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Organic Chemistry Highlights

Total Synthesis

Monday, February 7, 2011
Douglass F. Taber
University of Delaware

The Boger Synthesis of (-)-Vindoline

The periwinkle-derived alkaloids vinblastine (2a) and vincristine (2b) are still mainstays of cancer chemotherapy. The more complex half of these dimeric alkaloids, vindoline (1), presents a formidable challenge for total synthesis. Building on his previous work (Org. Lett. 2005, 7, 4539. DOI: 10.1021/ol051975x), Dale L. Boger of Scripps, La Jolla devised (J. Am. Chem. Soc. 2010, 132, 3685. DOI: 10.1021/ja910695e) a strikingly simple solution to this problem, based on sequential cycloaddition.

The starting point for the synthesis was the ester 3, derived from D-asparagine. This was extended to 4, condensation of which with 5 gave the enol ether 6. On heating, 7 cyclized to 8, which lost N2 to give the zwitterion 9. Addition of the intermediate 9 to the indole then gave 10. In one reaction, the entire ring system of vindoline, appropriately oxygenated, was assembled, with the original stereogenic center from D-asparagine directing the relative and absolute configuration of the final product.

To complete the synthesis, the pendant carbon on 11 had to be incorporated into the pentacyclic skeleton. After adjusting the relative configuration of the secondary alcohol, the N was rendered nucleophilic by reduction of the amide to the amine. Oxidation delivered 14, that on activation as the tosylate smoothly rearranged to the ketone 15. Reduction and regioselective dehydration then completed the synthesis of vindoline (1).

D. F. Taber, Org. Chem. Highlights 2011, February 7.