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Organic Chemistry Highlights

Total Synthesis

Monday, September 7, 2009
Douglass F. Taber
University of Delaware

The Trost Synthesis of (-)-Ushikulide A

(-)-Ushikolide A (4), isolated from a culture broth of Streptomyces sp. IUK-102, showed powerful activity against murine splenic lymphocyte proliferation (IC50 = 70 nM). The most important player in the synthesis of 4 described (J. Am. Chem. Soc. 2008, 130, 16190. DOI: 10.1021/ja807127s) by Barry M. Trost of Stanford University was the ProPhenol ligand 1.

The precursor 2 was prepared by coupling the mesylate 7, the alkyne 12, and the aldehyde 13. The first role of catalyst 1 was in mediating the enantioselective coupling of commercial 5 with 6 to give, after saponification and CuCl decarboxylation, the mesylate 7. The preparation of 12 began with the Noyori hydrogenation of the ester 8 to the alcohol 9 in the expected high ee. Note that although this transformation was carried out at 1800 psi, such reductions proceed well and in similar ee at 60C and 60 psi. Brown crotylation of the derived aldehyde 10 delivered 11, that was homologated to the alkyne 12.

The third fragment 13 was prepared by chiral auxiliary directed aldol reaction. Combination of 12 with 13 was followed by Au-mediated cyclization, converting the internal alkyne of 14 to the spiroketal of 15. Pd-catalyzed coupling of 15 with 7 then led to 2 with high diastereocontrol.

The aldol addition of the enolate of 17 to 18 proved elusive under the usual conditions, but with 30 mol % of the Zn catalyst 1 the reaction proceeded smoothly, to deliver 19 with high diastereocontrol.

To complete the synthesis, hydroboration with 9-BBN was effected on the free carboxylic acid 3, and Pd-mediated coupling of the derived borane was carried out with the free iodo alcohol 2. As a result, the product hydroxy acid 20 could be taken directly to the subsequent macrolactonization.

D. F. Taber, Org. Chem. Highlights 2009, September 7.