of the two epoxidation reactions below: • In the case of the hydroxyl group, the syn- epoxide is formed (consider TS stabilisation) Allylic alcohol syn • Key idea: Cyclic transition states can reverse/change “expected” stereoselectivity Stereochemical Control: “Tethered” Reagents • Consider the outcome of the two epoxidation reactions below: Stereochemical Control: “Tethered” Reagents • Consider the outcome of the two epoxidation reactions below: • The vanadyl group chelates the epoxidation reagent and the alcohol to produce the synepoxide. • Key idea: Transient “tethering” of reagents can (and often does) lead to high levels of stereochemical control In summary…. • Stereospecific and Stereoselective Reactions: ILOs • Be able to draw accurate representations of molecules clearly showing stereochemical features. • Be confident in the use of stereochemical terms and use those words correctly to support your mechanistic and stereochemical explanations. • Describe and predict the stereochemical outcome of reactions on simple, fused and bridged cyclic systems. • Rationalise observed stereochemical outcomes where cyclic intermediates/transition states are part of the proposed reaction mechanism. 2. Diastereoselectivity in acyclic systems: reaction at C=O Diastereoselectivity in acyclic systems • In acyclic systems, diastereoselectivity is generally far less effectively controlled, due to increased conformational freedom (relative to cyclic systems) • Consider the reduction of the ketone below: • We may not expect to observe any (reasonable) diastereoselectivity here – “faces” are of (approximately) equal reactivity. Diastereoselectivity in acyclic systems • In acyclic systems, diastereoselectivity is generally far less effectively controlled, due to increased conformational freedom (relative to cyclic systems) • Consider the reduction of the ketone below: • We may not expect to observe any (reasonable) diastereoselectivity here – “faces” are of (approximately) equal reactivity. • Problem: How to make single diastereoisomers when faced with acyclic systems? But first, some concepts and convention 2.1 Prochirality and Topicity Prochirality • A prochiral* species is one that can be converted to a chiral species in a single step. • Consider the trigonal (sp2) centres below: prochiral not prochiral *IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997) http://goldbook.iupac.org/terms/view/P04859 Prochirality: Topicity • If reaction on one of the two prochiral faces leads to one of two enantiomers, these faces are described as enantiotopic • If reaction on one of the two prochiral faces leads to one of two diastereoisomers, these faces are described as diastereotopic • If an identical product is formed regardless of which face is attacked = homotopic Recall: Prochirality: Re and Si (recap) • Faces of a prochiral trigonal carbon atom are assigned Re- and Si- by viewing the carbon atom from that side and assigning to the groups priority 1-3 (using CIP convention). • Clockwise = Re; Anticlockwise = Si • Example: Prochirality • Tetrahedral centres can also be described as prochiral. • If a tetrahedral carbon atom bears two identical groups, and upon replacement of one of those groups it becomes a chiral centre, it can be described as prochiral. • Enantiotopic groups (as the H atoms above are) can be be assigned labels too! Prochirality • Tetrahedral centres can also be described as prochiral. • If a tetrahedral carbon atom bears two identical groups, and upon replacement of one of those groups it becomes a chiral centre, it can be described as prochiral. • Enantiotopic groups (as the H atoms above are) can be be assigned labels too! • pro-R and pro-S can be assigned to these groups by artificially (i.e. through a thought process) elevating one group to higher priority, then doing the usual CIP analysis. 2.2 Acyclic systems: The Felkin-Anh Model Acyclic systems: Diastereoselective reactions • Observed: Addition of a Grignard reagent to the α-chiral aldehyde below is moderately diastereoselective. 3:1 ratio (Convention: product is typically drawn with the longest carbon chain “zig-zagging”) Acyclic systems: Diastereoselective reactions • Observed: Addition of a Grignard reagent to the α-chiral aldehyde below is moderately diastereoselective. 