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Organic Chemistry Highlights

Total Synthesis

Monday, November 5, 2007
Douglass F. Taber
University of Delaware

The Trost Synthesis of (-)-Terpestacin

(-)-Terpestacin (3), isolated from Arthrinium sp. FA1744, inhibits the formation of syncytia by HIV-infected T cells. A key step in the total synthesis of 3 reported (J. Am. Chem. Soc. 2007, 129, 4540. DOI: 10.1021/ja070571s) by Barry M. Trost of Stanford University was the Ru-catalyzed cyclization of 1 to 2. This synthesis of (-)-terpestacin (3) elegantly illustrates the power of the Trost enantioselective Pd catalysts.

The preparation of 1 began with the commercially-available diketone 4. With the enol as the nucleophile, opening of racemic isoprene monoepoxide 5 using the Trost chiral Pd catalyst led to the ether 6 in high ee. It is impressive that even though it was directed by a quaternary stereogenic center, the subsequent Claisen rearrangement to 7 proceeded with complete facial selectivity. Oxidation to the nonenolizable α-diketone 8 then set the stage for the conjugate addition. Again, even though the directing stereogenic center was quaternary, the addition proceeded with substantial diastereocontrol. Further study of the elements that govern the facial selectivity of the Lewis acid-mediated (Sakurai) addition of allyl silanes to enones would certainly be warranted.

The sulfone 11 was prepared in four steps from commericially-available geranyl bromide, with the absolute configuration being set by Sharpless asymmetric epoxidation. Subsequent to the alkylation of 11 with the bromide 10, the now-surplus sulfone was removed reductively with Pd(OAc)2 and NaBH4. It is noteworthy that the enone of 1 was stable to those conditions.

The cyclization of 1 with the second-generation Grubbs catalyst delivered the desired E alkene 2 in 43% yield. As had been observed before by others, the free allylic alcohol was the preferred substrate for the Ru metathesis catalyst. No cyclization was observed with tetraenes that had the alcohol protected.

With 2 in hand, it remained to install the side chain. The relative configuration of the pentenyl side chain of 14 was set by again using chiral Pd catalysis. The Claisen rearrangement proceeded smoothly, to give, after protection, the ether 15.

The oxidative cleavage of the side chain of 15 initially presented some difficulties. Eventually, it was found that AD-Mix-α (but not β) could effect selective dihydroxylation. Periodate cleavage followed by reduction then gave 16, which was deprotected to (-)-terpestacin (3).

Note that both 5 and 13 were racemic. Except for the secondary alcohol on the fifteen-membered ring, the absolute configuration of every stereogenic center in the (-)-terpestacin (3) prepared by this synthesis derived from the absolute configuration of the enantiomerically-pure Pd complexes used as first 5 and then 13 were incorporated selectively into the natural product.

D. F. Taber, Org. Chem. Highlights 2007, November 5.