Enantioselective Total Synthesis of FR900482

Masashi Suzuki, Mika Kambe, Hidetoshi Tokuyama, Tohru Fukuyama

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

The development of two approaches for the enantioselective total synthesis of FR900482 is described. A precursor for the formation of the benzazocine ring was assembled effectively by a modification of the Sonogashira coupling of an aryl triflate with a chiral acetylene unit derived from tartaric acid and the subsequent novel ketone formation via conjugate addition of pyrrolidine to the o-nitrophenylacetylene derivative. The first-generation approach to the key pentacyclic intermediate of our racemic total synthesis utilizes an intramolecular Mitsunobu reaction of an ω-hydroxynitrobenzenesulfonamide to form the benzazocine ring and a stepwise sequence to construct the hydroxymethyl group at the C(7) position. The key intermediate could be synthesized in optically pure form via formation of the characteristic hydroxylamine hemiacetal and a stereoselective epoxide formation. In the second-generation approach, the N-hydroxybenzazocine ring could be constructed directly from an ω-formylnitrobenzene derivative by intramolecular reductive hydroxylamination. The crucial stereoselective hydroxymethylation and the formation of the hydroxylamine hemiacetal could be performed efficiently by a one-pot sequence. After leading to the pentacyclic key intermediate, the total synthesis of (+)-FR900482 was accomplished by a modification of our protocol established in the racemic total synthesis. Stereochemical issues involved in the hydroxymethylation at the C(7) position and formation of the hydroxylamine hemiacetal are also discussed in detail.

Original languageEnglish
Pages (from-to)2831-2843
Number of pages13
JournalJournal of Organic Chemistry
Volume69
Issue number8
DOIs
Publication statusPublished - 2004 Apr 16
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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