DKR of sec-alcohols

The research groups of Williams [19] and Backvall [20] were the first to report the combination of enzymes and transition metals for DKR of sec-alcohols. 

Kim and Park subsequently reported that ruthenium precatalyst (2) racemizes alcohols svithin 30 minutes at room temperature [23]. However, when combined 

Kim and Park et al. have reported a polymer-supported derivative (4), which, together with the enzyme, can be recycled and reused [27]. 

Sheldon et al. have combined a KR catalyzed by CALB with a racemization catalyzed by a Ru(II) complex in combination with TEMPO (2,2,6,6-tetramethylpi-peridine 1-oxyl free radical) [28]. They proposed that racemization involved initial ruthenium-catalyzed oxidation of the alcohol to the corresponding ketone, with TEMPO acting as a stoichiometric oxidant. The ketone was then reduced to racemic alcohol by ruthenium hydrides, which were proposed to be formed under the reaction conditions. Under these conditions, they obtained 76% yield of enantiopure 1-phenylethanol acetate at 70° after 48 hours. 

Very recently the Meerwein-Ponndorf-Verley-Oppenauer (MPVO) reaction has been exploited for the racemization of alcohols using inexpensive aluminum-based catalysts. Combination of these complexes with a lipase (CALB) results in an efficient DKR of sec-alcohols at ambient temperature. To increase the reactivity of the aluminum complexes, a bidentate ligand, such as binol, is required. Also, specific acyl donors need to be used for each substrate [31] (Eigure 4.9). 

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Figure 4.9 DKR of sec-alcohols using a lipase and inexpensive Al complexes.

Figure 4.19 DKR of sec-alcohols catalyzed by acid zeolites and a lipase.

Scheme 5.23 DKR of sec-alcohols using CALB and Shvo s complex (1).

Naturally occurring Upases are (R)-selective for alcohols according to Kazlauskas rule [58, 59]. Thus, DKR of alcohols employing lipases can only be used to transform the racemic alcohol into the (R)-acetate. Serine proteases, a sub-class of hydrolases, are known to catalyze transesterifications similar to those catalyzed by lipases, but, interestingly, often with reversed enantioselectivity. Proteases are less thermostable enzymes, and for this reason only metal complexes that racemize secondary alcohols at ambient temperature can be employed for efficient (S)-selective DKR of sec-alcohols. Ruthenium complexes 2 and 3 have been combined with subtilisin Carlsberg, affording a method for the synthesis of... 

Fig. 8. 32 Chemoenzymatic DKR of sec-alcohols based on (transition) metal-catalyzed substrate racemization. Rm,Rl=medium or large substituents, respectively [M] = (transition) metal complex.

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