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

Abstract

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 (EYRCM) 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).

Multi-Bond Forming Processes in Efficient Synthesis

“…[158] Two-fold ene-yne metathesis, pioneered by the group of Grubbs in the 1990s, [159] has also proven to be an efficient strategy for the synthesis of structures containing up to four new rings. [160,161] Some of the most recent examples feature in the work reported by the groups of Yang, [162] Fukuyama, [163] Metz, [164] Oguri, [165] Movassaghi, [166] Mulzer, [167] and Lee. [168] Olefin metathesis steps have also been combined with other transformations in independent reaction sequences.…”

5.27 Ene–Yne Metathesis

“…175 The metathesis cascade (which was studied extensively in model systems) 176 was initiated by the second-generation Grubbs complex to afford an intermediate tricyclic diene, which was deprotected in situ to give the triol 29 (equation 94). The bond-forming events are orchestrated by alkene reactivity; the most reactive allyl ether initiated the cascade and the less reactive geminally disubstituted alkene terminated it.…”

Copper(II) Trifluoromethanesulfonate

“…A copper triflate-catalyzed asymmetric aldol reaction has been disclosed between a strained cyclopropyl ketene thioacetal and methyl pyruvate (eq 54). 48 The enantiomerically enriched thiol ester was afforded in 95% yield and 92% ee on a 20-g batch. Enantioselective Alkylation.…”