Organic Chemistry Portal
Organic Chemistry Highlights

Search Org. Chem. Highlights:

Match: or and

Monday, April 16, 2007
Douglass Taber
University of Delaware

Stereocontrolled Natural Product Synthesis: Cyclic Ethers and Macrolides

Duncan J. Wardrop of the University of Illinois, Chicago, established (Org. Lett. 2006, 8, 3659. DOI: 10.1021/ol0609053) 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: 10.1021/ol0614471) 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: 10.1021/ol0611705) and Amos B. Smith III of the University of Pennsylvania (Org. Lett. 2006, 8, 3315. DOI: 10.1021/ol0611752) 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: 10.1021/ol062011o) 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: 10.1021/ja0670660) 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.

D. F. Taber, Org. Chem. Highlights 2007, April 16.