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Organic Chemistry Highlights

Total Synthesis

Monday, April 6, 2009
Douglass F. Taber
University of Delaware

The Hoveyda Synthesis of (-)-Clavirolide C

Conjugate addition-enolate trapping, a strategy originally developed by Gilbert Stork, has become a powerful method for stereocontrolled ring construction. A key step in the synthesis of (-)-Clavirolide C (3) reported (J. Am. Chem. Soc. 2008, 130, 12904 DOI: 10.1021/ja8058414) by Amir H. Hoveyda of Boston College occurred early on, with the enantioselective conjugate addition of Me3Al to 1 to give the silyl enol ether 2. Enantioselective conjugate addition to establish a quaternary center β on a cyclohexanone had been established (Transition Metal-Mediated Construction of Carbocycles: Dimethyl Gloiosiphone A (Takahashi), Pasteurestin A (Mulzer), and Pentalenene (Fox) 2008, August 18), but not yet on cyclopentanones. Professor Hoveyda found that a modified form of the Ag catalyst that they had published earlier, in combination with the Lewis acidic AlMe3, effected conjugate addition to 1 in 84% ee. Quenching of the reaction mixture with triethylsilyl triflate led to the enol silyl ether 2.

The assembly of the 11-membered ring of 3 also began with an enantioselective conjugate methylation, of the lactone 4 with Me2Zn, again using a catalyst developed by Professor Hoveyda. Opening of the lactone 5 followed by Swern oxidation gave the Weinreb amide 6, that was homologated and reduced to give 7.

Addition of n-BuLi to 2 regenerated the enolate. There were two issues in the addition of that enolate to the aldehyde 7: syn vs. anti stereocontrol, and control of the configuration of the newly formed ternary center on the ring relative to the already-established quaternary center. Inclusion of Et3B in the reaction mixture assured anti aldol formation, but there was only a modest preference for the desired bond formation trans to the slightly more bulky butenyl group, to give 8.

Medium rings are more strained than are larger rings. The diene 8 was reluctant to close with the second generation Grubbs catalyst, but the catalyst developed by Professor Hoveyda worked well. The δ-lactone of 3 was then constructed by acylation of 9 with 10 followed by reductive cyclization with SmI2. Conjugate addition to the derived enone 12 on the outside face of the medium ring alkene gave the desired 13 (9:1 dr). This reaction may be proceeding via the s-cis conformer, as the more stable s-trans conformer would have been expected to give the other diastereomer. Dehydration of 13 then delivered (-)-Clavirolide C (3).

This concise synthesis of the dolabellane 3 showcases the power of the catalytic enantioselective methods for the construction of both ternary and quaternary, including cyclic quaternary, centers that Professor Hoveyda has developed. Clearly, asymmetric transformation of inexpensive prochiral ring precursors such as 1 and 4 will make advanced, high ee intermediates such as 2 and 5 much more readily available than they have been in the past.

D. F. Taber, Org. Chem. Highlights 2009, April 6.