Ketones enantioselective reduction with boronate

Reaction of achiral and chiral bis(oxazolines) (BOX) with catecholborane (CATBH) provides boron-BOXate complexes that can be used as catalysts in the enantioselective reduction of ketones. It has been shown that asymmetric transfer of the hydride ion from the boron atom of CATBH to the prochiral carbonyl is the rate-determining step of the catalytic reaction.314... 

The boron atom dominates the reactivity of the boracyclic compounds because of its inherent Lewis acidity. Consequently, there have been very few reports on the reactivity of substituents attached to the ring carbon atoms in the five-membered boronated cyclic systems. Singaram and co-workers developed a novel catalyst 31 based on dicarboxylic acid derivative of 1,3,2-dioxaborolane for the asymmetric reduction of prochiral ketones 32. This catalyst reduces a wide variety of ketones enantioselectively in the presence of a co-reductant such as LiBH4. The mechanism involves the coordination of ketone 32 with the chiral boronate 31 and the conjugation of borohydride with carboxylic acid to furnish the chiral borohydride complex 34. Subsequent transfer of hydride from the least hindered face of the ketone yields the corresponding alcohol 35 in high ee (Scheme 3) <20060PD949>. 

CBS reductions are best when the ketone s two substituents are well-differentiated sterically— just as Ph and Me are in the example above. Only when the ketone is complexed with the other boron atom (in the ring) is it electrophilic enough to be reduced by the weak hydride source. The hydride is delivered via a six-membered cyclic transition slate, with the enantioselectivity arising from the preference of the larger of the ketone s two substituents (RL) for the pseudoequatorial position on this ring. 

For aryl ketones the Corey-Bakshi-Shibata (CBS) reduction using oxazaborolidines as catalysts for the boron hydride mediated hydrogenation is particularly useful, with maximum selectivities up to 99 % ee (see Scheme 4) [34]. The excellent review by Corey et al. [35] also shows clearly the power for chemo- and enantioselective reduction of purely aliphatic a,//-enones and -ynones only on the carbonyl group. In the re-... 

Long-range mediation by achiral boronate (IJ-asymmetric induction) in ketone reduction by borane is feasible. Enantioselective reduction of imines with stoichiometric quantities of a cyclic dialkoxyborane prepared from tartaric acid has been reported. 

Another approach in the search for useful chiral reducing agents has been the derivatization of borane and boron hydrides [110, 111, 114]. Some of the most successful chiral reagents based on boron are those derived from the hydroboration of a-pinene, which is conveniently available in both enantiomeric forms (Scheme 2.22). Midland reported that the hydroboration product of a-pinene with 9-BBN, a reagent that subsequently came to be known as Alpine-Borane (179), is superb in the enantioselective reduction of aiyl alkynyl ketones [124]. He showcased the use of Alpine-Borane in the context of an enantioselective synthesis of Prelog-Djerassi lactone 181... 

A catalytic amount (5-20 mol %) of this reagent, along with additional BH3 as the reductant, can reduce ketones such as acetophenone and pinacolone in > 95% e.e. There are experimental data indicating that the steric demand of the boron substituent influences enantioselectivity. The enantioselectivity and reactivity of these catalysts can be modified by changes in substituent groups to optimize selectivity toward a particular ketone. 

The reducing ability of NHC-borane complexes was later expanded to the use of chiral NHC-borane complexes in the asymmetric reduction of ketones carried out by Lindsay and McArthur [89]. They used borane complexes of the NHCs shown in Figure 15.19 to reduce acetophenone to chiral 1-phenylethanol. Though initially enantioselectivities were lower than would be desired, they then tested the effect of substitution around the boron center. A bulkier NHC coupled with a smaller Lewis acid additive (Bp3.0Et2) led to a 90% yield and 56% enantiomeric excess (ee) for acetophenone, with variations on these yields and enantioselectivities depending on the ketone. 

High enantioselectivities are obtained using tartaric acid-derived boronate ester 31 in combination with lithium borohydride or sodium borohydride for asymmetric reduction of alkyl or aryl ketones. The chiral Lewis add is easUy prepared in one hour, and the resulting alcohols are obtained in enantiomeric excesses of 88-99% (Equation 46) [44]. 

Highly enantioselective boron-mediated reduction of prochiral ketones with the aminoborate ester derived from (S)-diphenyl prolinole. 

---