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

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

Publication History

Received: 19 September 2023

Accepted after revision: 22 November 2023

Accepted Manuscript online:
22 November 2023

Article published online:
17 January 2024

• References and Notes

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