Spongipyran Synthetic Studies. Total Synthesis of (+)-Spongistatin 2.
Evolution of a convergent synthetic strategy to access (+)-spongistatin 2 (2), a potent cytotoxic marine macrolide, is described. Highlights of the synthesis include: development of a multicomponent dithiane-mediated linchpin union tactic, devised and implemented specifically for construction of the spongistatin AB and CD spiro ring systems; application of a Ca(II) ion controlled acid promoted equilibration to set the thermodynamically less stable axial-equitorial stereogenicity in the CD spiroketal; use of sulfone addition/Julia methylenation sequences to unite the AB and CD fragments and introduce the C(44)-C(51) side chain; and fragment union and final elaboration to (+)-spongistatin 2 (2) exploiting Wittig olefination to unite the advanced ABCD and EF fragments, followed by regioselective Yamaguchi macrolactonization and global deprotection. Correction of the CD spiro ring stereogenicity was subsequently achieved via acid equilibration in the presence of Ca(II) ion to furnish (+)-spongistatin 2 (2). The synthesis proceeded with a longest linear sequence of 41 steps.
Smith
Amos B
AB
Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, PA, 19104.
Lin
Qiyan
Q
Doughty
Victoria A
VA
Zhuang
Linghang
L
McBriar
Mark D
MD
Kerns
Jeffrey K
JK
Boldi
Armen M
AM
Murase
Noriaki
N
Moser
William H
WH
Brook
Christopher S
CS
Bennett
Clay S
CS
Nakayama
Kiyoshi
K
Sobukawa
Masao
M
Lee Trout
Robert E
RE