Chiral acyl donors kinetic resolution

These chiral acyl donors can be used for quite effective kinetic resolution of racemic secondary alcohols. For example, enantiomeric aryl alkyl ketones are es-terified by the acyl pyridinium ion 8 with selectivity factors in the range 12-53 [10], In combination with its pseudo-enantiomer 9, parallel kinetic resolution was performed [11], Under these conditions, methyl l-(l-naphthyl)ethanol was resolved with an effective selectivity factor > 125 [12]. Unfortunately, the acyl donors 8 and 9 must be preformed, and no simple catalytic version was reported. Furthermore, over-stoichiometric quantities of either MgBr2 or ZnCI2 are required to promote acyl transfer. In 2001, Vedejs and Rozners reported a catalytic parallel kinetic resolution of secondary alcohols (Scheme 12.3) [13]. 

The improvement of the enantioselectivity E in kinetic resolution of a primary alcohol (10) through lipase-catalyzed transesterification was studied using a chiral acyl donor 11. The combination of the lipase, solvent and acyl donor was effective for the enantioselectivity.62... 

Figure 11 Representative kinetic resolution of primary alcohol ( )-10 using chiral acyl donor ( )-ll.

Scheme 8 Kinetic resolution of chiral acyl donors by esterification [91] and hydrolysis [92].

The alcohol used as cosubstrate in lipase reactions with chiral acyl donors may act as an enantioselective inhibitor that will be detrimental to the enantiomeric excess. This has been reported for C. rugosa lipase-catalyzed kinetic resolution by esterification of 2-meth-ylalkanoic acids (Scheme 17) [134]. 

The one-pot dynamic kinetic resolution (DKR) of ( )-l-phenylethanol lipase esterification in the presence of zeolite beta followed by saponification leads to (R)-l phenylethanol in 70 % isolated yield at a multi-gram scale. The DKR consists of two parallel reactions kinetic resolution by transesterification with an immobilized biocatalyst (lipase B from Candida antarctica) and in situ racemization over a zeolite beta (Si/Al = 150). With vinyl octanoate as the acyl donor, the desired ester of (R)-l-phenylethanol was obtained with a yield of 80 % and an ee of 98 %. The chiral secondary alcohol can be regenerated from the ester without loss of optical purity. The advantages of this method are that it uses a single liquid phase and both catalysts are solids which can be easily removed by filtration. This makes the method suitable for scale-up. The examples given here describe the multi-gram synthesis of (R)-l-phenylethyl octanoate and the hydrolysis of the ester to obtain pure (R)-l-phenylethanol. 

Schering Plough demonstrated the kinetic resolution of a secondary amine (24) via enzyme-catalyzed acylation of a pendant piperidine (Scheme 7.13) [32]. The compound 27 is a selective, non-peptide, non-sulfhydryl farnesyl protein transfer inhibitor undergoing clinical trials as a antitumor agent for the treatment of solid tumors. The racemic substrate (24) does not contain a chiral center but exists as a pair of enantiomers due to atropisomerism about the exocylic double bond. The lipase Toyobo LIP-300 (lipoprotein lipase from Ps. aeruginosa) catalyzed the isobu-tylation of the (+) enantiomer (26), with MTBE as solvent and 2,2,2-trifluoroethyl isobutyrate as acyl donor [32]. The acylation of racemic 24 yielded (+) 26 at 97% and (-) 25 at 96.3% after 24h with an E >200. The undesired enantiomer (25)... 

Quite efficient nucleophilic catalysts with planar (21a-c) and axial (22a-d) chirality were recently developed by Fu et al. [17-22] and Spivey et al. [23-25], The ferrocene-derived catalysts developed by Fu (21a-c) were first tested in the kinetic resolution of aryl alkyl carbinols with diketene as the acyl donor. 

Later studies focused on the planar chiral DMAP derivative 21c as catalyst and use of acetic anhydride as an inexpensive and readily available acyl donor [19]. Under these conditions (2 mol% catalyst loading, r.t.) kinetic resolution of several racemic alcohols could be achieved with selectivity factors up to 52 (Scheme 12.7). As a consequence, enantiomerically highly enriched alcohols (> 95% ee) could be obtained at conversions only slightly above 50%. 

Catalytic kinetic resolution of amines has been a typical domain of enzymatic transformations. Attempts to use low-molecular-weight catalysts have notoriously been frustrated by the rapid uncatalyzed background reaction of the amine substrate with the acyl donor [40]. The first solution to this problem was recently developed by Fu, who used the planar chiral catalyst 21d and O-acyl azlactone 40 as the acyl donor (Scheme 12.19) [41]. In this process, the acyl transfer from the azlactone 40 to the nucleophilic catalyst 21d is rapid relative to both direct transfer to the substrate and to the transfer from the acylated catalyst to the substrate amine. Under these conditions, which implies use of low reaction temperatures, selectivity factors as high as 27 were achieved (Scheme 12.19) [41]. 

In an approach to the synthesis of natural, chiral 4-ep/-sannamine, the O-acetyl derivative 76 has been prepared by kinetic resolution of the corresponding racemic alcohol using a lipase and vinyl acetate as acyl donor. ... 

Numerous examples exist on the kinetic resolution of chiral acyl acceptors. Among other compounds primary and secondary alcohols, various amines, and peroxides have been resolved. Representative examples are shown in Scheme 7. The secondary alcohol 2-octanol was resolved using S-ethyl octanethioate as acyl donor and C. antarctica lipase B [12]. The alkyl peroxide was acylated with isopropenyl acetate using P. cepacia lipase [87]. The primary amine was resolved by C. antarctica lipase B-catalyzed acylation of ethyl octanoate at reduced pressure [88]. The primary alcohol was successfully resolved by acylation of vinyl acetate at — 40 C [89]. 

ScheiTIG 21 A kinetic scheme for the sequential resolution of an acyl donor containing a chiral alcohol moiety according to Schemes 19 and 20. 

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