Studies on the synthesis of cyclobutane-containing strained natural products: Methodologies and the total synthesis of (+)-acanthodoral and (+)-kelsoene.

Abstract

The first total synthesis of (+/-)-acanthodoral has been achieved in 2.5% overall yield and 19 steps from 3-methylcyclohex-2-en-1-one. The key intermediate, (2,7,7-trimethyl-3,4,5,6,7,7a-hexahydro-3a<italic>H </italic>-inden-3a-yl)acetic acid was prepared efficiently through a Pd-catalyzed metallo-ene reaction of (2,2-dimethyl-6-methylenecyclohexyl)-2-methylprop-2-enyl methyl carbonate. Electrocyclic ring-opening of its 1,1-dibromocyclopropane derivative in (CF₃)₂CHOH with <italic>p</italic>-methoxybenzenethiol as a nucleophile provided methyl [(4a<italic>S</italic>*,8<italic>R</italic>*,8a<italic> S</italic>*)-7-bromo-1,1,6-trimethyl-8-(4-methoxy-phenylsulfanyl)-1,3,4,5,8,8a-hexahydronaphthalen-4a(2<italic> H</italic>)-yl]acetate with high regio- and stereoselectivity in excellent yields. Acyl radical 5-<italic>exo</italic> cyclization in an S_H2<super> '</super> process afforded 8-phenylthio-5,5,9-trimethyltricyclo[7.2.1.0<super> 1,6</super>]dodec-7-en-10-one, which was then converted into acanthodoral in 5 steps including a highly diastereoselective Wolff rearrangement. An enantioselective synthesis of (+)-acanthodoral has been achieved by starting from enantiomerically pure (+)-[(1<italic>S</italic>)-2,2-dimethyl-6-methylenecyclohexyl] methanol and following the procedures established for the synthesis of racemic acanthodoral. A general approach toward highly-substituted bicyclo[3.2.0]heptanes has been developed by utilizing homo-Favorskii rearrangement, acid-catalyzed skeleton rearrangement, and deoxygenation. This method was successfully applied to the total synthesis of kelsoene (starting from 1-methoxycyclohexa-1,4-diene in 16 steps and 12.5% overall yield). An enantioselective synthesis of (+)-kelsoene has been accomplished by using enantiomerically pure (+)-(<italic>S</italic>)-1,4-dioxaspiro[4.5]dec-8-en-7-yl pivaloate, which was efficiently accessed by Pd-catalyzed deracemization of the corresponding racemic methyl carbonate. In connection with an effort to develop a new, efficient method for the generation of radicals from alcohols and acids, a novel conversion of alcohols into iodides has been devised. Alkyl 2<super>'</super>-iodo-1,1<super> '</super>-biphenyl-2-yl(phenyl)phosphinites derived from alcohols were converted into iodides efficiently under neutral conditions (toluene, reflux). Moreover, the iodides thus obtained could be directly reduced under standard radical conditions (Bu₃SnH, cat. AIBN, 80&deg;C) in the same reaction vessel without purification of the iodides, achieving an efficient two-pot deoxygenation of alcohols.