Spongipyran Synthetic Studies. Evolution of a Scalable Total Synthesis of (+)-Spongistatin 1.
Three syntheses of the architecturally complex, cytotoxic marine macrolide (+)-spongistatin 1 (1) are reported. Highlights of the first-generation synthesis include: use of a dithiane multicomponent linchpin coupling tactic for construction of the AB and CD spiroketals, and their union via a highly selective Evans boron-mediated aldol reaction en route to an ABCD aldehyde; introduction of the C(44)-C(51) side chain via a Lewis acid-mediated ring opening of a glucal epoxide with an allylstannane to assemble the EF subunit; and final fragment union via Wittig coupling of the ABCD and EF subunits to form the C(28)-C(29) olefin, followed by regioselective Yamaguchi macrolactonization and global deprotection. The second- and third- generation syntheses, designed with the goal of accessing one gram of (+)-spongistatin 1 (1), maintain both the first-generation strategy for the ABCD aldehyde and final fragment union, while incorporating two more efficient approaches for construction of the EF Wittig salt. The latter combine the original chelation-controlled dithiane union of the E- and F-ring progenitors with application of a highly efficient cyanohydrin alkylation to append the F-ring side chain, in conjunction with two independent tactics to access the F-ring pyran. The first F-ring synthesis showcases a Petasis-Ferrier union/rearrangement protocol to access tetrahydropyrans, permitting the preparation of 750 mgs of the EF Wittig salt, which in turn was converted to 80 mg of (+)-spongistatin 1, while the second F-ring strategy, incorporates an organocatalytic aldol reaction as the key construct, permitting completion of 1.009 g of totally synthetic (+)-spongistatin 1 (1). A brief analysis of the three syntheses alongside our earlier synthesis of (+)-spongistatin 2 is also presented.
Smith
Amos B
AB
Department of Chemistry, Monell Chemical Senses Center and Laboratory of Research on the Structure of Matter, University of Pennsylvania, Philadelphia, PA, 19104.
Sfouggatakis
Chris
C
Risatti
Christina A
CA
Sperry
Jeffrey B
JB
Zhu
Wenyu
W
Doughty
Victoria A
VA
Tomioka
Takashi
T
Gotchev
Dimitar B
DB
Bennett
Clay S
CS
Sakamoto
Satoshi
S
Atasoylu
Onur
O
Shirakami
Shohei
S
Bauer
David
D
Takeuchi
Makoto
M
Koyanagi
Jyunichi
J
Sakamoto
Yasuharu
Y