Elsevier

Tetrahedron: Asymmetry

Volume 15, Issue 18, 20 September 2004, Pages 2765-2770
Tetrahedron: Asymmetry

TETRAHEDRON: ASYMMETRY REPORT NUMBER 74
Rational strategies for highly enantioselective lipase-catalyzed kinetic resolutions of very bulky chiral compounds: substrate design and high-temperature biocatalysis

https://doi.org/10.1016/j.tetasy.2004.06.055Get rights and content

Abstract

Rational approaches to successful lipase-catalyzed kinetic resolutions of very bulky chiral compounds are briefly reviewed: substrate design and high-temperature biocatalysis. The molecular design based on a stereo-sensing mechanism was the key to the success in the kinetic resolution of 5-[4-(1-hydroxyethyl)phenyl]-10,15,20-triphenylporphyrin. The lipase-catalyzed transesterification of 1,1-diphenyl-2-propanol in n-decane proceeded with excellent enantioselectivity at high temperatures up to 120 °C in an autoclave.

Introduction

Chiral functional molecules, such as chiral ligands in asymmetric synthesis and chiral synthetic receptors in host–guest chemistry, are occasionally large and bulky and can often show poor reactivity for lipases. Herein, rational methods for achieving the highly enantioselective kinetic resolution of very bulky chiral compounds are briefly reviewed. 5-[4-(1-Hydroxyethyl)phenyl]-10,15,20-triphenylporphyrin was successfully designed on the basis of a stereo-sensing mechanism shown below. The completely enantioselective acylation of 1,1-diphenyl-2-propanol, which is consistent with the mechanism, proceeded at high temperatures up to 120 °C, with the highest conversion being obtained at 80–90 °C.

Section snippets

Theoretical background

Lipases are currently one of the best biocatalysts for the preparation of a wide range of optically active alcohols.1 The most unusual but attractive feature of lipases is the simultaneous achievement of high enantioselectivity and broad substrate specificity, in addition to high catalytic activity and thermostability in organic solvents. In fact, hundreds of secondary alcohols have been resolved with high enantioselectivities by a single lipase, for example, a lipase from Burkholderia cepacia

Substrate design and limitation of the size of substrate

A gigantic and rigid secondary alcohol, 5-[4-(1-hydroxyethyl)phenyl]-10,15,20-triphenylporphyrin 1, was designed on the basis of the transition-state models (Scheme 1).5 The transition-state models indicate that any large substrate, if well designed, should be acceptable because the larger substituent of the faster-reacting enantiomer is directed toward the external solvent. Figure 1b and c suggest that one enantiomer of 1 [(R)-1 for lipases and (S)-1 for subtilisins] is susceptible to the

High-temperature biocatalysis

In a series of mechanistic studies, a bulky alcohol, 1,1-diphenyl-2-propanol 7, was found to show no reactivity for B. cepacia lipase immobilized on Celite, lipase PS (Amano Enzyme), at 30 °C.4d No reactivity of 7 seemed strange because 1 had been resolved with high enantioselectivity using the same enzyme (Table 1, entry 1). The transition-state model (Fig. 1b) predicts that lipases will show activity for 7 because 7 has a small substituent (Me group) on one side. Careful inspection of the

Conclusion

The results of the kinetic resolution of 1 and other bulky chiral compounds 3 and 5 indicate that the scope of the substrate specificity of lipases is much wider than generally believed. Substrate design based on the mechanism was the key to the success, while the potential abilities of lipases for bulky substrates were developed with the aid of the mechanism. In a case where a bulky substrate 7 showed very poor reactivity due to steric hindrances, elevating the reaction temperature with a

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