Total Synthesis and Bioactivity Mapping of Geodiamolide H

Abstract

The first total synthesis of the actin‐stabilizing marine natural product geodiamolide H was achieved. Solid‐phase based peptide assembly paired with scalable stereoselective syntheses of polyketide building blocks and an optimized esterification set the stage for investigating the key ring‐closing metathesis. Geodiamolide H and synthetic analogues were characterized for their toxicity and for antiproliferative effects in cellulo, by characterising actin polymerization induction in vitro, and by docking on the F‐actin target and property computation in silico, for a better understanding of structure‐activity relationships (SAR). A non‐natural analogue of geodiamolide H was discovered to be most potent in the series, suggesting significant potential for tool compound design.

Marine natural products

“…474 The rst total synthesis of various plakorsin and ancorinoside lipids have been reported, 475,476 as has the synthesis of polyketide peroxides muqubilin and several negombatoperoxides. 477 The total synthesis of geodiamolide H has been achieved, 478 while the production of four potential stereoisomers has called for the structural revision of characellide B, although no alternative structure was proposed. 479 The structure of taumycin A 1165 has been revised following its synthesis.…”

Double Asymmetric Hydrogenation of (E)‐2‐Substituted‐4‐oxo‐2‐alkenoic Acids: An Efficient Synthesis of Chiral α, γ‐Disubstituted γ‐Butyrolactones

“… [1–5] As versatile building blocks, chiral substituted γ ‐butyrolactones can be facilely utilized as intermediates for the synthesis of many blockbuster drugs and bioactive agents. For instance, the hydrolysis product of α , γ ‐disubstituted γ ‐butyrolactones could be transformed to sacubitril (an enkephalinase inhibitor used for heart failure) and geodiamolide A–F [6–9] . Its functionalized tetrahydrofuran derivatives could be effectively converted to orlistat (treatment for obesity) and (+)‐cryptophycin 52 (a potent antimitotic antitumor agent) [10–13] …”

“…[1][2][3][4][5] As versatile building blocks, chiral substituted γ-butyrolactones can be facilely utilized as intermediates for the synthesis of many blockbuster drugs and bioactive agents. For instance, the hydrolysis product of α, γ-disubstituted γ-butyrolactones could be transformed to sacubitril (an enkephalinase inhibitor used for heart failure) and geodiamolide A-F. [6][7][8][9] Its functionalized tetrahydrofuran derivatives could be effectively converted to orlistat (treatment for obesity) and (+)-cryptophycin 52 (a potent antimitotic antitumor agent). [10][11][12][13] Intrigued by the great importance, significant efforts have been made on the development of concise and efficient approaches toward diastereo-and enantioselective construction of α, γ-disubstituted γ-butyrolactones.…”