Asymmetric total synthesis of acetoxymodhephenes and toward a total synthesis of oxetanocin A

Abstract

The key points in the synthesis of modhephene-derivatives are how to construct propellane skeleton and how to introduce three consecutive quaternary carbon centers. First, for synthesis of optically pure modhephene-derivatives, a quaternary carbon center at α-position of β-ketoester 128 was enantioselectively introduced via asymmetric Michael addition reaction using optically pure chiral β-enaminoester 129. Secondly, core skeleton of modhephene- derivatives was constructed through a tandem radical reaction sequence, which involved the rearrangement, as the key step in the total synthesis of modhephene-derivatives. Dienyne 137, prepared from b-keto ester 128, undergo tributyltin mediated radical reaction to form tricyclo[4.3.3] propellane 138. Finally, tricylco[3.3.3] propellane structure was generated via ring contraction reaction using Lewis acid catalyzed rearrangement of α, β-epoxy ketones 173, 174 in synthesis of acetoxymodhephenes. Through manipulation of functional group, syntheses of modhephene-derivatives were completed. The readily available epoxysulfone 326 provides controlled access to both the oxetanose 327 and deoxyfuranose 328 ring systems via either formal exo or endo ring opening of the derived carbanion, respectively. The mode of ring opening in these compounds is controlled by the choice of reagent, as the use of organolithium bases (with a Lewis acid promoter) effects exo ring opening of the epoxide, while the use of organomagnesium bases affords the product of formal endo ring opening. The anomeric sulfone functionality present in oxetane ring of these cyclization can also be used to further functionalize these compounds. This strategy is currently being employed in a synthesis of the antiviral oxetanocin A.