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Synlett 2024; 35(14): 1707-1712
DOI: 10.1055/a-2216-4521
letter

Synthesis of Biomimetic Thioesters for Studies of Ketoreductase Domains from the Biosynthesis of Cytotoxic Polyketides

Sebastian Derra
,
Julian Hoffmann
,
Frank Hahn  ∗
This work was supported by Exploration Grant of the Boehringer Ingelheim Foundation (BIS) and a Material Cost Allowance of the Fund of the Chemical Industry (FCI).
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Abstract

The synthesis of biomimetic thioesters for enzymatic studies of ketoreductase (KR) domains from polyketide synthases is described. A TBS-protected dihydroxyalkene fragment was synthesised by a sequence involving a Nagao acetate aldol reaction, a Mukaiyama propionate aldol reaction, and a methylene Wittig olefination. Fragment coupling to N-acetylcysteamine (SNAC) (E)-3-hydroxyhex-4-enethioates by an olefin cross-metathesis (OCM) and subsequent deprotection gave the potential KR product stereoisomers. An analogous OCM with a SNAC (E)-3-ketohex-4-enethioate did not give the desired KR precursor, but the reaction could successfully be replaced by a Horner–Wadsworth–Emmons olefination between a SNAC 3-ketothioester phosphonate and a TBS-protected dihydroxy aldehyde. After deprotection, an intramolecular cyclisation was observed that needs to be considered as a spontaneous side reactivity in the enzymatic assays.

Key words

biomimetic thioesters - biosynthesis - enzymic metathesis - Michael addition - natural products - olefination

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2216-4521.
  • Supporting Information


Publication History

Received: 19 September 2023

Accepted after revision: 22 November 2023

Accepted Manuscript online:
22 November 2023

Article published online:
17 January 2024

© 2024. Thieme. All rights reserved

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