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Organic Chemistry Highlights

Total Synthesis

Monday, March 7, 2011
Douglass F. Taber
University of Delaware

The Bradshaw/Bonjoch Synthesis of (-)-Anominine

The Hajos-Parrish cyclization was a landmark in the asymmetric construction of polycarbocyclic natural products. Impressive at the time, the proline-mediated intramolecular aldol condensation proceeded with an ee that was low by modern standards. Ben Bradshaw and Josep Bonjoch of the Universitat de Barcelona optimized this protocol, then used it to prepare (J. Am. Chem. Soc. 2010, 132, 5966. DOI: 10.1021/ja101994q) the enone 3 en route to the Aspergillus alkaloid (-)-Anominine (4).

The optimized catalyst for the enantioselective Robinson annulation was the amide 5. With 2.5 mol % of the catalyst, the reaction proceeded in 97% ee. With only 1 mol % of catalyst, the reaction could be taken to 96% yield, while maintaining the ee at 94%. Conjugate addition proceeded across the open face of 3 to give, after selective protection, the monoketal 7. After methylenation and deprotection, oxidation with IBX delivered the enone 9.

With the angular quaternary centers of the natural product in place, the molecule became increasingly congested. Attempted direct alkylation of 9 led mainly to O-methylation. A solution to this problem was found in condensation with the Eschenmoser salt, followed by N-oxide formation and elimination to give the tetraene 10. Selective reduction by the Ganem protocol followed by equilibration completed the net methylation.

Under anhydrous conditions, the oxide derived from the allylic selenide 12 did not rearrange. On the addition of water, the rearrangement proceeded smoothly. Protection and hydroboration converted 13 into 14. The bulk of the folded molecule protected the exo methylene of 14, so hydrogenation followed by protection and oxidation delivered 15.

Conjugate addition of indole to 15 set the stage for oxidation and bis-methylenation to give 17. Selective Ru-mediated cross coupling with 18 followed by deprotection then completed the synthesis of (-)-Anominine (4), which proved to be the enantiomer of the natural product.

D. F. Taber, Org. Chem. Highlights 2011, March 7.