Table of Contents

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Introduction

Part I: Basic Concepts at the Molecular Level

Chapter 1: Structure and Properties
1. 1.1 The Covalent Bond and the Octet Rule
2. 1.2 Representation of Chemical Structures
3. 1.3 Description of Chemical Structure
4. 1.4 Problems of Correlating Chemical Structure with Properties
5. References
Chapter 2: Concepts of Stereochemistry
1. 2.1 Elements and Groups of Symmetry
2. 2.2 Classification of the Basic Concepts of Stereochemistry
3. 2.3 Stereodescriptors
4. 2.4 Prostereogenic Elements, Prochirality
5. References
Problems to Chapters 1 and 2

Part II: Properties at the Level of Material Assemblies

Chapter 3: Timescale, Conformational Changes
1. 3.1 Conformational Motion of Ethane and Its Optical Inactivity
2. 3.2 Conformations and Optical Inactivity of n-Butane and 1,2-Dichloroethane
3. 3.3 Biphenyl and Substituted Biphenyls, Atropisomerism
4. References
Chapter 4: Absolute Configuration
1. 4.1 Methods to Determine Absolute Configuration 2
2. 4.2 Strategies to Determine Absolute Configuration by Chemical Correlation
3. References
Chapter 5: Methods for the Determination of Enantiomeric Composition
1. 5.1 Chiroptical Methods
2. 5.2 NMR Methods Based on Diastereotopicity
3. 5.3 Chromatographic and Related Methods Based on Diastereomeric Interactions
4. 5.4 Kinetic Methods Based on Enantiomer Selectivity
5. 5.5 Fusion Methods
6. 5.6 Methods Based on Isotope Dilution
7. 5.7 Potentiometric Methods
8. References
Chapter 6: Tautomerism
1. 6.1 Types of Tautomerism
2. 6.2 Prototropy
3. 6.3 Methods for Studying Tautomerism
4. 6.4 Nitrogen Inversion
5. References
Problems to Part II

Part III: General Characteristics of Stereoselective Reactions

Chapter 7: Types and Classification of Selectivities
1. 7.1 Main Types of Selectivity
2. 7.2 Classification of Selectivities
3. References
Chapter 8: Stereoselective and Stereospecific Reactions
1. 8.1 Stereospecificity
2. 8.2 Stereoselectivity
3. 8.3 Selective Syntheses of Enantiomers
4. 8.4 Diastereomer Selectivity
5. 8.5 Diastereotope Selectivity
6. 8.6 Enantiomer Selectivity
7. 8.7 Enantiotope Selectivity
8. 8.8 Combination of More Than One Type of Selectivity
9. References
Problems to Part III

Part IV: Applications of Enantioselective Methods

Chapter 9: Stoichiometric Methods of Enantioselective Synthesis
1. 9.1 Diastereotope Selective Methods
2. 9.2 Enantiotope Selective Methods
Chapter 10: Catalytic Methods of Enantioselective Synthesis
1. 10.1 Chemical Catalysis
2. 10.2 Biocatalysis
Index

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List of Illustrations

Chapter 1: Structure and Properties

Figure 1.1 Formation of the covalent bond of the hydrogen molecule.
Figure 1.2 Covalent bonds in some simple molecules (Lewis representation).
Figure 1.3 Representation of cycloalkanes by linear formulas.
Figure 1.4 Representation of open-chain compounds with linear formulas.
Figure 1.5 Various modes of representation for methanol, pyridine, and the antidepressant escitalopram.
Figure 1.6 Characterization of molecules consisting of two, three, and four atoms with internal coordinates.
Figure 1.7 Bond angles in selected triatomic molecules.
Figure 1.8 Kekulé formula and the bonding matrix of ethanol and dimethyl ether.
Figure 1.9 Kekulé formulas and the bond matrices of acetaldehyde and “vinyl alcohol.”
Figure 1.10 Number of molecules in a customary amount of various substances.
Figure 1.11 Properties of certain well-known compounds at the molecular level.
Figure 1.12 Structure of chlorocyclohexane.
Figure 1.13 Dipolar character of water and the hydrogen bond.

