Total Synthesis of Altohyrtin A (Spongistatin 1): Part 1

Abstract

The most active compound of the extraordinarily cytotoxic spongipyrans, spongistatin 1, isolated from marine sponges, appeared to be identical to altohyrtin A. The total synthesis of this macrolide has now firmly established the relative and absolute stereochemistry proposed by Kitagawa (see picture below), and has also verified that altohyrtin A and spongistatin 1 are identical.

Spongistatins: Biological activity and synthetic studies

“…The first total syntheses of altohyrtin C and altohyrtin A by the groups of Evans [16] and Kishi [17], respectively, confirmed the stereochemical assignments proposed by Kitagawa and Kobayashi and demonstrated the identity of spongistatin 2 to altohyrtin C and spongistatin 1 to altohyrtin A.…”

“…Total syntheses of spongistatins/altohyrtins have been reported by seven groups (Evans [16], Kishi [17], Smith [19,20], Paterson [21], Crimmins [22], Heathcock [23] and Ley [24]) each presenting different practical solutions for the assembly of the ABCD and EF key fragments. The bis-spiroketal subunit can be constructed through an anti-aldol reaction to form the C(15)eC (16) bond or via a KishieNozaki coupling to produce the C(17)eC (18) linkage.…”

“…Kishi [17] In their approach, Kishi and co-workers proposed the assembly of the bis(spiroketal) subunit through a TakaieOshimaeKishieNozaki coupling to build the C(17)eC (18) bond between a AB derived aldehyde and a D fragment vinyl iodide. The preparation of AB and D-ring precursors was based on the regioselective opening of epoxides with carbon nucleophiles (dithiane anions and organocuprates).…”

“…NIS-promoted dithiane hydrolysis followed by acidic treatment induced spiroketalization to the axial/axial AB subunit 42. Further elaboration and protecting groups' manipulation allowed oxidation of the alcohol at C (17) to provide the functionalized AB-spiroketal aldehyde 44.…”

Recherche de substances naturelles à activité thérapeutique (2)

“…La configuration absolue de la spongistatine 1, initialement déduite par G.R. Pettit, est confirmée en 1998 par Y. Kishi après synthèse totale [37,38]. En 2005, M. Ball réduit le nombre d'étapes de la synthèse totale de la spongistatine 1 de 65 à 46 [39], et, en 2008, le protocole de synthèse totale établi par A.B.…”