Collect. Czech. Chem. Commun. 2009, 74, 651-769
Published online 2009-06-01 14:24:54

Enantioselective synthesis of structurally intricate and complementary polyoxygenated building blocks of Spongistatin 1 (Altohyrtin A)

Alain Braun, Il Hwan Cho, Stephane Ciblat, Dean Clyne, Pat Forgione, Amy C. Hart, Guoxiang Huang, Jungchul Kim, Isabelle Modolo, Leo A. Paquette*, Xiaowen Peng, Stefan Pichlmair, Catherine A. Stewart, Jizhou Wang and Dmitry Zuev

Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210, U.S.A.


Enantioselective approaches to the construction of four complex building blocks of the structurally intricate marine macrolide known as spongistatin 1 are presented. The first phase of the synthetic effort relies on a practical approach to a desymmetrized, enantiomerically pure spiroketal ring system incorporating rings A and B. Concurrently, the C17–C28 subunit, which houses one-fifth of the stereogenic centers of the target in the form of rings C and D, was assembled via a composite of stereocontrolled aldol condensations. Once arrival at the entire C1–C28 sector had been realized, routes were devised to provide two additional highly functionalized sectors consisting of C29–C44 and C38–C51. A series of subsequent transformations including cyclization of the E ring and hydroboration to afford the B-alkyl intermediate for the key Suzuki coupling to append the side chain took advantage of efficient stereocontrol. Ultimately, complete assembly and functionalization of the western EF sector of spongistatin was thwarted by an inoperative Suzuki coupling step intended to join the side chain to the C29–C44 sector, and later because of complications due to protecting groups, which precluded the complete elaboration of the late stage C29–C51 intermediate.

Keywords: Total synthesis; Cytotoxic agents; Marine macrolides; Spiroketals; Coupling reactions.

References: 240 live references.