Chapter 2: Concepts of Stereochemistry

Figure 2.1 Examples of objects having axes of symmetry (C_n).
Figure 2.2 Examples of objects with a plane of symmetry σ.
Figure 2.3 Examples of objects having a center of symmetry i.
Figure 2.4 Examples of objects with an alternating axis of symmetry S_n.
Figure 2.5 Double potential energy minima. If E₀ < T, the first vibrational energy level is higher than the barrier separating the two energy minima [5].
Figure 2.6 Possible forms of isomerism.
Figure 2.7 Conformation, configuration, and various types of isomerism. The molecules shown all have the same molecular formula (C₆H₁₂). Molecules placed into a common box are either identical (≡) or exist as a set of conformations capable to interconversion ( $c02-math-0001$ ). (c.i.: constitutional isomers; D: diastereomers; and E: enantiomers).
Figure 2.8 Molecules related as stereoisomers owing to bonds of an order of less than one.
Figure 2.9 Significance of differentiation between an isomeric relationship (microscopic level) and isomerism (macroscopic level).
Figure 2.10 Possible intramolecular relationships of arrangements of groups of identical constitution.
Figure 2.11 Molecules containing homotopic atoms or groups.
Figure 2.12 Molecules with enantiotopic atoms or groups.
Figure 2.13 Molecules containing diastereotopic atoms or groups.
Figure 2.14 More than one type of topicity within the same molecule.
Figure 2.15 Possible modes of approach to a planar part of a molecule.
Figure 2.16 A molecule containing homotopic faces and addition of HCN to it.
Figure 2.17 Molecules containing enantiotopic faces.
Figure 2.18 Molecules containing diastereotopic faces.
Figure 2.19 Molecules containing stereogenic elements and new isomers derived therefrom.
Figure 2.20 Proposed absolute configuration of (+)-glyceraldehyde and the rules of Fischer's projection.
Figure 2.21 Rules to determine stereodescriptors according to the R/S system.
Figure 2.22 Stereogenic elements associated with central chirality.
Figure 2.23 Rules for the determination of the stereodescriptors for E/Z stereoisomers.
Figure 2.24 Basic types of axial chirality.
Figure 2.26 Propeller-like enantiomers.
Figure 2.25 Atropisomerism. Examples of the determination of the stereodescriptors M/P and R_a/S_a.
Figure 2.27 Enantiomers of hexahelicenes.
Figure 2.28 Molecules with a planar element of chirality.
Figure 2.29 Determination of the stereodescriptors for planar chirality.
Figure 2.30 Possible achiral precursors of (R)-lactic acid.
Figure 2.31 Stereoisomers of achiral compounds and prostereogenic centers.
Figure 2.32 pro-E/pro-Z Stereodescriptors.
Figure 2.33 pro-cis/pro-trans Stereodescriptors.
Figure 2.34 Molecules containing prostereogenic elements.
Figure 2.35 Assigning the stereodescriptors pro-R/pro-S.
Figure 2.36 Transformations of the pro-R/pro-S hydroxyl groups of glycerol.
Figure 2.37 Prochiral and meso compounds, center of pseudoasymmetry.
Figure 2.38 Some simple meso compounds.
Figure 2.39 Some compounds containing centers of pseudoasymmetry.
Figure 2.40 Prostereoisomerism resulting in a center of pseudoasymmetry.
Figure 2.41 Distinguishing stereoheterotopic (enantiotopic/diastereotopic) faces.
Figure 2.42 Assigning stereodescriptors to stereoheterotopic (enantiotopic/diastereotopic) faces.

Chapter 3: Timescale, Conformational Changes

Figure 3.1 Representation of ethane in Newman projection.
Figure 3.2 Conformations of ethane.
Figure 3.3 Conformations of n-butane.
Figure 3.4 Conformations of biphenyl.
Figure 3.5 Atropisomerism of o-substituted biphenyl derivatives.
Figure 3.6 Atropisomerism of compounds differing from biphenyls.

Chapter 4: Absolute Configuration

Figure 4.1 Configuration and optical rotation of glyceraldehyde enantiomers. Due to the lack of unambiguous methods to establish the relationship between (a) the microscopic (configuration) and (b) the macroscopic vectorial (e.g., optical rotation) properties until 1951, the absolute configuration of glyceraldehyde (c) was defined arbitrarily as d-(+)¹.
Figure 4.2 Absolute configuration of natural glucose. Note that an extended sense of configuration (i.e., the full assembly of four asymmetric units responsible for the chirality of the molecule) is related to the optical rotation to denote the absolute configuration.
Figure 4.3 Relative configuration within diastereomers.
Figure 4.4 Relative configuration between molecules of different constitution.
Figure 4.5 Correlation of the absolute configuration of lactic acid to d-(+)-glyceraldehyde.
Figure 4.6 The Wohl degradation of natural glucose to d-(+)-glyceraldehyde.
Figure 4.7 Correlation of the configuration of l-(+)-tartaric acid with glyceraldehyde.
Figure 4.8 Correlation of the configuration of glucose, mannose, and fructose by their common osazone.
Figure 4.9 Correlation of the configuration including reactions with inversion.

Chapter 5: Methods for the Determination of Enantiomeric Composition

Figure 5.1 Example of the application of a chiral derivatizing agent (e.g., using the well-separated methoxy signals in the ¹H NMR spectra).
Figure 5.2 Some chiral-derivatizing agents.
Figure 5.3 Application of a bidentate-derivatizing agent.
Figure 5.4 Reaction of 1-phenylethanol with PCl₃.
Figure 5.5 Use of chiral solvents (solvating agents).
Figure 5.6 Several chiral solvents (solvating agents).
Figure 5.7 Complexation with a chiral shift reagent.
Figure 5.8 Chromatographic separation on diastereoselective stationary phase (a: without or b: with chiral-derivatizing agent).
Figure 5.9 Principle of chromatographic separation on enantioselective (chiral) stationary phase.
Figure 5.10 Capacity and selectivity of chromatographic separation on CSPs.
Figure 5.11 Chromatographic separation on enantiomeric stationary phases.
Figure 5.12 Principle of enantiomeric recognition.
Figure 5.13 Structure of Chirasil-Val™ coating for gas chromatographic columns.
Figure 5.14 Whelk-O1-type CSP for liquid chromatography.
Figure 5.15 Shape-recognizing polymeric stationary phase.
Figure 5.16 Determination of the enantiomeric purity of (R)-lactic acid.
Figure 5.17 Determination of the enantiomer composition of amino acids by enzymatic method.
Figure 5.18 Kinetic resolution with mass-labeled carboxylic acids.
Figure 5.19 Examples of molecules used in kinetic resolutions.

