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

Chapter 2 38eclipsing the carbonyl group is energetically favored. This led Karabatsos topropose an alternative model 4 . Calculation suggested that the most favoredconformation G ( Scheme 2.4) would have the medium size group R M ofthe ketone G eclipsing the carbonyl group, and addition of the hydridewould occur from the side of the less bulky substituent R S to give thealcohol H ( Scheme 2.4 ).Rm ORm O H - RmRLRLH - Rs Rs R Karabatsos RLR RsG G HHOHRScheme 2.4: Reduction of ketones: Karabatsos model.A comparison of the other possible transition state with thisconformation allowed the magnitude of diasteroselectivity to be correlatedwith the experimental results.The most influential contribution towards the interpretation of 1,2asymmetric inductions in carbonyl group reductions was that of Felkin 5 .Attention was directed for the first time to the structure of the transitionstate, which was assumed to be very similar to that of the substrate.Torsional strain caused by interactions between the partially formedhydride-carbonyl bond and the full bonds at the adjacent centre wasassumed to cause attack perpendicular to the carbonyl group plane andstaggered to the largest or more electronegative group R L . The angle ofapproach was later revised by the Burgi-Dunitz trajectory 6a-c , derived fromcrystallographic studies. It placed the incoming hydride much closer to thesubstituent R S . This interaction was decisive for the selection of thistransition state over the alternative one, in which the position of the small R Sand the medium R M would be exchanged.Importantly and in agreement with the Felkin model, if two alkylsubstitutions are present, the more stable conformation has the larger groupperpendicular to the carbonyl group and points the remaining alkyl groupaway from the incoming nucleophile.2.1.2.1. Cyclic Carbonyl Compounds.