Advances in the stereoselective synthesis of antifungal agents and ...

Chapter 2 362. Theoretical Discussion of Techniques.2.1 Synthesis of enantiopure alcohols by asymmetricreduction of prochiral ketones2.1.1.IntroductionThe reduction of carbonyl groups in aldehydes and ketones to thecorresponding alcohols is ubiquitous in organic synthesis. Since the firstreport of such a reduction by diborane more than half a century ago, metalhydride reagents have became of major importance as reagents of choicefor these synthetic transformations. The opportunities for variations in themetal, ligands, counterions and reaction conditions have helped toovercome most problems encountered regarding the stereo-, regio-orchemo-selectivity in these reactions.2.1.2. Stereoselectivity.The origin and magnitude of stereoselectivity observed in the reductionof chiral carbonyl compounds has long been an area of intense theoreticaland practical studies. Efforts have concentrated largely on the 1,2-asymmetric induction that occurs in the hydride addition to a carbonylgroup flanked by an asymmetric centre. Cram's rule was formulated torationalize the results of nucleophilic addition to aldehydes and ketonescontaning non polar groups 1 . The most stable conformation A ( Scheme2.1 ) was assumed to arise by minimization of the interaction between thelargest group R L and the carbonyl group which was coordinated to theapproaching reagent. Addition then occured preferentially from the side ofthe smallest substituent R S rather than the larger medium sized group R M .The outcome of the reduction of ketone A to alcohol B following Cram'srule is illustrated in Scheme 2.1. This rule enabled a large body ofexperimental results to be correlated, however its theoretical base wassubsequentely shown to be flawed.