Prochiral acylated diols

Only a very few acyclic prochiral acylated diols have been subjected with moderate success to pig liver esterase-catalyzed hydrolysis with formation of the corresponding chiral monoacetates (1-3) (Table 11.1-4). For this kind of compounds, lipases are the hydrolases of choice. 

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. 

Table 11.1-17. Lipase-catalyzed enantiotopos-differentiating acylation of prochiral acyclic diols in organic solvents (CCL Candida cylindracea lipase, PFL Pseudomonas fluorescens lipase, PPL pig pancreas lipase, CVL Chromobacterium viscosum lipase, PSL Pseudomonas sp. lipase, RJL Rhizomucorjavanicus lipase, ANL Aspergillus niger lipase, CAL Candida antarctica lipase, not specified, PCL Pseudomonas cepacia lipase, CRL Candida rugosa lipase).

Mono cylDiols. Enzymatic synthesis of chiral monoacyl diols can be carried out either by direct enzymatic acylation of prochiral diols or by hydrolysis of chemically synthesized dicarboxylates. 

A number of examples of monoacylated diols produced by enzymatic hydrolysis of prochiral carboxylates are presented in Table 3. PLE-catalyzed conversions of acycHc diesters strongly depend on the stmcture of the substituent and are usually poor for alkyl derivatives. Lipases are much less sensitive to the stmcture of the side chain the yields and selectivity of the hydrolysis of both alkyl (26) and aryl (24) derivatives are similar. The enzyme selectivity depends not only on the stmcture of the alcohol, but also on the nature of the acyl moiety (48). 

In contrast to the hydrolysis of prochiral esters performed in aqueous solutions, the enzymatic acylation of prochiral diols is usually carried out in an inert organic solvent such as hexane, ether, toluene, or ethyl acetate. In order to increase the reaction rate and the degree of conversion, activated esters such as vinyl carboxylates are often used as acylating agents. The vinyl alcohol formed as a result of transesterification tautomerizes to acetaldehyde, making the reaction practically irreversible. The presence of a bulky substituent in the 2-position helps the enzyme to discriminate between enantiotopic faces as a result the enzymatic acylation of prochiral 2-benzoxy-l,3-propanediol (34) proceeds with excellent selectivity (ee > 96%) (49). In the case of the 2-methyl substituted diol (33) the selectivity is only moderate (50). 

Enzymatic desymmetrization of prochiral or meso-alcohols to yield enantiopure building blocks is a powerful tool in the synthesis of natural products. For example, a synthesis ofconagenin, an immunomodulator isolated from a Streptomyces, involved two enzymatic desymmetrizations [149]. The syn-syn triad of the add moiety was prepared via a stereoselective acylation of a meso-diol, whereas the amine fragment was obtained by the PLE-catalyzed hydrolysis of a prochiral malonate (Figure 6.56). 

Prochiral diols -enzymatic acylation [ENZYMES IN ORGANIC SYNTHESIS] (Vol 9)... 

This chapter covers the kinetic resolution of racemic alcohols by formation of esters and the kinetic resolution of racemic amines by formation of amides [1]. The desymmetrization of meso diols is discussed in Section 13.3. The acyl donors employed are usually either acid chlorides or acid anhydrides. In principle, acylation reactions of this type are equally suitable for resolving or desymmetrizing the acyl donor (e.g. a meso-anhydride or a prochiral ketene). Transformations of the latter type are discussed in Section 13.1, Desymmetrization and Kinetic Resolution of Cyclic Anhydrides, and Section 13.2, Additions to Prochiral Ketenes. 

Additions to prochiral ketenes [13.2] Desymmetrization of meso-diols [13.3] Dynamic kinetic resolution of azlactones rearrangement of O-acyl azlactones, O-acyl oxindoles, O-acyl benzofuranones [13.6]... 

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... 

Dodds and colleagues at Schering-Plough described the acylation of a prochiral diol 38 on the synthetic route to a potential antifungal drug, SCH 51048 (39) (Scheme 19.22). Numerous commercial... 

