Total Synthesis Highlights

62. Synthesis of (-)-Avrainvillamide and (+)-Stephacidin B
The dimeric alkaloid stephacidin B (1) was recently isolated from a fungus culture. The
“monomer” avrainvillamide (2) had previously been described. Andrew G. Myers of Harvard
University has reported (J. Am. Chem. Soc. 2005, 127, 5342.) the enantioselective total synthesis
of 2, and the dimerization of 2 to 1. The key intermediate in the synthesis was the tetracyclic
amide 3.
The absolute configuration of the target natural products was set by enantioselective reduction of
the enone 6. Usually, catalytic Itsuno-Corey reduction of cyclohexenones without an α-substituent
is not selective. In this case, advantage was taken of that lack of induction from the alkene side,
with the steric bulk on the other side of the ketone directing the reduction. Alkylation of 8 with 9
proceeded to give the expected axial product 10. Cyanation proceeded with remarkable
diastereocontrol, to give, after epimerization and hydrolysis, the amide 11. Conjugate addition of
thiophenol followed by spontaneous cyclization and dehydration led to the amide 12. With the
phenylthio enamide in place, the stage was set for the elegant final cyclization: hydrogen atom
abstraction from the dihydroaromatic followed by fragmentation delivered the formamide radical,
that cyclized efficiently to give the tetracyle 13. Oxidation and iodination of the enone then gave
3.