Total Synthesis of Halicholactone and Neohalicholactone¹

Abstract

The total synthesis of the marine natural products neohalicholactone (1) and halicholactone (2), in enantiomerically pure form, are reported. Key steps in the synthesis of each compound include a cis-selective Wittig reaction, stereoselective cyclopropanation, nine-membered lactone formation using the Yamaguchi method and late-stage stereoselective Cr(II)/Ni(II) mediated coupling of vinyl iodides 39 and 50 with aldehyde 14. In the case of the neohalicholactone synthesis the two major components which were coupled in this convergent synthesis were each derived from the enantiomers of commercially available malic acid. The synthesis served to confirm the original assignment of absolute configuration which was made by Yamada and Clardy. We also demonstrated, through the preparation of diastereoisomers, that another reported compound closely related to neohalicholactone is likely to be the C-15 epimer 67.

Strategies for the Synthesis of the Cyclopropyl-Substituted Lactone Family of Oxylipins

“…[36][37][38] Wills's work confirmed stereostructures 53 and 54 as halicholactone and neohalicholactone, respectively. Subsequent syntheses of 53 by Takemoto 39 and by Kitahara 40 corroborated Wills's findings.…”

Natural occurrence, biological activities and synthesis of eight-, nine-, and eleven-membered ring lactones

“…A formal synthesis of 80 and 81 was described in 1998. 58 Critcher et al reported the synthesis of the right-hand hemisphere 59 and the first asymmetric total synthesis of halicholactone (80) and neohalicholactone (81), 55 confirming the original assignments of absolute configuration of the stereocenters of 81 originally proposed by Yamada and Clardy. 53 They also demonstrated, through the preparation of diastereomers of 81, 55 that the natural product isolated by Proteau et al 54 was, in fact, a C15 epimer of this nine-membered lactone.…”

“…The three total syntheses [55][56][57] of halicholactone (80) and neohalicholactone (81) reported in literature will be briefly presented here, since Shiina 5 discussed them in details in his review. A formal synthesis of 80 and 81 was described in 1998.…”

Métodos de preparação de lactonas de anel médio

“…Critcher et al 25 aplicaram essa estratégia na primeira síntese assimétrica da halicholactona e da neohalicholactona, concluída em 1997 (Esquema 3).…”