Enantioselective Evans-Tishchenko Reduction of β-Hydroxyketone Catalyzed by Lithium Binaphtholate

Lithium diphenylbinaphtholate catalyzed the enantioselective Evans-Tishchenko reduction of achiral β-hydroxyketones to afford monoacyl-protected 1,3-diols with high stereoselectivities. In the reaction of racemic β-hydroxyketones, kinetic optical resolution occurred in a highly stereoselective manner.


Optimization of Reaction Conditions
First we investigated the Evans-Tishchenko reduction of α,α-dimethyl-β-hydroxypropiophenone (2a) with benzaldehyde (3a) in THF at r.t. using lithium binaphtholate 1a, prepared in situ from binaphthol and BuLi, as a catalyst (Table 1, entry 1). The reaction gave the corresponding monobenzoyl 1,3-diol 4aa, but with low chemical yield (36%) and enantioselectivity (2% ee). Screening binaphthol derivatives revealed that introducing substituents to the 3,3'-positions of the catalyst dramatically increased both the chemical yield and enantioselectivity (entries 2-6). Among the various substituents surveyed, phenyl groups gave the best result (entry 4, 82% yield, 96% ee). Compared to THF, the use of ether or toluene as solvent gave unsatisfactory results (entries 7 and 8). Although lowering the reaction temperature increased the enantioselectivity (entry 9), the reaction did not proceeded smoothly at −78 °C (entry 10).

Evans-Tishchenko Reduction of Various Achiral β-Hydroxy ketones
With the optimum conditions in hand, we next examined the Evans-Tishchenko reduction of various β-hydroxyketones and aldehydes. The reaction of 2a with pivalaldehyde (3b) as a hydride source, which should afford pivaloyl ester, gave the corresponding product 4ab with the same absolute configuration as that with benzaldehyde in high yield at 0 °C, but was accompanied by the side product 5ab (5% yield), which was formed by transesterification of 4ab (Table 2, entry 2). The obtained enantioselectivity decreased to 90% ee, probably due to the higher reaction temperature (0 °C in entry 2 vs. −40 °C in entry 1). β-Hydroxyketone 2b, with cyclohexane at the α-position gave similar results as 2a with benzaldehyde (3a) or pivaldehyde (3b) (entries 3 and 4). Isopropyl ketone 2c gave the product 4ca in high enantioselectivity, but accompanied by 31% of the transesterification product 5ca (entry 5). Under the reaction conditions, either 4ca or 5ca was isomerized into a mixture of 4ca and 5ca (4ca:5ca = 2:1) without losing the enantioselectivity. The reaction of methyl ketone 2d and benzaldehyde (3a) gave excellent results, however, the products 4da and 5da (4da:5da = 2:1) were isolated as a single dibenzoyl ester 7da after benzoylation of the mixture of 4da and 5da (entry 6), because the monobenzoyl products 4da and 5da could not be separated.

Evans-Tishchenko Reduction of Chiral β-Hydroxypropiophenone
Using chiral β-hydroxyketones under the above conditions, a kinetic optical resolution occurred in a highly enantioselective manner (Scheme 2). The reaction of racemic α-methyl-β-hydroxyketone 8 and benzaldehyde (3a) at −45 °C for 24 h afforded monobenzoyl 1,3-diol 9 in 48% yield with 86% ee, and the unreacted starting material 8 was recovered in 42% yield with 88% ee. The stereochemistry of 9 was determined by the conversion to the stereochemically-known diol 10 [31] by debenzoylation with sodium methoxide in methanol. Scheme 3 explains the 1,2-syn stereochemistry using bicyclic transition model A for the reaction of 8 and benzaldehyde 3a. The α-methyl group preferred the equatorial position over the axial position, producing 1,2-syn product predominantly.

Reaction of An α-Unsubstituted-β-Hydroxypropiophenone
In the reaction of α-unsubstituted-β-hydroxypropiophenone 11, the Evans-Tishchenko product was not observed, but rather the monobenzoyl triol 12 was obtained in high yield with a high enantioselectivity (Scheme 4). Compound 12 may be formed by the transesterification of the aldol-Tishchenko adduct 13. It is interesting that the Evans-Tishchenko reduction proceeded exclusively in methyl ketone 2d, while β-hydroxypropiophenone (11) gave predominantly the aldol-Tishchenko adduct, although both hydroxyketones have enolizable positions. This may be because the Li-coordinated cyclic structure promoted the enolate formation or the approach of the aldehyde, though the detail is not clear. The absolute configuration of 12 was determined by conversion to stereochemically-known triol 14 [32].

Conclusions
We have demonstrated that lithium diphenylbinaphtholate catalyzes the enantioselective Evans-Tishchenko reduction of β-hydroxyketones, affording monoacyl-protected 1,3-diols in high stereoselectivities. In the reaction of racemic β-hydroxyketone, kinetic optical resolution occurs in a highly stereoselective manner. Further investigations to expand the substrate scope and to explore the reaction mechanism are currently underway.