Prochiral Compounds. The enantiodifferentiation of prochi-ral compounds by lipase-catalyzed hydrolysis and transesterification reactions is fairly common, with prochiral 1,3-diols most frequently employed as substrates. Recent reports of asymmetric hydrolysis include diesters of 2-substituted 1,3-propanediols and 2-0-protected glycerol derivatives. The asymmetric transesterification of prochiral diols such as 2-0-benzylglycerol and various other 2-substituted 1,3-propanediol derivatives is also fairly common, most frequently with Vinyl Acetate as an irreversible acyl transfer agent. 

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... 

Miller developed peptide-based iV-methylimidazole catalysts and applied them to acylative kinetic resolution of N-acylated amino alcohol 29 (Scheme 22.6). The p-hairpin secondary structure of the peptide backbone in catalysts 30 and 31 constitutes a unique environment for effective asymmetric induction. Acylative kinetic resolution of 29 with acetic anhydride in the presence of catalyst 31 proceeded with high s values (s = up to 51). The asymmetric acylation was further extended to remote asymmetric desymmetrisation of a o-symmetric nanometer-scale diol substrate, 32 (Scheme 22.7). Catalyst 33 enabled the enantiotopic hydrojq groups in 32 to be distinguished even though they are located 5.75 A from the prochiral stereogenic centre, and 9.79 A from each other. 

Enzyme-catalyzed acyl transfer can be applied to a number of different S3mthetic problems. The majority of applications that have been reported involve the desym-metrization of prochiral and meso-diols or the kinetic resolution of racemic primary and secondary alcohols. Since, as a rule, an enzyme s preference for a specific enantiomer is not reversed when water is replaced by an organic solvent, it is always the same enantiomer which is preferably accepted in hydrolysis and ester synthesis. Taking into consideration that hydrolysis and esterification represent... 

Prochiral and meso-compounds have been widely transformed into chiral products through transesterification reactions as shown with the acylation of diols (Fig. 14,1 and II). In transesterification, the prochiral or meso-substrate can also be a dicarboxylic acid diester. Common to such compounds is a plane of symmetry... 

On the basis of their previous work utilizing oligopeptides containing alkylimidazoles in asymmetric acylation reactions. Miller has reported the successful desymmetrization of bisphenol 171. Treatment of diol 171 with peptide 172 (5 mol%) and acetic anhydride gave ester 173 in 80% yield and 95% ee. This unprecedented desymmetrization represents a particularly challenging and impressive case as the desired site of functionalization is >5.7 A from the prochiral stereogenic center of the substrate (Scheme 29). ... 

Figure 9.6 Enantioselective acylation of prochiral diols 16a,b in continuous-flow lipase-filled PBR.

Hydrolases and mainly lipases have appeared as valuable biocatalysts for the development of asymmetric transformations. Several strategies have been carried out involving the classical KR and DKR of racemic alcohols and the desymmetrization of meso- and prochiral diols. Taking into account the reversibility of this type of process in complementary hydrolysis pathway and adequate conditions must be established to favor synthetic acylation reactions. 

Finally, it is worthy mentioning other families of diols that are less known but have also been selectively desymmetrized using lipase acylation protocols. Hammel and Deska reported the acetylation of prochiral tetrasubstituted allenic diols, )deld-ing highly enantioenriched axially chiral allenyl monoesters (68-99% ee) with good yields (59-90%), after their reaction with five equivalents of vinyl butanoate in 1,4-diox-ane at 40 °C using PPL as biocatalyst [158]. Other prochiral diols bearing a heteroatom such as boron [159] or sulfur [160], have also been studied, leading usually to modest yields or selectivities. 

The most important technical applications of catalytic hydrolysis and acylation involve technical enzymes, as used in food processing, washing powders, or derace-misations. Especially the latter application has also found significant application in chemical synthesis. The kinetic resolution of chiral, racemic esters, anhydrides, or alcohols relies on the faster conversion of only one substrate enantiomer by the chiral catalyst, whereas the other enantiomer ideally remains unchanged. A special case within kinetic resolutions is the desymmetrization of prochiral mexo-compounds like mera-anhydrides (2) or meso-diols, (5) that requires a selective conversion of one of the two enantiotopic functional groups (carbonyl or OH-group, Scheme 7.1). 

---