開催日: 2017/09/20 - 2017/09/22
Halichondrins are polyether macrolides, originally isolated from the marine sponge Halichondria okadai by Uemura, Hirata, and coworkers.2) Due to their intriguing structural architecture and extraordinary antitumor activity, halichondrins have received much attention from the scientific community. Although our group have previously reported efficient syntheses of halichondrins and norhalichondrins, an attempt of synthesizing homohalichondrins via the same route gave only a modest success.3) In this presentation, we report a convergent, efficient, and scalable synthesis of all the members, including homohalichondrins A~C, in the halichondrin class of natural products. We have designed two new fragments, which were prepared from same intermediate, by disconnecting between C37-C38. During the course of this study, we have developed new coupling reactions. NHK coupling for aldehyde 6 and vinyl iodide 7 proceeded without protection on C30 hydroxy group by adding excess of Cp2ZrCl2 and DTBMP. Final coupling between 2 and 3 was accomplished with newly developed Zr/Ni-mediated one-pot ketone synthesis. By developing these assembly chemistry, halichondrins A and B were synthesized in 28 steps (29 steps for halichondrins C) from commercially available D-galactal.4) 1) This work was performed in the Kishi laboratory at Department of Chemistry, Harvard University, Cambridge, Massachusetts, U.S.A. 2) (a) D. Uemura, Y. Hirata, et al., J. Am. Chem. Soc. 1985, 107, 4796. (b) Y. Hirata, D. Uemura, Pure Appl. Chem. 1986, 58, 701. 3) A. Ueda, A. Yamamoto, D. Kato, and Y. Kishi, J. Am. Chem. Soc. 2014, 136, 5171. 4) (a) K. Yahata, N. Ye, Y. Ai, K. Iso, and Y. Kishi, submitted for publication. (b) Y. Ai, N. Ye, Q. Wang, K. Yahata, and Y. Kishi, submitted for publication.