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

Abstract

Antitumor agents (−)‐acylfulvene and (−)‐irofulven are prepared in an approach that employs the powerful enyne ring‐closing metathesis reaction to secure the spiro‐bicyclic AB rings. Other key features of this synthesis include an efficient aldol‐based introduction of the stereocenter at C2, a diazene‐mediated reductive allylic transposition, and a ring‐closing metathesis/oxidation sequence.

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

“…Thus, enynes 55f-p were subjected to G2 (10 mol%) in PhH at 65 °C for 1 h to afford the desired tricyclic dienes 60f-p in modest to good yields (Scheme 16). 10 In situ 1 H NMR monitoring of these reactions revealed clean conversion in all cases. Thus, the moderate yields are attributed to the sensitivity of these silanes towards silica gel chromatography.…”

“…The reactivity of the silyl ether substrates 91k and 91l were significantly enhanced under the EYRCM conditions and required only 15 mol% catalyst loading of G2 at 90 °C (Scheme 23). 10 After in situ desilylation of the EYRCM product, a mixture of the desired triol 82k and byproduct 92 were isolated in 52% and 20% yield, respectively. Conversely, the styrenyl derivative 91l 10 containing a C7-C8 trisubstitued styrenyl alkene underwent the EYRCM cascade and desilylation reaction smoothly to afford the desired triol 82l exclusively in 79% yield (Scheme 23).…”

“…Unfortunately, when we tried to apply these conditions to the reductive allylic transposition of substrate 97l, the yield of the isolated product 99l was modest (54%, entry 4) as a result of the poor solubility of this substrate. 10 To address the lack of reactivity of alcohol 97l, we added neopentyl alcohol to improve the efficiency of the Mitsunobu displacement. 53 Unfortunately, neopentyl alcohol further decreased the solubility of the substrate resulting in poor yield of olefin 99l (35%, entry 5).…”

“…9 Our laboratory has disclosed concise enantioselective syntheses of (−)-acylfulvene (1) and (−)-irofulven (2). 10 Key features of our approach include a stereoselective aldol addition of a strained ketenehemithioacetal 26, which secures the C2 stereocenter and enables ready access to aldehyde (+)-22 (Scheme 2). A key enyne ring-closing metathesis (EYRCM) 11 cascade reaction of trienyne 21 generates the AB-ring system 20.…”

N-Isopropylidene-N‘-2-nitrobenzenesulfonyl Hydrazine, a Reagent for Reduction of Alcohols via the Corresponding Monoalkyl Diazenes

“…6 We recently reported the use of the related reagent N-isopropylidene-N′-2-nitrobenzene-sulfonyl hydrazine (IPNBSH) for a difficult allylic reductive transposition step in our total syntheses of (−)-acylfulvene and (−)-irofulven. 7 Herein we report our results on the general utility of IPNBSH, a complimentary reagent to NBSH, for conversion of alcohols to the corresponding monoalkyl diazene intermediates.The stereospecific displacement of an alcohol by the reagent NBSH under the Mitsunobu reaction conditions affords the corresponding 1,1-disubstituted sulfonyl hydrazine 2 (Scheme 1). 3 Warming of the reaction mixture to ambient temperature provides the corresponding monoalkyl diazene 3 by elimination of 2-nitrobenzenesulfinic acid.…”