Combination of Asymmetric Organo‐ and Biocatalysis in Flow Processes and Comparison with their Analogous Batch Syntheses

Abstract

A sequential-type as well as a tandem-type chemoenzymatic flow cascade combining an organocatalytic aldol reaction and a biocatalytic reduction to form stereoselectively a 1,3-diol with two stereogenic centers were developed. Initially, a comprehensive screening of 24 alcohol dehydrogenases was carried out and the identified candidates were applied in different multistep flow cascades. All four stereoisomers of the desired 1,3-diol product are accessible via a sequential flow approach with product formation-related conversions of up to 76 % over two steps, isolated yields of up to 64 % and enantiomeric excess of > 99 % in all cases. In addition, a tandem-type flow process, performing both reaction steps simultaneously, was established leading to 51 % conversion with > 99 % ee and 8 : 1 d.r. and representing a combination of the fields of asymmetric chemocatalysis, biocatalysis and flow chemistry.

What’s new in flow biocatalysis? A snapshot of 2020–2022

“…A sequential as (2020)(2021)(2022). well as a tandem-type chemoenzymatic flow cascade combining an organocatalytic aldol reaction and a biocatalytic reduction to form stereoselectively a 1,3-diol with two stereogenic centers were developed (Schober et al, 2022).…”

Construction of Chemoenzymatic Linear Cascades for the Synthesis of Chiral Compounds

“…and representing a combination of the fields of asymmetric chemocatalysis, biocatalysis and flow chemistry. [64] In 2015 Suljic et al developed an asymmetric bio-and organocatalytic cascade one-pot reaction for the α-arylation of aldehydes via aldol reaction. [65] Starting from 1,4-dihydroxybenzene, a laccase-catalysed aerobic oxidation provides the corresponding quinone, which is used as the electrophile in a Michael reaction with aldehydes catalysed by the Jørgensen catalyst to provide the desired products upon intramolecular cyclisation in moderate to good yields and moderate to excellent enantioselectivity (Scheme 5b).…”

“…Tandem‐type process performed both reactions simultaneously, leading to 51 % conversion with >99 % ee and 8 : 1 d.r . and representing a combination of the fields of asymmetric chemocatalysis, biocatalysis and flow chemistry [64] . In 2015 Suljic et al .…”

Cascade Processes Merging Chemical and Enzyme Catalysis

“…7 Also, in a series of reports, the group of Gröger exploited the proline-catalyzed aldol reaction between aldehydes and acetone to synthesize a broad range of chiral 1,3-diols (Scheme 1c), 8,9 with such a system being recently applied under a continuous-flow setup. 10 Besides lipases and KREDs, laccases were also used in combination with small-molecule catalysis to make chiral compounds. In 2015, Suljic et al used a laccase to oxidize hydroquinone to benzoquinone which was used as the acceptor in an asymmetric Michael addition of aldehydes catalysed by the Jørgensen catalyst (Scheme 1d).…”