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Organic Chemistry Highlights

Total Synthesis

Monday, March 2, 2015
Douglass F. Taber
University of Delaware

The Fuwa Synthesis of Didemnaketal B

Didemnaketal B (3) may be an artifact of isolation, derived from Didemnaketal C, in which one of the methyl esters is instead an ethylsulfonate. Nevertheless, it is B, not C, that is a potent inhibitor of HIV protease. Haruhiko Fuwa of Tohoku University has provided (Chem. Eur. J. 2014, 20, 1848. DOI: 10.1002/chem.201303713) a detailed account of the synthesis of 3, including the necessary revision of the absolute configuration of seven of the stereogenic centers. A central feature of the modular synthesis of 3 was the cyclization of 1 to the thermodynamically most favorable diastereomer of the spiroketal 2.

Three components were combined for the synthesis of 3. The upper sidechain was prepared from commercial citronellal (4). Reduction followed by protection and ozonolysis delivered the aldehyde 5, that was carried on to the alkyne 6. Hydroiodination using the method previously reported by the authors (Carbon-Carbon Bond Formation 2011, May 30) gave 7, that was oxidized to the ester 9.

Lactone formation by ring closing metathesis is difficult because of the substantial preference for the extended conformation of the ester. As illustrated by the conversion of 10 to 11, this can be overcome by complexation with a Lewis acid. Conjugate addition followed by phosphorylation completed the preparation of the enol phosphate 12.

The third component of 3 was the lactone 15, prepared by deprotonation/kinetic protonation of 13. This was carried on to the sulfone 16. Although the Julia-Kocienski reaction usually strongly favors the E alkene, in this case it was necessary to optimize both the base and the solvent. Sharpless asymmetric dihydroxylation followed by coupling with the enol phosphate 12 then completed the preparation of the diol 1.

Addition of the ketene silyl acetal 18 to the aldehyde derived from 2 proceeded to give the undesired diastereomer 19. This was overcome by oxidation to the ketone followed by enantioselective reduction. The iodide 9 was added to the aldehyde 20 to give a 1.8:1 mixture of diastereomers, the major of which was Didemnaketal B (3).

This full paper is worth reading in detail. The work reported underlines the importance of powerful protocols for carbon-carbon bond formation that maintain high diastereocontrol in stereochemically complex environments.

D. F. Taber, Org. Chem. Highlights 2015, March 2.