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Asymmetric Synthesis Introduction. Outline Introduction Introduction Principles Principles Addition to carbonyl compounds Addition to carbonyl compounds.

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Presentation on theme: "Asymmetric Synthesis Introduction. Outline Introduction Introduction Principles Principles Addition to carbonyl compounds Addition to carbonyl compounds."— Presentation transcript:

1 Asymmetric Synthesis Introduction

2 Outline Introduction Introduction Principles Principles Addition to carbonyl compounds Addition to carbonyl compounds α-Substitution using chiral enolates α-Substitution using chiral enolates Asymmetric aldol reactions Asymmetric aldol reactions Additions to C=C bonds Additions to C=C bonds Reduction and oxidation Reduction and oxidation Rearrangements Rearrangements Hydrolysis and esterification Hydrolysis and esterification

3 Vancomycin

4 Vancomycin models

5 Definitions Stereospecific reaction Stereospecific reaction A reaction in which the configuration of the substrate influences the configuration of the product, orA reaction in which the configuration of the substrate influences the configuration of the product, or A reaction in which only a specific isomer reacts, in such a way that its configuration influences the configuration of the product.A reaction in which only a specific isomer reacts, in such a way that its configuration influences the configuration of the product. Stereoselective reaction Stereoselective reaction A reaction in which one specific isomer is formed to a greater extent than any other.A reaction in which one specific isomer is formed to a greater extent than any other. Asymmetric synthesis Asymmetric synthesis A synthesis in which the stereoisomers of a chiral molecule are formed in unequal quantities.A synthesis in which the stereoisomers of a chiral molecule are formed in unequal quantities.

6 Stereodifferentiation Enantiodifferentiating reaction Enantiodifferentiating reaction Differentiation is provided by the reagent or reaction environment, and refers to the reagents ability to differentiate between enantiofaces, enantiotopes, or enantiomers.Differentiation is provided by the reagent or reaction environment, and refers to the reagents ability to differentiate between enantiofaces, enantiotopes, or enantiomers. Diastereodifferentiating reaction Diastereodifferentiating reaction Reactions are influenced by chirality in the substrate and form diastereomers in unequal quantities. May differentiate between diastereofaces, diastereotopes, or diastereomers.Reactions are influenced by chirality in the substrate and form diastereomers in unequal quantities. May differentiate between diastereofaces, diastereotopes, or diastereomers.

7 Introduction Biologically active molecules are also chiral Biologically active molecules are also chiral Enantiomers possess different types of activity Enantiomers possess different types of activity Both are active, have different potenciesBoth are active, have different potencies Both have similar activityBoth have similar activity Both are active but type of activity is different.Both are active but type of activity is different. Only one enantiomer is active, other is devoid of activityOnly one enantiomer is active, other is devoid of activity

8 Examples Hypertensive agent L- Methyldopa Hypertensive agent L- Methyldopa Propoxyphene – both enantiomers are biologically active. D isomer is an analgesic while L isomer has antitussive property Propoxyphene – both enantiomers are biologically active. D isomer is an analgesic while L isomer has antitussive property

9 Potential Problems of Enantiomers & their Solution In the racemic mixture In the racemic mixture only half may have beneficial result so the dosage must be increased to reach the therapeutic windowonly half may have beneficial result so the dosage must be increased to reach the therapeutic window one enantiomer may have adverse effect when takenone enantiomer may have adverse effect when taken To get pure enantiomers To get pure enantiomers Resolution of the racemate or intermediate in the synthetic route – expensive & introduces disposal of other enantiomerResolution of the racemate or intermediate in the synthetic route – expensive & introduces disposal of other enantiomer Use of enantiomerically pure starting material – must be readily availableUse of enantiomerically pure starting material – must be readily available

10 Asymmetric Synthesis An array of synthetic methods which result in the desired transformation and control the absolute stereochemistry of chiral centres created as a result of the synthetic operations is called asymmetric synthesis An array of synthetic methods which result in the desired transformation and control the absolute stereochemistry of chiral centres created as a result of the synthetic operations is called asymmetric synthesis In order to achieve asymmetric synthesis one or more components of the reaction must be chiral, or chiral auxiliaries (stoichiometric or catalytic amounts) or catalysts can be used In order to achieve asymmetric synthesis one or more components of the reaction must be chiral, or chiral auxiliaries (stoichiometric or catalytic amounts) or catalysts can be used Chiral components could make the possible enantiomeric transition states diastereomeric, different energies Chiral components could make the possible enantiomeric transition states diastereomeric, different energies

11 Enantiomeric Transition States Energy mirror Enantiomeric transition states RS

12 Diastereomeric Transition States Energy Diastereoisomeric transition states RS

13 Example a b Diastereomeric excess (d.e.) = (major diastereomer(%) – minor diastereomer (%)) = (% a - % b) = 99-1 = 98% 1 2

14 Use of Chiral Auxiliary Prochiral substrate + Chiral auxiliary Join substrate and Chiral auxiliary Prochiral substrate Chiral auxiliary Chiral auxiliary Remove chiral auxiliary and isolate modified substrate Modified substrate Modified substrate Chiral auxiliary + React at prochiral substrate to produce chiral center(s) Cycle starts

15 Example of chiral auxiliary Chiral auxiliary

16 Evans Auxiliary (S)-Valine

17 Why does it work?

18 Requirements for Chiral Auxiliaries Enantiomerically pure Enantiomerically pure Cheap and easy to obtain in quantity Cheap and easy to obtain in quantity Easy to attach to substrate Easy to attach to substrate High and predictable control of stereoselectivity High and predictable control of stereoselectivity Easy purification of diastereomers Easy purification of diastereomers Easy removal without loss of purity Easy removal without loss of purity Easy separation and recovery Easy separation and recovery

19 Two chiral components (1)

20 Two chiral components (2)

21 Two chiral components (3) Matched pair Mismatched pair Double asymmetric induction

22 Schematic Representation of Asymmetric Catalysis Prochiral substrate + Chiral Catalyst Catalyst-substrate Complex forms Prochiral substrate Chiral Catalyst Reaction occurs Under the control Of chiral catalyst Chiral Catalyst Modified substrate decomplexes from catalyst Modified substrate Modified substrate Chiral Catalyst + Another catalytic cycle starts

23 Example of chiral catalyst

24 Methods for asymmetric synthesis Chiral reagent: No manipulations required, but lacks generality. Chiral reagent: No manipulations required, but lacks generality. Chiral solvent: No practically useful procedures. Chiral solvent: No practically useful procedures. Chiral solvating agent: As chiral reagent. Chiral solvating agent: As chiral reagent. Chiral auxiliary: Predictable, reliable, recycled. Chiral auxiliary: Predictable, reliable, recycled. Chiral catalyst: Ideal, but few catalysts give high ee and accept wide substrate range, and enantiomer mixtures are obtained. Chiral catalyst: Ideal, but few catalysts give high ee and accept wide substrate range, and enantiomer mixtures are obtained. Update: Jones, J Chem Soc, Perkin , 1-21

25 Questions ?


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