Chapter 6: Tautomerism

Figure 6.1 Examples of isomerizations of various types.
Figure 6.2 Examples of valence tautomerism.
Figure 6.3 Valence tautomerism between two enol forms.
Figure 6.4 Examples of tautomeric equilibria involving migrating ligands other than protons.
Figure 6.5 Examples of simple oxo–enol tautomerism.
Figure 6.6 Examples of the formation of multiple enol forms from ketones.
Figure 6.7 Examples of the formation of degenerate tautomers from ketones.
Figure 6.8 Effect of structure on the equilibrium of oxo-enol tautomers.
Figure 6.9 Oxo–enol tautomers with β-dioxo compounds and β-oxo-esters.
Figure 6.10 Oxo–enol tautomers of nonsymmetrically substituted 1,3-diketones.
Figure 6.11 Imine–enamine tautomerism.
Figure 6.12 Amide–imido acid-, thioamide–imido thioacid-, urea–isourea-, and thiourea–isothiourea-type tautomerisms.
Figure 6.13 Amide–imido acid (Y = O), thioamide–imido thioacid (Y = S), and urea–isourea (Y = NH) type tautomerisms in cyclic compounds.
Figure 6.14 Tautomerism of nitro compounds.
Figure 6.15 Tautomerism of cyanic acid/isocyanic acid, thiocyanic acid/isothiocyanic acid.
Figure 6.16 Unsubstituted, N-monosubstituted, and N,N′-disubstituted carbodiimides and cyanamides.
Figure 6.17 Ring–chain tautomerism of hydroxyl–oxo compounds.
Figure 6.18 Ring–chain tautomerism of 2-formylbenzoic acid and thiosemicarbazones.
Figure 6.19 Inversion of amines containing a tetrahedral nitrogen atom.
Figure 6.20 Examples of restricted nitrogen inversion.
Figure 6.21 Stabilization of the configuration of the nitrogen atom by partial protonation.

Chapter 7: Types and Classification of Selectivities

Figure 7.1 Substrate-selective reactions.
Figure 7.2 Product-selective reactions.
Figure 7.3 Classification of selective reactions [2].
Figure 7.4 Chemoselective reductions.
Figure 7.5 Chemoselective reactions favoring the transformation of a single functional group among two or more available.
Figure 7.6 Avoiding further reaction of the product in a chemoselective reaction.
Figure 7.7 Different reactivity of ethyl propargylate in chemical- and enzyme-catalyzed reactions.
Figure 7.8 Chemoselective alternative protecting group elimination by alkaline hydrolysis and chymotrypsin, respectively.
Figure 7.9 Regioselective hydrolysis of sulfate esters with sulfatase enzyme.
Figure 7.10 Regioselectivity in enolate formation.
Figure 7.11 Kinetically controlled regioselectivity in a base-catalyzed enolization.
Figure 7.12 Thermodynamically controlled regioselectivity in acid-catalyzed Robinson anellation.
Figure 7.13 Regioselectivity between groups of identical constitution.
Figure 7.14 Regioselective hydrolysis with porcine liver carboxyl esterase (PLE) enzyme.
Figure 7.15 Regioselective enzymatic acylation in steroid synthesis.

