Total synthesis of the antitumor marine sponge alkaloid agelastatin A

Didier Stien, Glen T. Anderson, Charles E. Chase, Yung Hyo Koh, Steven M. Weinreb

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102 Scopus citations

Abstract

The first total synthesis of the cytotoxic marine metabolite agelastatin A (1) has been achieved in about 14 steps performed in 12 operations in approximately 7% overall yield starting from cyclopentadiene. Hetero Diels- Alder cycloaddition of cyclopentadiene with N-sulfinyl methyl carbamate (7) afforded cycloadduct 8, which without purification was converted to allylic sulfoxide 9 and then by a [2,3]-sigmatropic rearrangement into bicyclic oxazolidinone 11. The C-5a nitrogen was introduced into the oxazolidinone Boc derivative 16 by a Sharpless/Kresze allylic amination with SES sulfodiimide 12c. Palladium-promoted cyclization of 2-acyl pyrroles 20 and 21 via a π- allylpalladium intermediate 22 led to ABC-tricycles 23 and 24, respectively. A hydroxyl urea D-ring model system was constructed by hydroborating 24, leading eventually to keto amide 31 and then to tetracycle 33. A modified strategy was developed for synthesis of the pivotal tricyclic ketone 58, involving as key steps a chemoselective hydrolysis of N-Boc oxazolidinone 54 and an internal conjugate addition of pyrrolo cyclopentenone 57. A TMS group was used as a convenient substitute for the C-1 bromine substituent of agelastatin A, and thus silylpyrrole 58 could be converted to bromopyrrole 59. Finally, the D-ring could be annulated onto an α-amino ketone derived from 59 using methyl isocycanate, providing racemic agelastatin A (1).

Original languageEnglish (US)
Pages (from-to)9574-9579
Number of pages6
JournalJournal of the American Chemical Society
Volume121
Issue number41
DOIs
StatePublished - Oct 20 1999

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Stien, D., Anderson, G. T., Chase, C. E., Koh, Y. H., & Weinreb, S. M. (1999). Total synthesis of the antitumor marine sponge alkaloid agelastatin A. Journal of the American Chemical Society, 121(41), 9574-9579. https://doi.org/10.1021/ja992487l