Prochiral diacetates

In an asymmetric synthesis, the enantiomeric composition of the product remains constant as the reaction proceeds. In practice, ho vever, many enzymatic desymmetrizations undergo a subsequent kinetic resolution as illustrated in Figure 6.5. For instance, hydrolysis of a prochiral diacetate first gives the chiral monoalcohol monoester, but this product is also a substrate for the hydrolase, resulting in the production of... 

Also, desymmetrization of prochiral hydroxyalkylphosphine P-boranes was successfully performed using similar reagents and conditions. In the case of bis(hydroxymethyl)phenylphosphine P-borane 87, both its acetylation and hydrolysis of the diacetyl derivative 89 gave good results, although in addition to the expected monoacetate 88, the diol 87 and diacetate 89 were always present in the reaction mixture (Equation 42). °°... 

Immobilized PLE was applied to promote stereoselective acetylation of prochiral bis(hydroxymethyl)methyl-phenylgermane 106 (R = Me) with vinyl acetate as a solvent and acyl donor. Later on, the same group reported that each enantiomer of hydridogermane monoacetates 107 (R = H) was obtained either via acetylation of the bis-hydroxy derivative 106 (R = H) or hydrolysis of the corresponding diacetate 108 (R = H). In both methods, porcine pancreatic lipase was used and, obviously, each reaction led to a different enantiomer of 107 (Equation 51). ... 

CALB was again the favoured catalyst, selectively acetylating the pro-S alcohol (Scheme 1.47). To obtain the desired (5)-monoacetate in sufficient enantiopurity, the reaction was not terminated when all starting material had been consumed, but allowed to run a little further to transform a small portion of monoacetate to diacetate. This resulted in enantioenrichment of the desired (5")-monoacetate by the preferential acetylation of the unwanted (/f)-monoacetate to prochiral diacetate. 

Other similar lipase/esterase resolution processes have been developed such as the use of Bacillus that esterase to produce the substituted propanoic acids that are precursors of non-steroidal anti-inflammatory drags, snch as naproxen and ibuprofen etc., and the formation of chiral amines by Celgene. Other methods start from prochiral precursors and have the advantage that enantioselective synthesis allows the production of particular isomers in yields approaching 100%, rather than the 50% yields characteristic of resolution processes. For instance Hoechst have patented the production of enantiomers using Pseudomonas fluorescens lipase to either acylate diols or hydrolyse diacetate esters. 

Whereas preparation of a-amino acid derivatives by asymmetric allylation of an acyclic iminoglycinate gave a modest enantioselectivity (62% ee) in an early investigation [189], the use of conformationally constrained nucleophiles in an analogous alkylation resulted in high selectivities (Scheme 8E.43) [190], With 2-cyclohexenyl acetate, the alkylation of azlactones occurred with good diastereomeric ratios as well as excellent enantioselectivities. This method provides very facile access to a variety of a-alkylamino acids, which are difficult to synthesize by other methods. When a series of azlactones were alkylated with a prochiral gem-diacetate, excellent enantioselectivities were uniformly obtained for both the major and minor diastereom-ers (Eq. 8E.20 and Table 8E.12). 

An efficient synthesis of (R)- and (S)-1 -amino-2,2-difluorocycloropanecarboxylic acid (DFACC) 91 via lipase-catalyzed desymmetrization of prochiral diols 89 and prochiral diacetates 92 was recently reported.28 Thus, the lipase-catalyzed transesterification of 89 using vinyl acetate as acyl donor in benzene di-z-propyl ether (20 1) as organic solvent... 

Figure 46 Lipase-catalyzed desymmetrization of prochiral diols 89 and diacetates 92.28...

Enantiomerically pure derivatives of glycerol can be prepared in large quantities through the lipase (pig pancreas EC 3.1.1.3)-catalyzed hydrolysis of prochiral diacetate 28. The procedure gives (R)-29 (45% yield, 88% ee), which can be converted into the crystalline derivatives (7 )-30 or (5 )-30 (>99% ee) as shown in Scheme 13.21 [54]. 