Chapter 8: Stereoselective and Stereospecific Reactions

Figure 8.1 Stereospecific and stereoselective reactions.
Figure 8.2 Methods available for the preparation of pure enantiomers of a chiral compound.
Figure 8.3 Formation of the same product from a pair of diastereomers at different rates.
Figure 8.4 Formation of diastereomers at different rates starting from a mixture of diastereomers in a chemical (a) and a biocatalytic process (b).
Figure 8.5 Selective transformation of diastereomers to products of different constitution.
Figure 8.6 Diastereotope-selective transformation of a racemic substrate with (a) an achiral or (b) a chiral reagent (catalyst).
Figure 8.7 Diastereotope-selective reduction of a racemic ketone.
Figure 8.8 Changing enantiotopicity to diastereotopicity using a chiral auxiliary group.
Figure 8.9 Use of a recoverable chiral auxiliary group.
Figure 8.10 Use of a nonrecoverable chiral auxiliary group.
Figure 8.11 Enantiodivergent transformations using one enantiomer of the chiral auxiliary for the preparation of both enantiomers of the target compound.
Figure 8.12 Enantiomeric composition of the end product with or without diastereomer separation.
Figure 8.13 Enantiomeric composition of the product of a process with no diastereomer separation.
Figure 8.14 Enhancing the enantiomeric excess of (R)-1-(naphth-2-yl)ethanol by Horeau's method.
Figure 8.15 Upgrading enantiomeric excess by separating diastereomers formed with an achiral bidentate reagent (Horeau's method).
Figure 8.16 Crystallization-induced asymmetric transformation (CIAT) with diastereotope selectivity.
Figure 8.17 Crystallization-induced asymmetric transformation (CIAT) in the preparation of (S)-α-methyl-phenylalanine.
Figure 8.18 Selective biotransformations of diastereotopic methyl groups.
Figure 8.19 Diastereotope-selective addition using an aldolase enzyme.
Figure 8.20 Effects controlling selectivity in an aldolase-catalyzed addition.
Figure 8.21 An irreversible enantiomer-selective transformation (a) and enhancing the amount of the desired product by racemization of the unreacted enantiomer (b) or its transformation involving a configurational inversion (c).
Figure 8.23 Enantiomeric excess values of substrate (S) and product (P) in kinetic resolution under irreversible and reversible conditions.
Figure 8.22 Reversible and irreversible enantiomer-selective processes.
Figure 8.24 Enantiomeric excess (ee_S) of the unreacted substrate as a function of enantiomer selectivity (E) in kinetic resolution.
Figure 8.25 Kinetic resolution of racemic alcohols in chemical systems by acylation.
Figure 8.26 Parallel resolution of racemic 1-(naphth-1-yl)ethanol by acylation with quasi-enantiomeric chiral reagents.
Figure 8.27 Kinetic resolution of N-acyl-amino acids by hydrolysis with acylase-I.
Figure 8.28 Mechanism of action of serine hydrolases.
Figure 8.29 Reasons for the “irreversibility” of enzyme-catalyzed processes in aqueous media.
Figure 8.30 Possibilities to realize the “irreversibility” of hydrolase-catalyzed processes in nonaqueous media.
Figure 8.31 Kinetic resolutions by “opposite” reactions using the same catalyst.
Figure 8.32 Kinetic resolution of several racemic alcohols by lipase-catalyzed acylation (only the product of the fast reacting enantiomer is depicted).
Figure 8.33 Kinetic resolution of a racemic girochiral alcohol by HLADH-catalyzed oxidation.
Figure 8.34 Enantiomer and regioselective microbial Baeyer–Villiger oxidation of a bicyclic ketone.
Figure 8.35 The principle of dynamic kinetic resolution.
Figure 8.36 An enantiomer-selective hydrolysis with concurrent racemization (DKR) involving a single center of chirality (a) and epimerization of the remaining enantiomer in case of two centers of chirality (b).
Figure 8.37 Chemocatalytic dynamic kinetic resolution (DKR) by enantiomer-selective hydrogenation of an α,β-oxoester.
Figure 8.38 Utilization of dynamic kinetic resolution in the preparation of (S)-ketorolac.
Figure 8.39 Dynamic kinetic resolution by acid-catalyzed racemization.
Figure 8.40 Dynamic kinetic resolution with acid-catalyzed racemization.
Figure 8.41 Metal-catalyzed racemizations useful in dynamic kinetic resolutions.
Figure 8.42 Preparation of (R)-sulcatol acetate by DKR via ruthenium-catalyzed racemization.
Figure 8.43 Chemoenzymatic DKR by the Pd(II)-catalyzed racemization of allyl acetates.
Figure 8.44 Chemoenzymatic DKR using bromide ion-catalyzed racemization.
Figure 8.45 Manufacturing of l-lysine using purely biocatalytic dynamic kinetic resolution.
Figure 8.46 Principle of crystallization-induced dynamic resolution (CIDR).
Figure 8.47 A “pure” example of crystallization-induced solution dynamic kinetic resolution observed in the spontaneous resolution of narwedine.
Figure 8.48 Preparation of (R)-proline by crystallization-induced dynamic resolution.
Figure 8.49 Complete conversion of the unchanged substrate combining a biocatalytic kinetic resolution and a multistep inversion.
Figure 8.50 Complete conversion of a racemate by kinetic resolution using an epoxy-hydrolase (EH) followed by transformation of the substrate fraction in one step.
Figure 8.51 Selective transformation of enantiotopic faces (a) and groups (b) and enantiodivergent transformations of the products (c).
Figure 8.52 Selectivity (E) and enantiomeric excess of the product (ee_P1) in an irreversible enantiotope-selective process.
Figure 8.53 Alkylation of benzaldehyde catalyzed by (−)-DAIB (ee 15%) and interpretation of the nonlinear correlation of enantiomeric excess of catalyst and product.
Figure 8.54 Chiral molecules with C₂ symmetry used as catalysts or ligands in catalysts/reagents in enantiotope-selective reactions (most often both pure enantiomers are available).
Figure 8.55 Enantiotope-selective enzymatic oxidation of a prochiral diol.
Figure 8.56 Enantiotope-selective enzymatic hydrolysis of a meso-diester.
Figure 8.57 Ring opening of a prochiral epoxide with epoxy hydrolases of opposite enantiotope selectivity.
Figure 8.58 Transformation of enantiotopic faces by biocatalysis. Enantiotope-selective microbial oxidation of a prochiral sulfide.
Figure 8.59 Enantiotope-selective microbial reduction of a prochiral ketone.
Figure 8.60 Enzyme-catalyzed enantioselective addition of hydrogen cyanide onto benzaldehyde.
Figure 8.61 Microbial reduction with alternative enantiotope selectivity of prochiral E/Z double bonds.
Figure 8.62 Inversion of enantiotope selectivity using the same biocatalyst in a reaction of “opposite” direction.
Figure 8.63 “Inversion” of enantiotope selectivity in the preparation of cyclic monoacetate enantiomers.
Figure 8.64 Irreversible enantiotope-selective process involving further transformation of the product.
Figure 8.65 Kinetic amplification in the Sharpless epoxidation of a bis(allyl alcohol).
Figure 8.66 Kinetic amplification in the enantiotope-selective synthesis of atropisomers.
Figure 8.67 Enantiodivergent lactone formation from half esters obtained in selective reactions.
Figure 8.68 Simultaneous chemo- and enantiotope selectivity in the hydrolysis of a triester.
Figure 8.69 Diastereotope selectivity in the reduction of both enantiomers of a racemic ketone.
Figure 8.70 Simultaneous regio-, diastereotope, and enantiotope selectivities manifested in the reduction of a racemic triketone.

