Method for synthesizing (r)-3-amino-1-butanol by double-enzyme cascade catalysis

Abstract

The invention discloses a method for synthesizing (R)-3-amino-1-butanol through double-enzyme cascade catalysis. The method comprises the steps of: using 1,3-butanediol as a substrate, generating 4-hydroxy-2-butanone through an alcohol dehydrogenase catalyzed reaction; using 4-hydroxy-2-butanone as a substrate, Dehydrogenase or its mutants catalyze the reaction to generate chiral (R)‑3‑amino‑1‑butanol. The invention provides a brand-new green biosynthesis route, using cheap 1,3-butanediol as a raw material, and catalyzing the synthesis of chiral (R)-3-amino-1-butanol through double-enzyme cell co-expression. At the same time, the method provided by the invention has a cofactor self-circulation system and has good economic benefits. The invention has important application value.

Description

technical field [0001] The invention belongs to the field of biotechnology, and in particular relates to a method for synthesizing (R)-3-amino-1-butanol by cascade catalysis of two enzymes, in particular to a method for synthesizing by cascade catalysis of alcohol dehydrogenase and amine dehydrogenase A method for chiral (R)-3-amino-1-butanol. Background technique [0002] Chiral amino alcohol compounds are structural units of many biologically active molecules, and are important pharmaceutical and fine chemical intermediates, among which (R)-3-amino-1-butanol is a synthetic anti-AIDS integrase inhibitor dulutevir ( Dolutegravir) and can also be derivatized into β-lactams for the synthesis of penem antibiotics. [0003] (R)-3-Amino-1-butanol is mainly synthesized by chemical method, and there are few reports on enzymatic synthesis. In 1995, Gertzmann et al. used chiral (R)-alanine as a raw material. After protection by the amino group, the carbon chain was extended by diaz...

AI Technical Summary

Problems solved by technology

In 1977, Kinas et al. reacted crotonate with (R)-phenethylamine to generate a group of epimers with two chiral centers, which were separated by silica gel column chromatography to obtain a single isomer, and then passed through ester Reduction, debenzylation obtain (R)-3-amino-1-butanol; This method step is less and raw material is easy to get, is a kind of method that has hope to realize suitability for industrialized production, but there is following problem, because the first step reaction The selectivity is poor, and two enantiomers are obtained in almost equal amounts, which makes separation and purification more difficult. Chromatographic column separation is often used, with large eluent consumption, large losses, and low efficiency. At the same time, due to the use of expensive LiAlH 4 As a reducing agent, the cost of raw materials also increases significantly, and this method is not suitable for large-scale industrial production

In 1998, Tatsuya etc. reported a method for synthesizing (R)-3-amino-1-butanol, but the price of raw materials was expensive and the reaction conditions were harsh in this method

[0004] At present, in the synthesis method of (R)-3-amino-1-butanol, the chemical method requires high temperature, high pressure and metal catalyst, harsh reaction conditions, large pollution, low safety factor, and the yield is 60% to 70%.

The biological method has mild reaction conditions, but the conversion rate is low

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