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