Self-sustaining closed-loop multienzyme-mediated conversion of amines into alcohols in continuous reactions

Martina L Contente,Francesca Paradisi

doi:10.1038/s41929-018-0082-9

Abstract

The synthesis of alcohols from amines starting material is an excellent, yet challenging, strategy for the preparation of pharmaceuticals and polymers. Here, we developed a versatile, self-sustaining closed-loop multienzymatic platform for the biocatalytic synthesis of a large range of non-commercially available products in continuous flow with excellent yields (80>99%), reaction times and optical purity of secondary alcohols (>99 e.e.). This process was also extended to the conversion of biogenic amines into high value alcohols, such as the powerful anti-oxidant hydroxytyrosol, and the synthesis of enantiopure 2-arylpropanols via dynamic kinetic resolution of commercially affordable racemic amines. The system exploits the in situ immobilisation of transaminases and redox enzymes which were combined to cater for a fully automated, ultra-efficient synthetic platform with cofactor recycling, in-line recovery of benign by-products and recirculation of the aqueous media containing the recycled cofactors in catalytic amount, which increases the efficiency of the system by over 20-fold.

Highlights

MAIN Rapid functional group interconversion with potential retention or inversion of the stereochemistry significantly broadens the range of molecules that can be produced through an established chemical route
The importance of a one-shot amine-alcohol transformation has been already highlighted in the total synthesis of Scopadulin, an antiviral tetracyclic diterpenoid,[9] or the preparation of xylene glycols, precursors of synthetic fibers and resins starting from the corresponding diamines.[10]
A strategy for the bio-deracemisation of racemic aromatic amines leading to chiral alcohols was patented in 2014.11 A microbial cell factory approach was used in that case to overcome limitations due to cofactor recycling, whole-cell biocatalysis may suffer from sideproduct contamination, substrate permeability, and generation of debris

Summary

Introduction

MAIN Rapid functional group interconversion with potential retention or inversion of the stereochemistry significantly broadens the range of molecules that can be produced through an established chemical route. This strategy could be applied to the synthesis, among others, of high value alcohols from inexpensive biogenic amines, such as hydroxytyrosol (one of the most powerful anti-oxidant derived from dopamine),[36] tryptophol (from tryptamine, a key intermediate for a number of bioactive compounds),[37] and histaminol (from histamine) for which efficient syntheses are lacking (reported yields to date between 5 and 13.5%).[38, 39] This strategy mimics an in-vivo system and leads to an ultra-efficient zero-waste and closed-loop process with excellent atom efficiency and automation

Methods

Results

Conclusion