Enantioselective Total Synthesis of (−)-Acylfulvene and (−)-Irofulven

✍ Scribed by Mohammad Movassaghi; Grazia Piizzi; Dustin S. Siegel; Giovanni Piersanti

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 145 KB
• Volume: 45
• Category: Article
• ISSN: 0044-8249
• DOI: 10.1002/anie.200602011

✦ Synopsis

While sesquiterpene illudins M and S (1 and 2, respectively) are highly cytotoxic compounds isolated from Omphalotus illudens, a semisynthetic derivative, (À)-irofulven (4; hydroxymethyl acylfulvene (HMAF)), has recently demonstrated far superior efficacy as an antitumor agent. [1, 2] (À)-Irofulven ( 4) is currently in phase II clinical trials for the treatment of ovarian, prostate, and thyroid cancers both as monotherapy and combination therapy. [2] Significantly, it has demonstrated activity against a variety of solid tumors. Prior syntheses of irofulven using the Padwa carbonyl ylide 1,3-dipolar cycloaddition reaction and the Pauson-Khand reaction have been reported. [3] Herein, we describe a convergent enantioselective total synthesis of (À)-acylfulvene (3) and (À)-irofulven (4).

The inhibition of DNA synthesis and S-phase arrest in cells treated with these compounds stems from sequential nucleophilic addition at C8 and cyclopropyl ring opening, thus