Enzymatic resolution has been successfully applied to the preparation of optically active gem-difluorocyclopropanes (see Scheme 12.4). We succeeded in the first optical resolution of racemic gm-difluorocyclopropane diacetate, trans-43, through lipase-catalyzed enantiomer-specific hydrolysis to give (R,R)-(-)-44 with >99% ee (see equation 9, Scheme 12.4) [4a], We also applied lipase-catalyzed optical resolution to an efficient preparation of monoacetate cw-46 from prochiral diacetate m-45 (see equation 10, Scheme 12.4) [4a], Kirihara et al. reported the successful desymmetrization of diacetate 47 by lipase-catalyzed enantiomer-selective hydrolysis to afford monoacetate (R)-48, which was further transformed to enantiopure amino acid 15 (see equation 11, Scheme 12.4) [19]. We demonstrated that the lipase-catalyzed enantiomer-specific hydrolysis was useful for bis-gem-difluorocyclopropane 49. Thus, optically pure diacetate (R,S,S,R)-49 and (S,R,R,S)-diol 50, were obtained in good yields, while meso-49 was converted to the single monoacetate enantiomer (R,S,R,S)-51 via efficient desymmetrization (see equation 12, Scheme 12.4) [4b, 4e], Since these mono- and bis-gm-difluorocyclopropanes have two hydroxymethyl groups to modify, a variety of compounds can be prepared using them as building blocks [4, 22],... 

Selected prochiral and meso-substrates have been used with various esterases and lipases (Figure 2) and illustrate the wide variety of substrates that can be used with these enzymes. A complete listing of these types of substrates can be found in other sources [12,105,107,120,121]. It should be noted that the use of organic solvent can have a profound effect as to what product isomer is formed [127]. The use of porcine pancreatic lipase (PPL) to carry out an asymmetric hydrolysis of a meso-diacetate for the production of an intermediate in pheromone synthesis was recently reported [128]. Two specific examples are discussed here that used this approach directed at key chiral pharmaceutical intermediates. 

Table 11.1-3. Pig liver esterase-catalyzed enantiotopos-differentiating hydrolysis of prochiral cyclic diol diacetates in aqueous solution.

Table 11.1-7. a-Chymostrypsin-catalyzed enantiotopos-differentiating hydrolysis of prochiral cyclic dicarboxylic acid esters, acyclic dicarboxylic acid esters and cyclic diol diacetates and enantiomer-differentiating hydrolysis of racemic carboxylic acid esters in aqueous solution. 

Acetylcholine esterase-catalyzed hydrolyses have been reported only for a small number of prochiral diacetates (Table 11.1-8). However, several of secondary monoacetates, which are valuable synthetic building blocks, have been obtained with high enantioselectivity (2-6 and 11) by using this enzyme. Acetylcholine esterase should be considered for the hydrolysis of diacetates which are not substrates for lipases and pig liver esterase. 

Chiral ligand 651 is obtained from the appropriate natural amino-acid phenylalanine, whereas the corresponding derivatives of valine or leucine proved to be slightly less effective [46], Axially prochiral, enantiotopic, biaryl-2,6-diols have been converted to the respective chiral compounds via enzymatic desymmetrization. Thus Pseudomonas cepacia lipase (PCL) catalysed the atropisomerically-selective hydrolysis of diacetate 654 to give monoacetate 655 in 67% yield and 96% e. e. [47], Scheme 24. 

The azalactone 152 has been used as a prochiral nucleophile in a similar process providing the substitution product 153 and 154 upon reaction with either cyclohexenyl acetate 92 or the gem-diacetate... 

This chapter illustrates the application of lipases and esterases as user-friendly biocatalysts in (i) desymmetrization of prochiral or meso-diols and diacetates, (ii) kinetic resolution of racemic alcohols, and (iii) preparation of enantiopure intermediate(s) from a mixture of stereoisomers by enzymatic differentiation. All the examples were taken from our own works in natural products synthesis. 

Asymmetric hydrolysis of prochiral diacetate 17 with pig pancreatic lipase (PPL) yielded (R)-18 (Figure 24.9) [12]. This was converted to (S)-paraconic acid, purified as its amine salt, and eventually furnished A-factor, a microbial hormone. 

Asymmetric hydrolysis of prochiral diacetate 19 with lipase P (Amano) gave (R)-20 (Figure 24.10) [13]. Antibiotic 1233A was synthesized from (R)-20. 

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