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Organic Chemistry Highlights

Total Synthesis

Monday, January 3, 2005
Douglass Taber
University of Delaware

Enantioselective Synthesis of (+)-Tricycloclavulone

Triclavulone 3, recently isolated from Clavularia vulgaris, is one of the most complex of the family of about forty structurally-related fatty acid-derived marine prostanoids described from this species. Hisanaka Ito and Kazuo Iguchi of the Tokyo University of Pharmacy and Life Science recently reported (J. Am. Chem. Soc. 2004, 126, 4520. DOI: 10.1021/ja049750p) the total synthesis of 3, starting with the preparation of the enantiomerically-enriched bicyclic ketone 1.

The enantioselective Cu-catalyzed cycloaddition of the reactive enone 4 to the alkyne 5 proceeded efficiently, but with only modest enantiomeric excess. This was improved at a later point in the synthesis, by recrystallization of 2.

The folded geometry of 1 directed the Grignard addition, to give, after protection, the ester 7. Homologation to the allylic alcohol 8 set the stage for Grubbs ring closure, to give, after oxidation, the tricyclic sulfone 9, having the skeleton of triclavulone 3.

There were two more stereocenters to set. It was expected that cuprates would add to the open face of the strained cyclobutene. The control of the other stereocenter was more problematic. One solution was to prepare an α-sulfonyl lactone. To this end, the ketone was converted to the secondary carbonate. As hoped, conjugate addition was followed by intramolecular acylation, but the reaction continued to full acyl transfer, to give 10. Fortunately, desilylation of 10 proceeded with concomitant lactonization. Desulfonylation then gave 2, which could be brought to high ee by recrystallization.

With 2 in hand, the rest of the synthesis proceeded smoothly. Reprotection followed by reduction and oxidation gave the keto aldehyde 11. Condensation of the keto phosphonate 12 with 11 gave the enone 13. Enantioselective transfer hydrogenation of 13 gave the allylic alcohol 14 with 11:1 diastereoselectivity. Protecting group interchange then gave triclavulone 3, identical in every respect with natural material.

D. F. Taber, Org. Chem. Highlights 2005, January 3.