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

We report our full account of the enantioselective total synthesis of (−)-acylfulvene (1) and (−)-irofulven (2), which features metathesis reactions for the rapid assembly of the molecular framework of these antitumor agents. We discuss (1) the application of an Evans Cu-catalyzed aldol addition reaction using a strained cyclopropyl ketenethioacetal, (2) an efficient enyne ring-closing metathesis cascade reaction in a challenging setting, (3) the reagent IPNBSH for a late-stage reductive allylic transposition reaction, and (4) the final RCM/dehydrogenation sequence for the formation of (−)-acylfulvene (1) and (−)-irofulven (2).Damon Runyon Cancer Research Foundation (grant no. DRS-39-04)National Institutes of Health (U.S.) and National Institute of General Medical Sciences (U.S.) (grant no. GM074825)Amgen, Inc.AstraZeneca (Firm