Chemoenzymatic Cascades for the Enantioselective Synthesis of β‐Hydroxysulfides Bearing a Stereocentre at the C−O or C−S Bond by Ketoreductases

Abstract

Chiral β-hydroxysulfides are an important class of organic compounds which find broad application in organic and pharmaceutical chemistry. Herein we describe the development of novel biocatalytic and chemoenzymatic methods for the enantioselective synthesis of β-hydroxysulfides by exploiting ketoreductase (KRED) enzymes. Four KREDs were discovered from a pool of 384 enzymes identified and isolated through a metagenomic approach. KRED311 and KRED349 catalysed the synthesis of β-hydroxysulfides bearing a stereocentre at the CÀ O bond with opposite absolute configurations and excellent ee values by novel chemoenzymatic and biocatalytic-chemical-biocatalytic (bio-chem-bio) cascades starting from commercially available thiophenols/thiols and α-haloketones/alcohols. KRED253 and KRED384 catalysed the enantioselective synthesis of β-hydroxysulfides bearing a stereocentre at the CÀ S bond with opposite enantioselectivities by dynamic kinetic resolution (DKR) of racemic α-thioaldehydes.

Regio- and Enantioselective Construction of Tetrazole Hemiaminal Esters and Related Prodrugs via Biocatalytic Dynamic Kinetic Resolution

“…Enzymatic catalysis, as a highly specific and efficient process, offers distinct advantages over other catalytic methods. − Enzymes commonly exhibit remarkable chemical and stereospecificity, facilitating the targeted enhancement of desired reactions while minimizing the formation of byproducts. − Notably, enzymatic catalysis takes place under mild reaction conditions, − which aligns with practices for sustainable chemistry. − Herein, we report the first example of asymmetric 2,5-disubstituted tetrazole hemiaminal ester synthesis through an enzyme-catalyzed DKR process. Compared to the previous reports, significantly enhanced catalyst regio- and stereoselectivity were accomplished after comprehensive condition optimization.…”

Iodine-enabled organoelectrocatalysis: enantioselective cross dehydrogenative coupling of sulfides and aldehydes

“…Enantiomerically enriched α-sulfenylated aldehydes are key intermediates for preparing important chiral building blocks, 1 such as β-hydroxysulfides existing widely in natural products and pharmaceuticals, 2 chiral secondary alcohols and 1,2-disubstituted epoxides 3 (Fig. 1A).…”

Concise synthesis of (R)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis

“…This approach has successfully been used for the synthesis of a variety of natural products, synthetic APIs or interesting building blocks thereof and has experienced a lot of attention in the last years. [22][23][24][25][26][27][28][29][30][31][32][33][34] The concepts developed for opioid structures are exclusively based on early stage enzymatic transformations to access basic chiral synthons followed by a sophisticated chemical synthetic sequence over numerous steps (Scheme 1DI and II). [35][36][37][38][39][40][41][42][43][44][45] The biotransformations used involved either a broadly exploited toluene dioxygenase (for dihydroxylation) or a lipase (for a kinetic resolution).…”