Chapter 9: Stoichiometric Methods of Enantioselective Synthesis

Figure 9.1 A stereospecific S_N2 reaction.
Figure 9.2 Stoichiometric stereoselective synthesis of negamycin.
Figure 9.3 Initial steps of the total synthesis of rifamycin. (New stereogenic elements formed in a diastereoselective way are highlighted.)
Figure 9.4 Stereoselective alkylations aided by (S)-prolinol as chiral auxiliary group. (New stereogenic elements formed in a diastereoselective manner are highlighted.)
Figure 9.5 Stereoselective alkylations using an auxiliary group derived from (S)-prolinol. (New stereogenic elements formed in a diastereoselective manner are highlighted.)
Figure 9.6 Stereoselective alkylation employing an enantiodivergent strategy. (The new stereogenic elements formed in a diastereoselective manner are highlighted.) In the insert, the favored transition state of alkylation is shown.
Figure 9.7 Stereoselective alkylation using a chiral auxiliary group of C₂ symmetry. (New stereogenic elements formed in a diastereoselective manner are highlighted.)
Figure 9.8 Stereoselective aldol reaction of a chiral aldehyde and an achiral enolate. (The stereogenic elements newly formed in a diastereoselective manner were highlighted.) In the insert, the favored transition states are depicted; the two components are drawn in different colors.
Figure 9.9 Stereoselective aldol reaction of an achiral aldehyde and a chiral enolate. (New stereogenic elements formed in a diastereoselective manner are highlighted.)
Figure 9.10 Stereoselective aldol reactions of chiral enolates with chiral aldehydes. The upper row shows a “matched pair” and the lower one a “mismatched pair.” New stereogenic elements formed in a diastereotope selective manner are highlighted.
Figure 9.11 Stereoselective reduction of an achiral ketone with a chiral aluminum-hydride reagent. The new stereogenic element formed in an enantiotope selective way is highlighted. (TS A) Favored transition complex. (TS B) Disfavored transition complex.

