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Organic Chemistry Highlights

Total Synthesis

Monday, June 6, 2005
Douglass Taber
University of Delaware

Synthesis of (-)-Norzoanthamine

The marine alkaloid (-)-norzoanthamine (3) suppresses bone loss in ovariectomized mice, and so is of interest as a lead to antiosteoporotic drugs. A substantial challenge in the assembly of 3 is the stereocontrolled construction of the C ring, with its three all-carbon quaternary centers. In the synthesis of 3 by Masaaki Mayashita of Hokkaido University (Science 2004, 305, 495. DOI: 10.1126/science.1098851) the B and C rings were built and two of the three needed quaternary centers were set by the intramolecular Diels-Alder cyclization of 1 to 2.

The triene 1 was prepared from the enone 4, available in enantiomerically-pure form over several steps from pulegone. Triply-convergent coupling with the cuprate 5 and the aldehyde 6 led to the furan 7. Functional group manipulation then gave 1, setting the stage for the intramolecular Diels-Alder cyclization.

The cyclization of 1 proceeded with 72: 28 diastereoselectivity, leading, after hydrolysis, to the crystalline diketone 8 as the major product. Reduction of the ketones to the axial alcohols was followed by spontaneous lactonization, allowing easy differentiation of the several functional groups. Homologation to 10 followed by condensation with methyl carbonate and subsequent O-methylation then gave 11. C-Methylation of 11 then set the third quaternary center of the C ring. The deuteriums were introduced to minimize an unwanted intramolecular hydride transfer in a later step.

The EFG ring carbons were attached by condensing 13, derived from 12, with the aldehyde 14, followed by oxidation. Hydrogenation followed by deprotection and oxidation then led to the triketone 16. Selective enolization of the A-ring ketone allowed facile oxidation to the alkene. Deprotection and acid-catalyzed cyclization then gave 3. Note that the original stereocenter in 4 was used to set seven of the nine stereocenters of 3.

D. F. Taber, Org. Chem. Highlights 2005, June 6.