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Organic Chemistry Highlights

Total Synthesis

Monday, December 6, 2010
Douglass F. Taber
University of Delaware

The Chen Synthesis of (-)-Nakiterpiosin

(-)-Nakiterpiosin (3), isolated from the thin encrusting sponge Terpios hoshinota, has an IC50 against murine P388 leukemia cells of 10 ng/mL. Chuo Chen of UT Southwestern Medical Center developed (J. Am. Chem. Soc. 2010, 132, 371. DOI: 10.1021/ja908626k) a practical synthetic route to 3 based on the convergent coupling of 1 and 2.

The preparation of 1 was based on the intramolecular [4+2] cyclization of the furan 9, prepared by Friedel-Crafts acylation of furan (4) with maleic anhydride (5). The absolute configuration of the secondary alcohol was set by Noyori reduction, using sodium formate as the hydride source.

The cyclization of 9 to 10 proceeded with high diastereocontrol, presumably by way of a chelated transition state. As expected, cyclization of the silyl ether of 9 delivered the complementary diastereomer. As the cyclization of 9 was readily reversible, it was taken quickly to the bromide 11. Oxidative cleavage of the diol followed by selective reduction and protection then completed the synthesis of 1.

The preparation of 2 began with the commercial bromo acid 12. The enantiomerically-enriched epoxide 13 was constructed in the usual way, by homologation of the aldehyde to the allylic alcohol followed by Sharpless epoxidation. On exposure to the Yamamoto catalyst, 13 smoothly rearranged to the aldehyde 14. Condensation of 14 with 15 then gave 16, with only minimal erosion of enantiomeric excess over the two steps.

Unfortunately, 16 was the incorrect diastereomer, so it had to be inverted. With the aldehyde 17 in hand, conversion to the dichloride followed by functional group interchange completed the construction of 2.

Carbonylative coupling of 1 and 2 led to the enone 18. The photochemical Nazarov cyclization of 18 proceeded with the expected high diastereocontrol, to give, after epimerization, the desired trans-anti-trans product. Deprotection then completed the synthesis of (-)-Nakiterpiosin (3). It is noteworthy that the full A-ring functionality of 3 was compatible with the conditions of the photochemical cyclization.

The work of Chen toward the total synthesis of (-)-nakiterpoisin (3) led to a correction of the relative configurations both of the dichloromethyl substituent and of the secondary bromide. The availability of 3 by total synthesis is particularly exciting, because it has been shown to interfere with the Hedgehog signaling pathway. There is the potential, based on this activity, that derivatives of 3 may prove useful as adjuncts in cancer chemotherapy.

D. F. Taber, Org. Chem. Highlights 2010, December 6.