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

Projektinformationen

BioPhoCS

ID Finanzhilfevereinbarung: 838326

DOI

10.3030/838326

Projekt abgeschlossen

EK-Unterschriftsdatum 9 April 2019

Startdatum 1 Januar 2021

Enddatum 31 Mai 2023

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 224 933,76

EU-Beitrag

€ 224 933,76

Koordiniert durch

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)

Berichtszeitraum: 2021-01-01 bis 2022-12-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

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.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

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