3:1 ratio (Convention: product is typically drawn with the longest carbon chain “zig-zagging”) • What gives rise to this observed selectivity? Conformation is key • Consider the conformation of the α-chiral aldehyde • Guiding principles for low-energy conformers: staggered bonds (no eclipsing interactions) and large groups as far apart from each other as possible. CHEM10101 CHEM20412 • Consider six possible staggered conformations (60° rotations) Make a model • What gives rise to this observed selectivity? Conformation is key • Consider the conformation of the α-chiral aldehyde • Guiding principles for low-energy conformers: staggered bonds (no eclipsing interactions) and large groups as far apart from each other as possible. • Consider six possible staggered conformations (60° rotations) • Examine the conformers that have the largest group (Ph) perpendicular to C=O and H Conformation is key • Consider the conformation of the α-chiral aldehyde • Guiding principles for low-energy conformers: staggered bonds (no eclipsing interactions) and large groups as far apart from each other as possible. • Consider six possible staggered conformations (60° rotations) • Examine the conformers that have the largest group (Ph) perpendicular to C=O and H • Now, the nucleophile… π* C=O (LUMO) viewed from side A long time ago… (Structure and Reactivity: CHEM10101) Nucleophilic attack at C=O Angle of attack 107° (Burgi-Dunitz angle) • Csp2 ---> Csp3 Conformation is key • Which conformer is the most reactive with respect to an attacking nucleophile? • Consider the trajectory of attack at C=O • Four possible approaches Make a model Felkin-Anh model Conformation is key • Which conformer is the most reactive with respect to an attacking nucleophile? • Consider the trajectory of attack at C=O • Four possible approaches Felkin-Anh model Conformation is key • Which conformer is the most reactive with respect to an attacking nucleophile? • Consider the trajectory of attack at C=O • Four possible approaches Felkin-Anh model • The least hindered approach sees the nucleophile in relatively close proximity to only H Conformation is key • Which conformer is the most reactive with respect to an attacking nucleophile? • Consider the trajectory of attack at C=O • Four possible approaches Felkin-Anh model • The least hindered approach sees the nucleophile in relatively close proximity to only H syn 2.3: Electronegative Atoms and Chelation Electronegative atoms • Consider: the aldol reaction shown below is highly diastereoselective • Use the Felkin-Anh model Electronegative atoms • Consider: the aldol reaction shown below is highly diastereoselective • Use the Felkin-Anh model • Why is this example so diastereoselective? Electronegative atoms: stereoelectronics • Consider orbital overlap of C=O with the C-X (X = NBn2) on the adjacent carbon Electronegative atoms: stereoelectronics • Consider orbital overlap of C=O with the C-X (X = NBn2) on the adjacent carbon • Enhanced reactivity of C=O towards nucleophiles (in this case, addition) • C=O and C-X must be perpendicular • Most reactive conformations of the electrophile have NBn2 perpendicular Stereoelectronics + sterics! • General rule: when heteroatoms are present at the α-chiral centre, consider only conformations where the most the most electronegative atom is perpendicular to C=O Chelation • Observed: The reduction below is highly diastereoselective: • This is not the product predicted by the Felkin-Ahn model • The diastereoselectivity in this case can be rationalised by considering chelation Chelation • Observed: The reduction below is highly diastereoselective: • This is not the product predicted by the Felkin-Ahn model • The diastereoselectivity in this case can be rationalised by considering chelation rotate Et Et Et Et Make a model • Chelation stabilises this conformation, and the Lewis acidity of the metal ion increases the reactivity of C=O towards nucleophiles. Nucleophilic attack on α-chiral carbonyl compounds In summary…. • Diastereoselectivity in acyclic systems: Reaction at C=O – ILOs You should be able to: • Identify prochiral molecules, and assign prochiral trigonal centres as Re and Si and atoms/groups as pro-R and pro-S • Identify enantiotopic, diastereotopic and homotopic groups and faces • Use the Felkin-Anh model to explain and predict the