Elsevier

Tetrahedron: Asymmetry

Volume 15, Issue 8, 19 April 2004, Pages 1295-1299
Tetrahedron: Asymmetry

Lipase catalysed resolution of nitro aldol adducts

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Abstract

The kinetic resolution of a range of 1-nitro-2-alkanols by lipase-catalysed esterification using various lipases and succinic anhydride as an acyl donor has been studied. E values of up to 100 were obtained with Novozym 435 in the resolution of 1-nitro-2-pentanol with succinic anhydride in TBME. Acylation with succinic anhydride proved much more enantioselective than with vinyl acetate.

Introduction

The aldol reaction is one of the most important methods for C–C bond formation.1 In the related nitro aldol condensation, the Henry reaction, the coupling of a nitro alkane to an aldehyde or ketone results in the corresponding β-nitro alcohol. Such chiral nitro alcohols are of interest as building blocks in organic synthesis as they can be converted into chiral β-hydroxy amines via reduction of the nitro group. Alternatively, further carbon–carbon bond formation on the α-carbon of the nitro group can lead to a wide variety of other useful intermediates.[2], [3] The control of the stereochemistry is of importance for many synthetic purposes, especially for pharmaceutical and agricultural applications.

The products of Henry reactions are secondary alcohols; hence, they are suitable substrates for resolution by lipase catalysed enantioselective acylation (see Fig. 1). The lipase mediated kinetic resolution of secondary alcohols has been widely studied over the past 20 years4 and has become a common synthetic and industrial methodology for producing chiral compounds as pure enantiomers.[5], [6]

The choice of the acyl donor in such kinetic resolutions requires careful consideration because the transesterification equilibrium should be entirely on the side of the product.4 The often-used vinyl esters, which react irreversibly because the liberated vinyl alcohol isomerises into acetaldehyde, satisfy this requirement.4

The resolution of some β-nitro alcohols via transesterification with vinyl acetate as the acyl donor has been reported previously,[3], [7], [8] but the separation of the enantiomerically enriched ester and alcohol is often laborious. Acylation with a cyclic anhydride, which also reacts irreversibly, results in a half ester that can be readily extracted from the reaction mixture. This potential benefit for reaction work-up procedures has been reported for the resolution of several secondary alcohols.[9], [10], [11], [12], [13], [14]

Herein we report the applicability of succinic anhydride as an acyl donor in the lipase-mediated resolution of a number of alkyl- and phenylalkyl substituted nitro alcohols. Furthermore the effects of the lipase and reaction medium will also be discussed.

Section snippets

Resolution of nitro alcohols: lipases, acyl donors, solvents

The acylation of 1-nitro-2-pentanol 2c (Fig. 1), which we selected as a suitable test reactant, was performed in the presence of a range of microbial lipases (see Table 1). The reaction proved fast and enantioselective when performed in the presence of Novozym 435, an immobilised preparation of Candida antarctica lipase B (CaLB). Two cross-linked preparations of CaLB, the cross-linked enzyme aggregate (CLEA) and the cross-linked enzyme crystal (ChiroCLECTM CaB) were much less active, although

Conclusions

Succinic anhydride, besides having potential benefits for reaction work-up, was shown to be an efficient acyl donor for the resolutions of β-nitro alcohols. Much higher E values can be achieved compared to other common acyl donors such as vinyl acetate. The best results, with regard to both rate and enantioselectivity, were observed in tert-butyl methyl ether and diisopropyl ether.

Instruments

HPLC analyses were performed on a Chiralcel OD column with a flow rate of 0.6 mL/min and an eluent consisting of hexane–isopropyl alcohol–trifluoroacetic acid (95:5:0.1) for the aliphatic nitro alkanols and hexane–isopropyl alcohol–trifluoroacetic acid (80:20:0.1) for the aromatic nitro alkanols. Detection was performed with a Waters 486 UV detector at 215 nm.

Materials

All chemicals were of analytical purity and obtained from Sigma–Aldrich. The lipase from Candida rugosa was obtained from Sigma–Aldrich.

Acknowledgements

The authors wish to thank Novozymes (Bagsvaerd, Denmark), Altus Biologics (Cambridge, MA) and CLEA Technologies (Delft, The Netherlands) for generous gifts of enzymes. Financial support from Codexis Inc. (Redwood City, CA) is also gratefully acknowledged.

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