title: Spongipyran Synthetic Studies. Evolution of a Scalable Total Synthesis of (+)-Spongistatin 1.
abstract: 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.
authors.affiliation: Department of Chemistry, Monell Chemical Senses Center and Laboratory of Research on the Structure of Matter, University of Pennsylvania, Philadelphia, PA, 19104.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.forename: Chris
authors.initials: C
authors.lastname: Sfouggatakis
authors.forename: Christina A
authors.initials: CA
authors.lastname: Risatti
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Sperry
authors.forename: Wenyu
authors.initials: W
authors.lastname: Zhu
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Doughty
authors.forename: Takashi
authors.initials: T
authors.lastname: Tomioka
authors.forename: Dimitar B
authors.initials: DB
authors.lastname: Gotchev
authors.forename: Clay S
authors.initials: CS
authors.lastname: Bennett
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Onur
authors.initials: O
authors.lastname: Atasoylu
authors.forename: Shohei
authors.initials: S
authors.lastname: Shirakami
authors.forename: David
authors.initials: D
authors.lastname: Bauer
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Jyunichi
authors.initials: J
authors.lastname: Koyanagi
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Sakamoto