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Total Synthesis

Monday, January 5, 2015
Douglass F. Taber
University of Delaware

The Smith Synthesis of (-)-Calyciphylline N

The Daphniphyllum alkaloids are a diverse group, some of which exhibit potent biological activity. Amos B. Smith III of the University of Pennsylvania envisioned (J. Am. Chem. Soc. 2014, 136, 870. DOI: 10.1021/ja411539w) the preparation of the bicyclo[2.2.2] core of (-)-Calyciphylline N (3) by the intramolecular Diels-Alder cyclization of 1 to 2, with the silicon of 2 a surrogate for the secondary alcohol of 3.

Following the precedent of Mori (Tetrahedron Asymm. 2005, 16, 685. DOI: 10.1016/j.tetasy.2004.11.077), the requisite secondary center of 1 was set by methylation of the anion derived from the Evans acyl oxazolidinone 4. Reductive removal of the oxazolidinone led to the alcohol 5, that was reduced under Birch conditions, then isomerized with base to the desired conjugated diene 6. This was silylated with the alkenyl silane 7 to give the triene 1. Direct thermal cyclization of 1 gave a mixture of all four possible diastereomers of the cycloadduct. Fortunately, the Lewis acid-activated cyclization delivered 2 as the dominant diastereomer.

To differentiate the two ends of the alkene, the ester of 2 was extended to the alcohol 8. Epoxidation occurred from the more open face of the alkene, setting the stage for intramolecular opening and oxidation to give 9. Reduction with SmI2 and protection then completed the preparation of the ketone 10.

The third quaternary center of 3 was constructed by acetylation of 10 followed by Pd-catalyzed allylation, to give 11. On exposure to LDA, the derived iodide 12 smoothly cyclized to the cycloheptanone 13, the structure of which was confirmed by X-ray analysis.

The alkene of 13 was converted to the primary alcohol, which was protected. The aryl lithium 14 then was used to selectively open the cyclic silyl ether, to give 15. Coupling with phthalimide followed by carbonylative vinylation of the derived vinyl triflate delivered the dienone 16. Exposure to HBF4 effected the desired Nazarov cyclization, and at the same time converted the aryl silane to the fluorosilane, set for the Tamao oxidation that revealed the secondary alcohol. The two alcohols were sequentially protected to give 17.

Direct oxidation of the primary silyl ether gave the aldehyde. Following the precedent of Carreira in the preparation of the closely related alkaloid (+)-Daphmanidin E (The Carreira Synthesis of (+)-Daphmanidin E 2012, September 3), intramolecular aldol condensation followed by oxidation led to 18. Selective Ir-catalyzed hydrogenation followed by deprotection and cyclization then completed the synthesis of (-)-Calyciphylline N (3).

D. F. Taber, Org. Chem. Highlights 2015, January 5.