2 Outline Introduction Principles Addition to carbonyl compounds α-Substitution using chiral enolatesAsymmetric aldol reactionsAdditions to C=C bondsReduction and oxidationRearrangementsHydrolysis and esterification
5 Definitions Stereospecific reaction Stereoselective reaction A reaction in which the configuration of the substrate influences the configuration of the product, orA reaction in which only a specific isomer reacts, in such a way that its configuration influences the configuration of the product.Stereoselective reactionA reaction in which one specific isomer is formed to a greater extent than any other.Asymmetric synthesisA synthesis in which the stereoisomers of a chiral molecule are formed in unequal quantities.
6 Stereodifferentiation Enantiodifferentiating reactionDifferentiation is provided by the reagent or reaction environment, and refers to the reagent’s ability to differentiate between enantiofaces, enantiotopes, or enantiomers.Diastereodifferentiating reactionReactions 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 activityBoth are active, have different potenciesBoth have similar activityBoth 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 mixtureonly half may have beneficial result so the dosage must be increased to reach the therapeutic windowone enantiomer may have adverse effect when takenTo get pure enantiomersResolution of the racemate or intermediate in the synthetic route – expensive & introduces disposal of other enantiomerUse of enantiomerically pure starting material – must be readily available
10 Asymmetric SynthesisAn 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 synthesisIn 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 usedChiral components could make the possible enantiomeric transition states diastereomeric, different energies
11 Enantiomeric Transition States EnergyEnantiomeric transition statesRSmirror
12 Diastereomeric Transition States EnergyDiastereoisomeric transition statesRS
13 Example Diastereomeric excess (d.e.) = (major diastereomer(%) 21bDiastereomeric excess (d.e.) = (major diastereomer(%)– minor diastereomer (%))= (% a - % b) = 99-1 = 98%
14 Use of Chiral Auxiliary ProchiralsubstrateJoin substrate andProchiralsubstrateChiralauxiliaryChiralauxiliary+Chiral auxiliaryReact at prochiralsubstrate to producechiral center(s)Cycle startsModifiedsubstrateChiralauxiliaryRemove chiralChiralauxiliaryModifiedsubstrate+auxiliary and isolatemodified substrate
18 Requirements for Chiral Auxiliaries Enantiomerically pureCheap and easy to obtain in quantityEasy to attach to substrateHigh and predictable control of stereoselectivityEasy purification of diastereomersEasy removal without loss of purityEasy separation and recovery
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 , 1-21