outcome of nucleophilic attack at C=O for chiral carbonyl compounds. • Rationalise that chelation can have a marked effect on diastereoselectivity 3. Diastereoselectivity in acyclic systems: reaction at C=C 3.1: Acyclic alkenes: The Houk Model Stereoselectivity in acyclic systems: Alkenes • Alkenes can also have diastereotopic faces (see cyclic examples previously) • Observed: the reduction of the acyclic alkene below occurs with high diastereoselectivity Major >95% • The chiral alkene above has diastereotopic faces – why is one face more susceptible to attack? Conformation of alkenes: Allylic strain • Conformers of alkenes: Houk model • This alkene has two low energy conformers • With cis- alkenes, there is only one low energy conformer. Make a model • This is termed allylic or A1,3 strain Conformation of alkenes: Allylic strain • Conformers of alkenes: Houk model • This alkene has two low energy conformers • With cis- alkenes, there is only one low energy conformer. • This is termed allylic or A1,3 strain Stereoselectivity in acyclic systems: Alkenes • Epoxidation occurs at the less hindered face (as expected) • With the analogous trans-alkene, selectivity is much lower 6:4 ratio Make a model 3.2. Enolates and Stereoselective Aldol Stereoselectivity in acyclic systems: Enolates • A similar analysis can be used to rationalise the reactivity of some enolates R = Ph R = SiMe2Ph 83:27 95:5 • The enolate in this case can be considered analogous to a cis-substituted alkene • Consider the conformation with H eclipsing the double bond (as before). Alkylation occurs at the less-hindered face. Stereoselective Aldol • The aldol reaction is one of the most important C-C bond forming reactions • Mechanism: • Substituted enolates lead to diastereomeric products • Consider stereochemistry* of the enolate *In this case, cis- and trans- refer to the stereochemical relationship of the anionic oxygen atom and the substituent CHEM20411 CHEM22600 Stereoselective Aldol • Some enolates have no “choice” • Often (but not always!) cis-enolates = syn products preferentially trans-enolates = anti products preferentially Stereoselective Aldol • Importance of cyclic transition state (again!) 6-membered ring – “chair-like” TS • Consider approach of electrophile: • In this case, the trans-enolate means that the Me group is the pseudoequatorial position. • The favoured transition state structure has the R group of the aldehyde in the favoured pseudoequatorial position Stereoselective Aldol • Reaction of a trans-lithium enolate with an aldehyde • Can perform the same analysis for the cis-lithium enolate Make models Stereoselective Enolization • What controls the geometry of the enolate? • For lithium enolates, size is an important factor • Generally, as the steric demand of R decreases, diastereoselectivity decreases. In summary…. • Diastereoselectivity in acyclic systems: Reaction at C=C – ILOs You should be able to: • Describe and explain the origin of allylic strain in substituted alkenes • Use the Houk model to explain and predict the outcome of attack at C=C for substituted alkenes and enolates. • Rationalise and predict the outcome of diastereoselective aldol reactions by consideration of enolate geometry and the nature of the transition state in these reactions. 4. Molecules in Chiral Environments: Asymmetric Synthesis Molecules in Chiral Environments • Enantiomers behave identically unless they find themselves in a chiral environment • Consequently, two enantiomers of any chiral molecule will always interact with living systems in different ways • Odour receptors can detect enantiomeric differences: • There is an increasing demand for single enantiomer pharmaceuticals, agrochemicals and other fine chemicals (regulation, safety) • >80% of all new drugs currently entering the market are single enantiomers. • Asymmetric synthesis, the synthesis of single enantiomers, is essential. “The nose as a stereochemist” Chemical Reviews 2006, 4099 Chiral Pharmaceuticals Naproxen: anti-inflammatory (NSAID) (S) is 20 times as active as (R) Marketed as (S) Citalopram: selective serotonin reuptake inhibitor (SSRI) (S) is 100 times as active as (R) Marketed as (S) Ibuprofen: anti-inflammatory (NSAID) Racemises in vivo Marketed as (±) (+)-Darvon Painkiller (–)-Darvon Cough suppressant 4.1 Synthesis