Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

• Main Authors: Jan Hendrik Lang, Thomas Lindel
• Format: Article
• Language: English
• Published: Beilstein-Institut 2019-02-01
• Series: Beilstein Journal of Organic Chemistry
• Subjects: jasplakinolide; marine natural products; Negishi coupling; polyketides; stereoselective synthesis
• Online Access: https://doi.org/10.3762/bjoc.15.53

The synthesis of the polyketide section present in the potently cytotoxic marine cyclodepsipeptide jasplakinolide and related natural products, geodiamolides and seragamides, is reported. The key step is a Negishi cross coupling of (R)-(3-methoxy-2-methyl-3-oxopropyl)zinc(II) bromide and an (E)-iodoalkene that was synthesized via an aluminium ester enolate attack at (R)-propylene oxide. The overall synthesis comprises nine steps with an overall yield of 21%. It proved to be possible to liberate the free 8-hydroxynonenoic acid and to couple it with a protected tripeptide composed of L-alanine, N,O-dimethyl-D-iodotyrosine, and TIPS-protected L-threonine, which occurs as partial structure of seragamide A. The tripeptide section of seragamide A was assembled by solution-phase synthesis and an open-chain analogue of the natural product was obtained.