Process for preparing optically active 3-hydroxy-pyrrolidine derivatives by enzymatic hydroxylation

Abstract

A process for the preparation of optically active 3-hydroxypyrrolidine or N-substituted 3-hydroxypyrrolidines, wherein an oxygen atom is inserted stereoselectively into the corresponding pyrrolidines, respectively, by use of a bacterium having hydroxylation activity, or a prokaryotic host-organism having the gene(s) necessary for the hydroxylation, or an enzyme having hydroxylation activity derived therefrom. The bacterium may be selected from strains having alkane hydroxylases, strains degrading alkanes or mono-alicyclic compounds, or strains from the genera Pseudomonas, Mycobacterium, Corynebacterium, Nocardia, Sphingomonas, Cordona, Rhodococcus, Bacillus, Streptomyces, Sebekia and Methylococcus.

Description

[0001] The present invention relates to a process for preparing optically active 3-hydroxypyrrolidine derivatives, wherein an oxygen atom is inserted stereoselectively into corresponding pyrrolidines by use of biocatalysts. Such optically active 3-hydroxypyrrolidine compounds are useful as intermediates for the preparation of several pharmaceutical products and agricultural chemicals.DESCRIPTION OF THE PRIOR ART[0002] Optically active 3-hydroxypyrrolidine and N-substituted 3-hydroxypyrrolidine are useful intermediates for the synthesis of several pharmaceuticals, agrochemicals, and the like.[0003] In practice it is often advantageous, it not required, to use optically active 3-hydroxypyrrolidine in its N-protected form.[0004] One process for preparing (R)-3-hydroxypyrrolidine involving decarboxylation of (2S,4R)-4-hydroxy-L-proline is known [JP 05 / 255204 (1993); JP 60 / 23328 (1985); Hashimoto, M., et al, Chem. Lett., 1986, 893; Mehler, Th., et al, Synthetic Commun. 1993, 23, 2691]. H...

AI Technical Summary

Benefits of technology

[0024] Optically active N-substituted 3-hydroxypyrrolidine obtained by this process can be easily converted into optically active 3-hydroxypyrrolidine by deprotection.

Problems solved by technology

However, the starting material is very expensive.

All these reduction reagents are expensive, and difficult to handle; the steps of recovery of the product and destroying of the reagents after reaction are complicated and costly; and some racemization takes place during the reduction.

However, these methods are not suitable for large scale production, since six-step syntheses are involved in both methods, including an expensive reduction step.

Besides other drawbacks, the optically active starting materials are not easily available and many steps are needed for their preparation.

However, the yield is lower than 50%, the maximum theoretical yield of resolution; the separation of product is difficult.

A big drawback for all the resolution processes is the lack of a practical synthesis of the racemic starting materials.

This method, however, is not suitable for industrial production because of the use of the special borane reagent.

It is known that enzymatic reduction of N-benzyl-3-pyrrolidinone affords optically active N-benzyl-3-hydroxypyrrolidine [JP 06 / 141876 (1994); WO98 / 23768 (1998)], but the lack of a practical synthesis of the starting material remains one of the drawbacks of this process.

However, this reaction is not possible with classical chemical methods.

Enzymatic hydroxylation of pyrrolidines is difficult.

It is doubtful whether the method is applicable to the hydroxylation of N-acylpyrrolidines.

However, these processes are not practical, since such hydroxylations with fungi result in low yield, low concentration and low enantiomeric excess (e.e.) of the product, low speed of biotransformation, and formation of byproduct.