Development of Biotransamination Reactions towards the 3,4-Dihydro-2H-1,5-benzoxathiepin-3-amine Enantiomers

Daniel González-Martínez,Carlos Cativiela,Nerea Fernández-Sáez,Joaquín Campos,Vicente Gotor-Fernández

doi:10.3390/catal8100470

Abstract

The stereoselective synthesis of chiral amines is an appealing task nowadays. In this context, biocatalysis plays a crucial role due to the straightforward conversion of prochiral and racemic ketones into enantiopure amines by means of a series of enzyme classes such as amine dehydrogenases, imine reductases, reductive aminases and amine transaminases. In particular, the stereoselective synthesis of 1,5-benzoxathiepin-3-amines have attracted particular attention since they possess remarkable biological profiles; however, their access through biocatalytic methods is unexplored. Amine transaminases are applied herein in the biotransamination of 3,4-dihydro-2H-1,5-benzoxathiepin-3-one, finding suitable enzymes for accessing both target amine enantiomers in high conversion and enantiomeric excess values. Biotransamination experiments have been analysed, trying to optimise the reaction conditions in terms of enzyme loading, temperature and reaction times.

Highlights

We have reported several (RS)-benzo-fused seven-membered rings with oxygen and sulfur atoms in 1,5 relative positions with interesting anti-proliferative activities against the MCF-7 cancer cell line
[33,34,35,36,37,38], but especially since they have even as part of multienzymatic sequences [33,34,35,36,37,38], but especially since they have served as valuable served as valuable biocatalysts in the production active of pharmacologically products biocatalysts in the production of pharmacologically products [39,40,41,42,43],active we have focused[39,40,41,42,43], we have focused our efforts in the pursuit of an efficient biotransamination protocol for our efforts in the pursuit of an efficient biotransamination protocol for 3,4-dihydro-2H-1,53,4-dihydro-2H-1,5-benzoxathiepin-3-one benzoxathiepin-3-one (6)
The synthesis of the benzo-fused seven-membered ketone 6 is depicted in Scheme 1. 22-Mercaptophenol was alkylated with two equivalents of ethyl bromoacetate in refluxing acetone in the Mercaptophenol was alkylated with two equivalents of ethyl bromoacetate in refluxing acetone in presence of dry carbonate to givetodiester

Summary

Introduction

We have reported several (RS)-benzo-fused seven-membered rings with oxygen and sulfur atoms in 1,5 relative positions with interesting anti-proliferative activities against the MCF-7 cancer cell line. The most active compounds are 1 and 2 [1] (Figure 1) Other compounds, such as 3 [2] and 4 [3], exhibited more potent anti-ischemic effects than reference compounds, whilst 5 can be the prototype for the design of more potent anti-proliferative agents [4] (Figure 1). The (3R)-3,4-dihydro-2H-1,5-benzoxathiepin-3-amine core appears in red in compounds 3–5 (Figure 1). Such a (3R)-amino-1,5-benzoxathiepin scaffold has been obtained from L-cystine ((2R)-2-amino-3-[[(2R)-2-amino-2-carboxyethyl]disulfanyl]propanoic acid) [4,5]. The incorporation of α-amino acids into heterocyclic structures is an effective strategy for generating numerous peptidomimetics and combinatorial library scaffolds

Methods

Discussion

Conclusion