Enantioselective acylation, hydrolases

The dynamic kinetic resolution (DKR) of secondary alcohols and amines (Scheme 11.11) is a prominent, industrially relevant, example of chemo-enzymatic chemistry in which a racemic mixture is converted into one enantiomer in essentially 100% yield and in high ee. This is in sharp contrast to enzyme-catalyzed kinetic resolutions that afford the desired end-product in a yield of at most 50%, while 50% of the starting material remains unreacted. In DKR processes, hydrolases are typically employed as the enantioselective acylation catalyst (which can be either R or S selective) while a concurrent racemization process racemizes the remaining substrate via an optically inactive intermediate. This ensures that all starting material is converted into the desired end-product. The importance of optically pure secondary alcohols and amines for the pharmaceutical industry triggered the development of a number of approaches that enable the racemization of sec-alcohols and amines via their corresponding ketones and imines, respectively [42],... 

A general procedure for enantioselective acylation of an alcohol with enol acetate or sucdnic anhydride is as follows. Dissolve 1 g of substrate alcohol in solvent (35 mL of hexane, toluene, or tetrahydrofuran) containing vinyl or iso-propenyl acetate (3 mL) and triethylamine (0.5 mL) (see following note). Add 0.5 g of hydrolase powder or immobilized hydrolase the enzyme powder will not dissolve Stir the suspension with a magnetic stirrer and monitor the progress of... 

In this context, van Rantwijk and Sheldon reported in the last decade some remarkable examples of the potential of serine hydrolase for the enantioselective acylation of amines [183]. Here, more recent reactions will be discussed starting with KR of primary and secondary racemic amines and a few examples of the desymmetrization of diamines, a reaction that has scarcely been exploited. Acylation reactions are quite selective transformations for the formation of the desired final optically active amines and amides however, in some cases, a sister reaction such as the alkoxycarbonylation process using a carbonate instead of an ester will be mentioned in order to present some advantages, especially for the resolution of secondary cyclic amines. 

Table 4.2 Hydrolase-catalyzed enantioselective resolution by acylation of alkylamines. Preferentially acylated enantiomers shown. In some cases E-values are based on calculations from the literature data. Adapted from Ref. [109]. ...

Hydrolase-catalyzed enantioselective N-acylation is an important tool for the preparation of enantiopure a- and P-aminoacids. It has been observed that the reactions of many amino acid esters with ester acyl donors catalyzed by CALB is sometimes complicated by interesterification reactions. CALA has, however, emerged as a very chemoselective catalyst in favor of N-acylation of P-aminoesters. Some reviews on CALA and other hydrolases as catalysts for N-acylations of aminoesters are available [109, 126, 127]. 

Because of the results with numerous prochiral diesters and diols, which have been subjected successfully to hydrolase-catalyzed enantioselective hydrolysis and acylation, respectively, and because of the desire to predict the sense of the asymmetric induction in the conversion of a new substrate, active-site or substrate models have been developed for the hydrolases pig liver esterase171 731, pig pancreas... 

Although with lipase-catalyzed acylations all types of selectivities including enantiotopic selectivity can be realized [29, 30, 60, 79, 81, 83], there are only a few examples of hydrolase-catalyzed enantioselective biotransformations in real flow-through mode (Figure 9.6). 

Such a process, which runs in water and is based on a palladium-catalyzed racemization of O-acylated allyUc alcohols in combination with a hydrolase-catalyzed enantioselective hydrolysis of the ester, was developed in an early pioneering work by Allen and Williams [11]. In this type of DKR process, the resulting allylic alcohols of type, for example, (S)-6, were obtained with satisfactory to high enan-tioselectivities (Scheme 19.3). For example, under these conditions, the hydrolysis of racemic ester rac-5 in the presence of a lipase from Pseudomonas Jluorescms gave... 

The ideal acyl donor would be inexpensive, acylate quickly and irreversibly in the presence of hydrolase, be completely unreactive in the absence of hydrolase and, for kinetic resolutions, yield a product that is easily separated from the starting material. No acyl donor fulfills all of these criteria. The irreversibility is important for enantioselective reactions because reversibility lowers the enantiomeric purity of the product [24]. 

This chapter deals with the use of hydrolases for enantioselective transformations of alcohols and amines, describing acylation reactions as synthetic challenges. Initially, general comments regarding the action and use of hydrolases in different media will be discussed. Special attention will be paid to the selection of reactants... 

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