Synthetic Studies toward the C₁–C₁₂ Fragment of Amphidinolide U

Abstract

Amphidinolide U is a cytotoxic marine macrolide isolated from Amphidinium sp., sharing 75% of the amphidinolide C backbone. We report here a synthetic study of the C₁–C₁₂ fragment of amphidinolide U. The C₆–C₁₂ pattern was built using consecutive regioselective ring opening of epoxides, a directed reaction to control newly formed stereogenic centers. In parallel, the C₁–C₅ moiety was constructed by taking advantage of a symmetrical diol. Attempts to cross-couple the C₁–C₅ and C₆–C₁₂ fragments by using a Suzuki cross-coupling reaction led to poor conversion rates. The same transformation on a close substrate model used during past studies on the total synthesis of amphidinolides F and C2 was successful. These contrasting results could be explained by a presumed steric hindrance of the protecting group adjacent to the vinyl function involved in the cross-coupling reaction. Our investigations will stimulate the optimization of C(sp²)–C(sp³) cross-coupling reactions with bulky substrates, with the aim of achieving a total synthesis of amphidinolide U.

Key words

amphidinolides - polyketides - total synthesis - Suzuki cross-coupling - epoxides - protecting groups

Publication History

Received: 30 April 2023

Accepted after revision: 24 May 2023

Accepted Manuscript online:
24 May 2023

Article published online:
06 July 2023

• References and Notes

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