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

Información del proyecto

BioPhoCS

Identificador del acuerdo de subvención: 838326

DOI

10.3030/838326

Proyecto cerrado

Fecha de la firma de la CE 9 Abril 2019

Fecha de inicio 1 Enero 2021

Fecha de finalización 31 Mayo 2023

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 224 933,76

Aportación de la UE

€ 224 933,76

Coordinado por

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)

Período documentado: 2021-01-01 hasta 2022-12-31

Resumen del contexto y de los objetivos generales del proyecto

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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

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.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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