The CBS catalyst (S)-1 (CBS from its discovers: Corey, Bakshi and Shibata) is obtained from the reaction of amino alcohol (S)-2 and methylboronic acid with removal of water [JACS87-109-7925]. The B-methylated catalyst 1 is easier to isolate, gives higher ee values, and is more stable (it may be transferred in air) than the earlier B-H version (S)-3 [JACS87-109-5551]. Review = [Angew98-37-1986].
Ketone reduction reactions with (S)-1 as catalyst typically employ a 10 mol% loading with 0.6-1.0 eq. of BH3..THF as the reductant in THF at 0 oC or room temperature. A substoichiometric quantity of reductant BH3..THF may be used as up to two hydrogens are transferred. Reductant BH3..SMe2 may also be used. The reduction of acetophenone is representative (Scheme below). The secondary alcohol product is obtained after the addition of a proton source such as MeOH. To a good first approximation a simple mnemonic based on the relative size [RL = large (typically aryl), RS = small (typically alkyl)] of the ketone substituents predicts the configuration of the product alcohol. However it is not size operating through a disfavouring steric effect that principally controls enantioselectivity (see below).
The catalytic cycle involves the following steps: Step 1. Incorporation of BH3 = results in increased hydride donation ability and an increase in Lewis acidity of the catalyst boron. Step 2. Coordination of ketone substrate – activation as an electrophile. Step 3. Hydride transfer and asymmetric reduction. Step 4. Product release – regeneration of catalyst.
For step 3 calculations reveal a chair-like transition state structure with TS1 favoured over TS2, mainly as a result of a stabilising σ-π London dispersion interaction between the phenyl group of the substrate (C-H σ) and a phenyl group (π) of the catalyst [Angew21-60-4823]. The difference in diastereomeric transition states ΔΔG‡ = 8.4 kJ mol-1 (at 275 K) corresponds to an ee value of 95%, in excellent agreement with experiment. The polarizability per volume (α/v) of the R substituent of RCOMe increases in the order Et < n-Pr < t-Bu < Cy < Ph, and there is a reasonable correlation between α/v and ee. In a competition reduction experiment between t-BuCOMe and n-PrCOMe [with (S)-5 as catalyst, see below], in addition to the former resulting in a higher ee, it was also reduced at a faster rate. It was concluded that is a result of a stabilising LD interaction in the transition state for the reduction of the more sterically demanding substrate.
This interaction is increased where the catalyst phenyl group is replaced by a 3,5-dimethylphenyl or a 3,5-dimethylphenyl-4-methoxy group to give catalysts 4 and 5, and these can give significantly improved ee values with more challenging dialkylketone substrates.
With corresponding (R)-proline derived catalyst the corresponding diastereoisomer predominated with dr = 97 : 3 (i.e. essentially complete catalyst control). See TL94-35-6681.
74% ee with 5, 64% ee with 3. Reaction quenched with 0.5 M citric acid solution (7.5 eq.).
Catalyst Precursor Synthesis. Readily synthesised from proline [JOC91-56-751]
Precursor to 1 and 3
Aldrich (S) (R) Strem (S) (R) TCI (S) (R)
Precursor to 4