Synthesis of the C 7 -C 20 subunit of amphidinolides C and F has been accomplished utilizing a Me 3 Al-mediated ring opening of a vinyl iodide/allylic epoxide to establish the C 12,13 anti stereochemistry, an organolithium coupling/olefination sequence to construct the C 9 -C 11 diene moiety and a sulfone alkylation/hydroxylation strategy to join the C 7 -C 14 and C 15 -C 20 fragments.The amphidinolide natural products have generated considerable attention since their initial discovery in the 1980's by Kobayashi and co-workers. 1 Two of the most complicated members of this family are amphidinolides C (1) and F (2) (Scheme 1). 2 While most of the amphidinolides have attracted sizable synthetic interest from numerous researchers, macrolides 1 and 2 have been significantly underexplored and remain unconquered synthetic targets. 3 We were drawn particularly to amphidinolide C (1) as it is one of the most potent members of this natural product family against a range of cancer cell lines. 2 Additionally, the macrocyclic core of both 1 and 2 possesses significant synthetic challenges: (a) 11 stereogenic centers, (b) two separate substituted THF rings, (c) the sensitive C 15 ,C 18 -diketone moiety and (d) the C 9 -C 11 highly substituted diene. Herein, we detail a unified synthesis of the entire C 7 -C 20 western portion of amphidinolides C and F.Our retrosynthetic strategy for macrolides 1 and 2 is shown in Scheme 1. The three main disconnections are at the C 25,26 alkene sidearm, the C-O bond of the macrolactone and the C 14,15 bond. The C 25 -C 26 alkene should be accessible via a Julia-Kocienski olefinationthereby allowing access to both natural products 1 and 2 through a common intermediate. The C-O linkage of the macrolactone could be constructed via standard Yamaguchi-type cyclization. 4,5 The most difficult of these three dissection points is the C 14 -C 15 bond. The proposed route requires a challenging alkylation of an α-branched halide 6 followed by hydroxylation of the resultant sulfone coupled product with in situ decomposition to the corresponding ketone. 7 While these types of oxidative desulfurizations have been known for some time, this transformation has found only limited application in complex molecule synthesis. 8,9 Any strategy must also take care to avoid furan formation between the C 15 and C 18 carbonyl motifs. Finally, the C 9 -C 11 diene moiety should be accessible via an organolithium addition of vinyl iodide 6 to Weinreb amide 7 followed by methylenation.The C 9 -C 11 diene motif is worthy of additional comment. These types of highly substituted dienes have proven challenging to construct. One illustration of this point is the fact that no † Electronic supplementary information (ESI) available: Complete experimental procedures are provided, including 1 H and 13 C spectra, of all new compounds. See DOI: 10.1039/b916744gCorrespondence to: Rich G. Carter, rich.carter@oregonstate.edu.
NIH Public AccessAuthor Manuscript Org Biomol Chem. Author manuscript; available in PMC 2010 Novembe...