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Organic Chemistry Highlights

Total Synthesis

Monday, February 6, 2006
Douglass Taber
University of Delaware

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. DOI: 10.1021/ja0510616) 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.

Ullman coupling of 3 with the aryl iodide 4 to give 5 proved to be more effective than the alternative coupling with the areneboronic acid. Reduction of 5 with activated zinc powder converted the nitro group to the N-OH, which spontaneously cyclized to the nitrone 2. While 2 so preparared gave a 13C spectrum that was congruent with that of natural avrainvillamide, authentic material was not available, so a direct comparison could not be made.

In Et3N and CH3CN, 2 spontaneously dimerized to 1. As 2 is levorotatory (-35) and 1 is dextrorotatory (91), this ready interconversion of the monomer and the dimer will make it difficult to assign the absolute configuration of either natural product solely by comparison of rotations.

D. F. Taber, Org. Chem. Highlights 2006, February 6.