of Single Enantiomers: The Chiral Pool and Resolution The Chiral Pool: Chirality from Nature • Chiral Pool: A collection of naturally occurring enantiomerically pure compounds that can be used as starting materials for organic synthesis • Chiral Pool Strategy: Incorporation of part or all of one of these compounds into a target molecule. • Principal groups of compounds in the pool: Amino Acids The Chiral Pool: Chirality from Nature • Amino acid derivatives are also useful building blocks Amino alcohols α-hydroxy acids + H+ - H+ • Note 2 x inversion = retention of configuration recall NGP, CHEM20412 • Other α-hydroxy acids are available from natural sources The Chiral Pool: Chirality from Nature • Carbohydrates (and their derivatives) are also a rich source of starting compounds CHEM20412 • Other useful building blocks can be derived from natural sources, e.g. microbial fermentation to yield (S)-lactic acid • A main drawback of the chiral pool strategy is that often only one enantiomer is freely available (cost/rarity). • Another is the relatively small number of motifs which can be used as starting materials, (leading to long syntheses) Resolution CHEM10101 CHEM10600 • Single enantiomers can be produced by resolution of racemic mixtures • B = enantiomerically pure resolving agent • Recall that diastereoisomers have different chemical/physical properties, and can often be (but not always) easily separated. Resolution • A common approach: • In this case one diastereoisomer crystallises preferentially, while the other remains in solution. • Separation of diastereoisomers by chromatography is also common • This has a considerable advantage over the chiral pool – i.e. that both enantiomers are equally available (in theory) 4.2 Synthesis of Single Enantiomers: Chiral Auxiliaries Chiral Auxiliaries • Chiral Auxiliary: An enantiomerically pure molecule which can be attached to a starting material in order to facilitate a diastereoselective reaction Oppolzer Myers Evans Strategy 1. Attach (covalently) the auxiliary to the starting material 2. Carry out a diastereoselective reaction (because the starting material is now enantiomerically pure, only one enantiomer of the product(s) will be produced) 3. Remove the auxiliary (through another chemical process), leaving an enantiomerically enriched product. (Recover/recycle the auxiliary if possible) Chiral Auxiliaries: Alkylation of Enolates • Evans oxazolidinone auxiliaries can be synthesised from amino acids (and related compounds) • Evans oxazolidinone auxiliaries have been employed extensively in enolate chemistry • Example: Stereoselective alkylation of enolates Cis • Note the bulky auxiliary results in the cis-enolate being formed selectively Trans Chiral Auxiliaries: Alkylation of Enolates • Coordination of lithium and the steric demand of the isopropyl group direct the alkylation to the less hindered face of the enolate, resulting in high levels of diastereoselectivity. • The highest levels of diastereoselectivity are (perhaps unsurprisingly) observed for sterically demanding electrophiles. Major • It follows that a 94:6 ratio of diastereoisomers will result in a 94:6 ratio of enantiomers (The diastereomeric ratio (d.r.) can typically be increased by e.g. recrystallization/chromatography) Chiral Auxiliaries: Removing the Auxiliary • The oxazolidinone auxiliary can be removed by reduction 94:6 d.r. 94:6 e.r. 88% ee • Or, the auxiliary can be converted to different derivatives by judicious selection of reaction conditions R’MgBr In summary…. • Molecules in Chiral Environments: Asymmetric Synthesis - ILOs You should be able to: • Describe and explain the concept of the chiral pool and chiral pool strategy • Identify simple target molecules which can derived from chiral pool compounds and their derivatives, and propose methods for their synthesis. • Explain how resolution can be used to produce enantiomerically enriched/pure compounds from racemic mixtures. • Rationalise and predict the outcome of diastereoselective reactions controlled by chiral auxiliaries through consideration of molecular shape/geometry • Provide a mechanistic and stereochemical rationale for the stereoselectivity observed in auxiliary-controlled reactions of enolates. • Propose methods for removing auxiliaries as part of synthetic sequences.
