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Organic Chemistry Highlights

Total Synthesis

Monday, January 4, 2010
Douglass F. Taber
University of Delaware

The Williams Synthesis of (-)-4-Hydroxydictyolactone

(-)-4-Hydroxydictyolactone (3), representative of the cyclononene xenicanes isolated from the Dictyotacae algae, readily isomerizes thermally to the more stable (Z)-6,7-isomer. Attempts to directly form this strained ring system appeared to be fraught with difficulty. David R. Williams of Indiana University envisoned (J. Am. Chem. Soc. 2009, 131, 9038. DOI: 10.1021/ja902677t) that use of Suzuki coupling might ameliorate some of the strain, since at the point of commitment to bond formation, the Pd center would be included in the forming ring. This analysis led specifically to the trans ether 1, as cyclization of the trans ether appeared likely to be more facile than would cyclization of the alternative cis diastereomer.

The first challenge was the assembly of the array the four contiguous alkylated stereogenic centers of 1. To this end, the Z secondary ester 7 was prepared from the acetonide 4, available from mannitol, and (R)-(+)-citronellic acid, prepared by oxidation of the commercial aldehyde. Addition of 7 to LDA led to decomposition, but inverse addition of LDA to a mixture of the ester, TMSCl and Et3N smoothly delivered the ketene silyl acetal. On warming, Ireland-Claisen rearrangement of the ketene silyl acetal led to the acid 8 with remarkable diastereocontrol.

The last alkylated stereogenic center of 1 was installed by reductive cyclization of the formate ester 9. Again, the cyclization proceeded with remarkable diastererocontrol. While the intramolecular reaction of in situ prepared allyl metals is well precedented, the addition to a formate ester had not previously been reported.

Although 11 appears to be ready for the long-awaited Suzuki coupling, in fact the TIPS protecting group substantially slowed hydroboration. The free alcohol/methyl acetal was the best substrate for hydroboration, but the free alcohol entered into other side reactions. After extensive experimentation, a happy medium was found with the methyl acetal/TBS ether 1.

Selenylation of the lactone 12 followed by oxidative elimination of the selenide delivered the expected Z alkene. Removal of the silyl protecting group had to precede introduction of the second alkene, as the product 3 deteriorated rapidly on exposure to the alkaline conditions of TBAF cleavage.

Strained medium rings such as the (E,Z)-cyclononadiene assembled in this study have been particularly challenging to prepare. It will be interesting to see how generally useful the Suzuki coupling turns out to be for the construction of such rings.

D. F. Taber, Org. Chem. Highlights 2010, January 4.