Chapter 10: Catalytic Methods of Enantioselective Synthesis

Figure 10.1 Preparation of a chiral rhodium complex catalyst.
Figure 10.2 Hydrogenation with a chiral rhodium complex catalyst. (L(PPh₂)₂ = a chiral bisphosphine ligand, S = solvent)).
Figure 10.3 Catalytic cycle of the saturation of a double bond catalyzed by a chiral rhodium–phosphine complex.
Figure 10.4 Enantiotope-selective reduction of ketones with a chiral ruthenium (S)-BINAP (60) complex catalyst. New stereogenic elements formed in a stereoselective way are highlighted. (S = solvent).
Figure 10.5 Enantiotope-selective reduction of ethyl acetoacetate (61) with a chiral ruthenium complex catalyst. The catalytic cycle.
Figure 10.6 Enantiotope-selective reduction of ethyl acetoacetate (61) with a chiral ruthenium complex catalyst. Symmetry relationships of the complexes.
Figure 10.7 Stereoselective reduction of ketones with the aid of a chiral catalyst having a pyrrolidino[1,2-c][1,3,2]oxazaborolane skeleton. The catalytic cycle. In the offset, steric interactions controlling stereoselectivity are shown.
Figure 10.8 Enantiotope-selective reduction of an aliphatic ketone (63) with a catalyst containing the chiral pyrrolidino[1,2-c][1,3,2]oxaborolane (CBS) skeleton (64). The individual components are drawn in different colors.
Figure 10.9 Enantiotope-selective reduction of unsaturated esters 69 and 70 with the aid of a chiral cobalt complex catalyst. New stereogenic elements formed in a stereoselective way are highlighted. In the bottom row, two tautomers (a and b) of the chiral ligand (73) are shown that can be interconverted by a C₂ symmetry operation.
Figure 10.10 Enantiotope-selective reduction of an aromatic ketone (75) with transfer hydrogenation effected by a chiral samarium catalyst (74). New stereogenic elements formed in a stereoselective way are highlighted.
Figure 10.11 Enantiomeric forms of the in situ prepared catalyst of Sharpless epoxidation. (Abbreviations: ethoxycarbonyl group, E = EtOOC, DET = diethyl tartrate.)
Figure 10.12 Enantiotope-selective epoxidation of a primary allylic alcohol (77) catalyzed by a chiral titanium complex. New stereogenic elements formed in a stereoselective way are highlighted.
Figure 10.13 Stereoselective epoxidation of a chiral allylic alcohol (80) catalyzed by a chiral titanium complex. The new stereogenic elements formed in a diastereoselective way are highlighted. Double asymmetric induction. Upper row: Without a chiral catalyst (substrate selectivity). Middle row: Opposite selectivity of substrate and catalyst (mismatched pair). Lower row: Cooperating substrate and chiral catalyst selectivity (matched pair).
Figure 10.14 Stereoselective epoxidation of a racemic secondary allylic alcohol catalyzed by a chiral titanium complex. The preferred enantiomers (green and red) and the new stereogenic elements formed in a diastereotope-selective mode (gray with achiral catalyst and purple with chiral catalyst) are highlighted. Upper row: Without chiral catalyst (only moderate diastereotope selectivity). Kinetic resolution: Middle row: In the catalytic system, the (S)-alcohol reacts faster and the (R)-alcohol remains unchanged. Bottom row: In the catalytic system, the (R)-alcohol reacts faster and the (S)-alcohol remains unchanged.
Figure 10.15 Stereoselective epoxidation of chiral secondary allylic alcohols (83) catalyzed by chiral titanium complexes. Newly formed stereogenic elements formed in a diastereotope-selective manner (purple for the fast reaction and gray for the slow reaction) and the conserved ones (green for the preferred enantiomer and dotted green for the less-reactive enantiomer) are highlighted. Upper row: Fast reaction (f), bottom row: slow reaction (s). Ratio of reaction rates: k_f/k_s = 104.
Figure 10.16 Structures of the Heme B prosthetic group of a cytochrome P-450 enzyme and of two enantiomeric salen–manganese complex catalysts. (In the figure, the oxidized forms of (S,S)- and (R,R)-[N,N′-bis(3,5-di-terc-butylsalicylidene)-1,2-cyclohexandiamino]manganese(III)-chloride catalyst are shown.)
Figure 10.17 Stereoselective oxidation of olefins (87, 89, and 91) catalyzed by a chiral manganese complex. Stereogenic elements generated in an enantioselective manner are highlighted.
Figure 10.18 Regio- and stereoselective reaction of epoxy alcohols (93) with azide ions as nucleophile with the aid of a titanium catalyst. Inverted (gray) and conserved (dotted box) stereogenic elements are highlighted.
Figure 10.19 Structures of chiral chromium and cobalt–salen complex catalysts. (Since the epoxy alcohols obtained by Sharpless epoxidation are chiral molecules, to achieve selectivity, there is no need for a chiral catalyst.)
Figure 10.20 Enantiotope-selective ring opening of a meso-epoxide catalyzed by a salen–chromium complex. The inverted stereogenic element is highlighted.
Figure 10.21 Stereoselective ring opening of a symmetrical epoxide catalyzed by a chiral salen–cobalt complex. The inverted stereogenic element is highlighted.
Figure 10.22 Enantiomer and regioselective reaction of a racemic terminal epoxide (105) catalyzed by the two enantiomers of a chiral salen–chromium complex. The reacting stereogenic element is highlighted. Kinetic resolution: Top row: the catalytic system transforms the (S)-epoxide, while the (R)-epoxide remains unchanged. Bottom row: The catalytic system transforms the (R)-epoxide, while the (S)-epoxide remains unchanged.
Figure 10.23 Chiral (DHQD)₂PHAL and (DHQ)₂PHAL ligands (Ligands shown in Figure 10.23 are commercially available under the name AD-mix-β and AD-mix-α as a mixture of the reagents {K₂CO₃, K₃[Fe(CN)₆]} and the precatalyst {K₂OsO₄*2(H₂O)}.) for stereoselective oxidations.
Figure 10.24 Enantiotope-selective oxidation of a terminal olefin (107) with a chiral osmium–tetroxide complex catalyst [(DHQD)₂PHAL]. The new stereogenic element formed in stereoselectivity is highlighted.
Figure 10.25 Enantiotope-selective oxidation of a trans-olefin catalyzed by the osmium-tetroxide complex of (S,S)-111. New stereogenic elements formed in a stereoselective manner are highlighted. In the bottom row, the complex from the chiral catalyst and the olefin is shown.
Figure 10.26 Catalytic cycle of the Heck reaction (L is a chiral ligand).
