Intramolecular (4+3) cycloadditions of thiophenes and total synthesis of toxicodenane A

Abstract

We achieved the total synthesis of toxicodenane A, a novel sesquiterpenoid possessing an oxygen-bridged 6,7-fused bicyclic skeleton. Intramolecular (4+3) cycloaddition of 2.30 generating cycloadduct 2.31 in 42% yield, was employed as the key step to construct the oxygen-bridged bicyclic framework with a quaternary stereocenter in the targeted molecule. Subsequent Barton deoxygenation to reduce carbonyl and Wittig olefination to introduce exocyclic double bond, successfully produced ether 2.63. Late-stage oxidation converting ketone to enone and 1,4-addition installing gem-dimethyl group completed the synthesis towards toxicodenane A. Overall, starting from commercially available furan, the synthesis was accomplished in 20 steps.

Intramolecular (4+3) cycloadditions of epoxy/aziridinyl enolsilane tethered thiophenes have been examined. A total of fourteen thienyl substrates have been found to undergo (4+3) cycloaddition to provide sulfur-bridged cycloadducts in yields of up to 83% with moderate to good diastereoselectivity. Complete conservation of enantiomeric purity was observed when the optically enriched substrate was used. The cycloaddition is assumed to proceed via a sulfur-stabilized carbocationic intermediate through a stepwise mechanism to generate the endo/exo cycloadducts. A three-carbon tether has a significant impact on the reaction outcome, favouring the formation of (4+3) cycloadducts over alkylation products. The substituents R1 and R3 exert considerable influence on the yield and selectivity through stabilizing effect and steric effect. When R3 = Me, the cycloaddition is high-yielding and exo-selective.

Desulfurization of the sulfur-bridged cycloadducts has been studied. The sulfur bridge was cleaved through thermal or LiAlH4-mediated SO2 elimination to produce a non-bridged 6,7-fused bicyclic skeleton. A highly functionalized framework consisting of a diol functionality and a diene moiety was successfully constructed in a diastereoselective manner.