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Asymmetric Synthesis

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Asymmetric Synthesis Introduction Outline Introduction Principles Addition to carbonyl compounds -Substitution using chiral enolates Asymmetric aldol reactions ... – PowerPoint PPT presentation

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Title: Asymmetric Synthesis


1
Asymmetric Synthesis
  • Introduction

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

3
Vancomycin
4
Vancomycin models
5
Definitions
  • Stereospecific reaction
  • A 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.
  • Stereoselective reaction
  • A reaction in which one specific isomer is formed
    to a greater extent than any other.
  • Asymmetric synthesis
  • A synthesis in which the stereoisomers of a
    chiral molecule are formed in unequal quantities.

6
Stereodifferentiation
  • Enantiodifferentiating reaction
  • Differentiation is provided by the reagent or
    reaction environment, and refers to the reagents
    ability to differentiate between enantiofaces,
    enantiotopes, or enantiomers.
  • Diastereodifferentiating reaction
  • 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
  • Enantiomers possess different types of activity
  • Both are active, have different potencies
  • Both have similar activity
  • Both are active but type of activity is
    different.
  • Only one enantiomer is active, other is devoid of
    activity

8
Examples
  • Hypertensive agent L-Methyldopa
  • 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
  • only half may have beneficial result so the
    dosage must be increased to reach the therapeutic
    window
  • one enantiomer may have adverse effect when taken
  • To get pure enantiomers
  • Resolution of the racemate or intermediate in the
    synthetic route expensive introduces disposal
    of other enantiomer
  • Use 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
  • 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

11
Enantiomeric Transition States
Energy
Enantiomeric transition states
R
S
mirror
12
Diastereomeric Transition States
Energy
Diastereoisomeric transition states
R
S
13
Example
a
2
1
b
Diastereomeric excess (d.e.) (major
diastereomer() minor diastereomer ())

( a - b) 99-1 98
14
Use of Chiral Auxiliary
Join substrate and
Prochiral substrate
Prochiral substrate
Chiral auxiliary
Chiral auxiliary

Chiral auxiliary
React at prochiral substrate to produce chiral
center(s)
Cycle starts
Remove chiral
Chiral auxiliary
Modified substrate
Chiral auxiliary
Modified substrate

auxiliary and isolate modified substrate
15
Example of chiral auxiliary
Chiral auxiliary
16
Evans Auxiliary
(S)-Valine
17
Why does it work?
18
Requirements for Chiral Auxiliaries
  • Enantiomerically pure
  • Cheap and easy to obtain in quantity
  • Easy to attach to substrate
  • High and predictable control of stereoselectivity
  • Easy purification of diastereomers
  • Easy removal without loss of purity
  • 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
Catalyst-substrate
Prochiral substrate
Prochiral substrate
Chiral Catalyst
Chiral Catalyst

Complex forms
Reaction occurs Under the control Of chiral
catalyst
Another catalytic cycle starts
Modified substrate
Chiral Catalyst
Modified substrate
Chiral Catalyst
Modified substrate

decomplexes from catalyst
23
Example of chiral catalyst
24
Methods for asymmetric synthesis
  • Chiral reagent No manipulations required, but
    lacks generality.
  • Chiral solvent No practically useful procedures.
  • Chiral solvating agent As chiral reagent.
  • Chiral auxiliary Predictable, reliable,
    recycled.
  • 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 2002, 1-21
25
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