Figure 10.27 Enantiotope-selective Heck reaction of phenyl triflate (112) and 2,3-dihydrofuran (113) catalyzed by the chiral palladium complex of the oxazole 111. The new stereogenic element formed in a stereoselective way is highlighted.
Figure 10.28 Catalytic cycle of the Suzuki–Miyaura reaction (L: chiral ligand).
Figure 10.29 Stereoselective Suzuki–Miyaura reaction of 1-bromonaphthalene (116) and (2-methyl-naphthalinyl)-boronic acid (117) catalyzed by the chiral palladium complex (121) prepared from (S,S)-N-amino-2,5-diphenylpyrrolidine (120)and glyoxal (119). The newly formed stereogenic element (chiral axis) is highlighted.
Figure 10.30 Enantiotope-selective Michael addition of diethyl zinc (123) onto cyclohexanone (122) catalyzed by the chiral copper complex of the phosphorus amidite 124.
Figure 10.31 Enantiotope-selective Michael addition of diethyl malonate (128) onto 1,3-diphenylpropenone (127) catalyzed by the chiral ammonium salt 126.
Figure 10.32 Double-enantiotope selectivity in Michael addition of butanal (130) onto β-nitrostyrene (131) with the assistance of the chiral prolinamide-derived organocatalyst (133). New stereogenic elements formed in stereoselective manner are highlighted (de 98%, ee > 99%).
Figure 10.33 Stereoselective reaction of benzaldehyde (134) and diethyl zinc (123) catalyzed by titanium complex (137) of TADDOL (136). In the top row, preparation of the chiral TADDOL complex (137) is shown.
Figure 10.34 Structure of the reactive complex composed of benzaldehyde and the TADDOL – titanium complex (red, blue, and green, respectively). Left: top view of the complex; right: bottom view of the complex. Owing to the C₂ symmetry of the ligand, the two complexes are identical. Addition of the diethyl zinc nucleophile takes place at the proximal Si face of the aldehyde. The dimethyl-1,3-dioxolane ring of TADDOL at the distal side precluding for steric reasons the attack of the nucleophile from behind was omitted for reasons of clarity (Oⁱ = isopropoxy group).
Figure 10.35 Enantiotope-selective reaction of benzaldehyde and diethyl zinc catalyzed by (−)-exo-(dimethylamino)isoborneol (138).
Figure 10.36 Autocatalytic stereoselective reaction of 2-(3,3-dimethylbut-1-yn-1-yl)pyrimidine-5-carbaldehyde (140) and diisopropyl zinc (141). In the top row, formation of the zinc complex (143) responsible for the catalytic effect is shown.
Figure 10.37 Autocatalytic enantiotope-selective reaction of 2-(3,3-dimethylbut-1-yn-1-yl)pyrimidine-5-carbaldehyde (140) and diisopropyl zinc (141). Left: Enantiomeric excess of the individual experiments; right: accumulated optical yields of experiments.
Figure 10.38 Double-enantiotope-selective aldol reaction. New stereogenic elements formed in a stereoselective way are highlighted. In the offset box, the reactive complex (147) formed from S-ethylpropanethioate silyl enolether (144, pink), benzaldehyde (134, red), N-[(N-methylpyrrolidin-2-yl)methyl]naphthalene-1-amine (145, blue), tin (II)-triflate (green), and tributyltin fluoride (brown).
Figure 10.39 Regio-, diastereo-, and enantiotope-selective aldol reaction. New stereogenic elements formed in a double-enantiotopic-selective way are highlighted.
Figure 10.40 Diastereospecific and enantiotope-selective Simmons–Smith reaction. Newly formed stereogenic elements are highlighted. Top left: The in situ processes necessary for the generation of the zinc-organic compounds. Top offset: The structure of the reactive complex. The new bonds forming the cyclopropane ring are shown as heavy dashed lines.
Figure 10.41 Possible products of the Diels–Alder reaction of N-(E)-crotonoyl-oxazolidin-2-one (159) and cyclopentadiene (160): endo-adducts (161a and 161b) and exo-adducts (162a and 162b).
Figure 10.42 Preparation of the chiral aluminum catalyst (166) used for the Diels–Alder reaction of N-(E)-crotonoyl-oxazolidin-2-one (159) and cyclopentadiene (160).
Figure 10.43 Possible products of the Diels–Alder reaction of N-acryloyl-oxazolidin-2-one (167) and cyclopentadiene (160).
Figure 10.44 Chiral ligands (170 and 171) used for the catalysis of the Diels–Alder reaction of N-acriloyl-oxazolidin-2-one (167) and cyclopentadiene (160). Structure of the reactive complex.
Figure 10.45 Kinetic resolution of an N-acetylamino acid (174) with an l-aminoacylase.
Figure 10.46 Main types of enzyme-catalyzed kinetic resolution of esters.
Figure 10.47 Main types of the enzyme-catalyzed kinetic resolution of alcohols.
Figure 10.48 Kinetic resolution of 4-phenylbut-3-yn-2-ol (177) by esterification with vinyl acetate (178) catalyzed by Candida antarctica lipase B (CaLB).
Figure 10.49 Stereospecific aldol reaction of 4-(isobutiroylamino)benzaldehyde (180) with acetone (181) and the retro-aldol reaction of racemic 182 catalyzed by the catalytic antibody Ab38C2.
Figure 10.50 Kinetic resolution of 2-(but-3-enoyl)-4-(2-fluoro-2-methylpropyl)-4,5-dihydro-1,3-oxazol-5-one (183) catalyzed by lipase B from Candida antarctica (CaLB).
Figure 10.51 Dynamic kinetic resolution of 5-benzylhydantoin (186) with the aid of l- or d-hydantoinase and hydantoin racemase.
Figure 10.52 Schematic representation of the operation of oxidoreductases. Left: The reductive and oxidative reactions with the regeneration process of the coenzyme. Right: Stereochemical representation of hydride ion transfer for the majority of alcohol dehydrogenases: Prelog's rule.
Figure 10.53 Reductive amination of trimethylpyruvic acid (190) with leucine-dehydrogenase (LDH) combined with the regeneration reaction with a formate dehydrogenase (FDH). Right: Stereochemical representation of hydride transfer.
Figure 10.54 Regio-, diastereo-, and enantiotope-selective oxidation of bromobenzene using the microorganism Pseudomonas putida.
Figure 10.55 Enantiotope-selective oxidation of 4-isopropylcyclohexanone (194) with recombinant Saccharomyces cerevisiae containing the CHMO gene of Acinetobacter. Note that the similar oxidation reaction of 2-isopropylcyclohexanone (196) is regio- and enantiomer selective.
Figure 10.56 Enantiotope-selective preparation of (R)- and (S)-mandelic acid (198) with the aid of hydroxynitrile lyase (HNL) enzymes.
Figure 10.57 Enantiotope and diastereotope-selective preparation of KDN (201) catalyzed by the aldolase enzyme Neu5Ac aldolase.

