The Rational Design of Highly Stereoselective Boron Enolates Using Transition-State Computer Modeling: A Novel, Asymmetric Anti Aldol Reaction for Ketones

The design and development of highly enantioselective anti aldol reactions based on computer-aided transition-state modeling is reported. The new chiral boron ligand L = 6 was conceived based on its conformational preferences and on minimization of (±) double gauche pentane interactions. Modeling the transition structures for the aldol reaction of Z enolates 1 (L = 6) predicted a selectivity which is equal to or slightly lower than that calculated and experimentally tested with L = Ipc (isopinocampheyl) (see Table I). The predictions for E enol borinates (2) were synthetically more interesting: the new ligand (6) was calculated to be much more selective than Ipc (see Table II). Preparation of the boron reagent {[(Menth)CH2]2BCl-OEt2} (11) necessary for the synthesis of ligand 6-derived E enolates is reported, starting from commercially available enantiomerically pure (-)-menthone. Enolization of a range of cyclic and acyclic ketones {[(Menth)CH2]2BCl-OEt2, Et3N, 1:1 CH2Cl2-Et2O, -78°C} and addition of an aldehyde (-78°C) gave anti aldols with high diastereoselectivity (86:14 to 100:0 anti:syn) and in good enantiomeric excess (56-88% ee). These conditions ensured high stereoselectivity toward formation of the E enolate (2), which then reacted preferentially by attack on the re face of the aldehyde (re:si 3.5:1 Io 15.6:1). Also in the aldol reactions with methyl ketone enolates (3) the new reagent compared favorably with the existing methods.