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

Informazioni relative al progetto

BioPhoCS

ID dell’accordo di sovvenzione: 838326

DOI

10.3030/838326

Progetto chiuso

Data della firma CE 9 Aprile 2019

Data di avvio 1 Gennaio 2021

Data di completamento 31 Maggio 2023

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 224 933,76

Contributo UE

€ 224 933,76

Coordinato da

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)

Periodo di rendicontazione: 2021-01-01 al 2022-12-31

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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