List of Tables

Chapter 1: Structure and Properties

Table 1.1 Lewis and Kekulé formulas of some simple molecules
Table 1.2 Valence states of selected elements common in organic compounds
Table 1.3 Characteristic values of bond lengths commonly occurring in organic compounds

Chapter 2: Concepts of Stereochemistry

Table 2.1 Classification of some basic concepts of stereochemistry

Chapter 3: Timescale, Conformational Changes

Table 3.1 Relative populations of the conformational states A and B as a function of their Gibbs free energy difference ΔG
Table 3.2 Extended interpretation of the conformational states of n-butane

Chapter 5: Methods for the Determination of Enantiomeric Composition

Table 5.1 Methods for the determination of enantiomeric composition [1]
Table 5.2 Composition of a mixture obtained by applying a bidentate achiral-derivatizing agent

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Introduction

Nowadays, the development of molecular sciences brings about a revolutionary change of our world, life, and culture as once did the industrial revolution laying the foundations of our modern world. This molecular revolution, one of the milestones of which was the elucidation of the structure of the hitherto largest known natural compound, the human genome, extends in a dimension hitherto unheard of our knowledge of both ourselves and the universe. A key element of this molecular revolution is chemistry, and within it organic chemistry, contributing a lion's share in the twentieth and twenty-first centuries to the significant achievements of biology, medical, material, and environment sciences.

Similar to other sciences, organic chemistry plays a key role in our knowledge of the universe, and within chemistry a special place is allotted to the study of organic molecules. Apart from the potential of synthetic organic chemistry to construct molecules to be found in nature, it is capable to construct molecules not produced in nature.

A key problem of organic synthesis is selectivity, and within this domain stereoselectivity, a capacity to prepare selectively just one of the possible stereoisomeric structures. The importance of stereochemistry has been recognized in the very early period of organic chemistry: J. B. Biot observed in 1815 that certain organic compounds and their solutions rotate the plane of planar polarized light. L. Pasteur (1948) separated (resolved) the optically inactive tartaric acid to two optically active forms and made one of the most important hypotheses in stereochemistry, namely that the two forms are related as mirror images. J. A. LeBel and J. J. van't Hoff (1874) recognized the tetrahedral bond structure of carbon and that this structure enables, in the case of four different ligands, the existence of two nonidentical mirror image structures (enantiomers). H. E. Fischer after having identified and synthesized most of the 16 possible stereoisomeric forms of aldohexoses (1891) suggested a representation of three-dimensional structures in two dimensions, while M. A. Rosanoff (1905) proposed the conventional absolute configuration of d-(+)-glyceraldehyde.

Stereochemistry and stereoselective synthesis received a significant impetus in the middle of the past century when J. M. Bijvoet (1951) determined the actual absolute configuration of (+)-tartaric sodium rubidium salt with the aid of anomalous scattering in X-ray diffraction.

The relevance of stereochemical studies was recognized by awarding a series of Nobel Prizes. The foundation of modern stereochemistry was laid down in the monograph of M. S. Newman (1956). D. H. R. Barton and O. Hassel were awarded the Nobel Prize (1969) for conformational studies, while V. Prelog and J. W. Cornforth (1975) for analyzing the stereochemistry of enzyme-catalyzed reactions. Nobel-Prize-winning studies were carried out by D. J. Cram, J. M. Lehn, and C. J. Pedersen (1987) of selective interactions in supramolecular systems; W. S. Knowles, R. Noyori, and B. Sharpless (2001) for elaborating stereoselective synthetic methods.

The practical importance of stereochemistry is accentuated by the fact that nowadays almost exclusively enantiopure drugs can be registered and the inactive enantiomers are regarded as “contaminants.” It is therefore not surprising that manufacturing enantiopure compounds is a multibillion dollar business increasing about 10% per year. Accordingly, development of stereoselective methodology of manufacturing and analyzing pure enantiomers is becoming a central issue for the pharmaceutical, pesticide, cosmetic, and even of household chemical industry.

To write a textbook on any field of science is always challenging, especially about stereochemistry and stereoselective methodology, which is now in extremely fast development. The present work is intended to serve not only students of chemistry but also a wider circle of readers, namely to those whose main interest is outside stereochemistry or even organic chemistry, but who wish to have an overview about the problems, the scope, and potentials of this highly interesting field of chemistry. We hope to find among our potential readers biochemists, polymer chemists, pharmacologists, pharmacists, biologists, and workers in other branches of biosciences.

Stereochemistry and Stereoselective Synthesis

An Introduction

About the Companion Website

Introduction

Part I
Basic Concepts at the Molecular Level