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Organic Chemistry Highlights

Total Synthesis

Monday, July 5, 2004
Douglass Taber
University of Delaware

Enantioselective Total Synthesis of (+)-Amphidinolide T1

Amphdinolide T1 1 is representative of a family of macrolides, isolated from the Amphidinium marine dinoflagellates, that show significant antitumor properties. Arun Ghosh of the University of Illinois at Chicago recently completed (J. Am. Chem. Soc. 2003, 125, 2374. DOI: 10.1021/ja021385j) a total synthesis of 1, based conceptually on the convergent coupling of the enantiomerically-pure fragments 2 and 3.

For each of the two fragments, a key component was assembled by the syn selective aldol condensation developed by Ghosh. For 2, addition to 3-benzyloxypropionaldehyde gave 4, which was carried on to the protected lactol 6. Homologation to 7 allowed Grubbs coupling with the fragment 8, leading to 9. Activation of the lactol by condensation with benzenesulfinic acid then gave 2.

The enantiomerically-pure aldehyde 14was prepared by adding dithiane to the commercially-available glycidyl tosylate 10. For the other half of 3, another syn-selective aldol condensation gave 12, which was carried on to the iodide 13. Reduction with t-butyl lithium, addition of the resulting organolithium to 11 and oxidation then gave the coupled ketone, which was homologated using the Petasis procedure to give 14.

In fact, the sensitive disubstituted alkene of 14 turned out to not be stable to the subsequent AlCl3 coupling conditions, so the alkene and the secondary alcohol were protected together as the bromoether 15. Condensation of the derived enol ether 16 with the sulfone 2 in the presence of DTBMP (2,6-di-t-butyl-4-methylpyridine) then gave 17. Yamaguchi lactonization followed by regeneration of the alkene by zinc reduction completed the synthesis of 1.

D. F. Taber, Org. Chem. Highlights 2004, July 5.