Stereocontrolled Natural Product Synthesis: Cyclic Ethers and Macrolides

Duncan J. Wardrop of the University of Illinois, Chicago, established (Org. Lett. 2006, 8, 3659. DOI) the five-membered ether ring of (±)-magnofargesin (3) by the addition of benzenesulfinate to the activated alkyne derived from 1. The alkylidene carbene so generated then inserted into the C-H bond adjacent to the ether oxygen, to give 2.

Six-membered ring cyclic ethers, in particular 2,6-dialkyl tetrahydropyrans, are ubiquitous in natural products. Several of the Annonacae acetogenins show remarkable antitumor activity. (-)-Jimenezin (6) is unusual in that it contains a six-membered ring. In the course of a synthesis of 6, Reinhard W. Hoffmann and Ulrich Koert of the Philipps-Universität Marburg (Org. Lett. 2006, 8, 3829. DOI) assembled that ring by cyclization of the allyl borinate 4 to 5 with high diastereocontrol.

Both Christine Willis of the University of Bristol (Org. Lett. 2006, 8, 3319. DOI) and Amos B. Smith III of the University of Pennsylvania (Org. Lett. 2006, 8, 3315. DOI) have reported syntheses of the dimeric (-)-calvosolide A (9). In the Willis synthesis, the 2,6-dialkyl tetrahydropyran was prepared by the acid-catalyzed (“Prins”) cyclization of 7 to 8. In the Smith synthesis, the 2,6-dialkyl tetrahydropyran was prepared by the Petasis-Ferrier rearrangement of 10 to 11.

In each case, completion of the synthesis of (-)-calvosolide A (9) involved macrolide construction by the Yamaguchi method, formation of the mixed anhydride with 2,4,6-trichlorobenzoyl chloride. Extending macrolactonization to larger rings, to prepare 14, a component of the defensive secretion of a soldier termite, Isamu Shiina of the Tokyo University of Science found (Org. Lett. 2006, 8, 4955. DOI) that a modified protocol using the anhydride of 2-methyl-6-nitrobenzoic acid was more effective.

Timothy F. Jamison of MIT has put forward (J. Am. Chem. Soc. 2006, 128, 15106. DOI) a complementary method for macrolide formation, pyrolysis of the ethoxy acetylene 15, to prepare (+)-acutiphycin 17. This method for ketene generation was originally developed by Raymond L. Funk.

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Douglass F. Taber

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