Bio- & Photo-Catalytic Methods for the Construction of Enantiomerically Pure C-S Bonds in Thiols and Sulphides

Project Information

BioPhoCS

Grant agreement ID: 838326

DOI

10.3030/838326

Project closed

EC signature date 9 April 2019

Start date 1 January 2021

End date 31 May 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 224 933,76

EU contribution

€ 224 933,76

Coordinated by

UNIVERSITY COLLEGE LONDON
United Kingdom

Periodic Reporting for period 1 - BioPhoCS (Bio- & Photo-Catalytic Methods for the Construction of Enantiomerically Pure C-S Bonds in Thiols and Sulphides)

Reporting period: 2021-01-01 to 2022-12-31

Summary of the context and overall objectives of the project

The chiral C–S bond is largely present in natural products and pharmaceutical agents, therefore, many methods have been developed for its asymmetric construction. However, the majority of the reported methods achieve the construction of chiral C–S bonds chemically, and there has been a surprising dearth of enzymatic approaches. The reported enzymatic methods for the assembly of chiral C–S bonds could be divided into two categories. (a) Microbial reduction of thioketones with baker's yeast carrying a complex enzyme system. However, except for the not easily accessible and unstable thioketones, poor yields for the desired thiols were obtained in all cases due to extensive and rapid hydrolysis of thioketones. Besides, although high stereoselectivities could be achieved in a few favourable cases, unsatisfactory enantioselectivities were observed in most cases. (b) Enzymatic kinetic resolution (KR) or dynamic kinetic resolution (DKR) of racemic C–S bonds, such as lipase-catalyzed KR of thioesters, 5-(hydroxymethyl)furfural oxidase (HMFO)-catalyzed KR of thiols, monoamine oxidase (MAO), nitrilase or ketoreductase (KRED)-catalyzed partial DKR of functionalized sulfides. Nevertheless, poor yields (<50% in KR) and moderate enantioselectivities were observed in most cases. The overall objectives of this project is to develop an efficient biocatalytic method for the construction of chiral C–S bonds, which will be able to addresses the long-standing issues faced in current enzymatic methods.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In this project, we develop the construction of chiral C–S bonds with good to excellent yields and outstanding enantioselectivities by the strategy of ERED101 catalyzed reduction of α-thio substituted electron-deficient alkenes including α,β-unsaturated esters/ketones/aldehydes/nitriles. Moreover, a series of one-pot chemoenzymatic and biocatalytic cascades have also been developed for the diastereoselective and enantioselective assembly of chiral β-hydroxysulfides bearing two adjacent stereocentres at the C−S and C−O bonds. Our method not only successfully addresses the long-standing issues faced in current enzymatic methods, but also expands the toolbox for chiral C–S bond construction.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

We successfully developed an efficient biocatalytic method for the construction of chiral C–S bonds by the strategy of ERED101 catalyzed reduction of α-thio substituted electron-deficient alkenes in this project. We anticipate that our method will be widely used by the synthetic community for the enantioselective construction of chiral C–S bond in various valuable compounds. The successful development of this method will allow chemists and industries to access facile and sustainable approaches to prepare a wide range of challenging chiral sulphides to be used in the manufacturing of pharmaceutical ingredients, fine chemical tools (ligands, catalysts), agrochemicals and fragrances.

Summary for publication