Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, June 5, 2006
Douglass Taber
University of Delaware

The Boger Route to (-)-Vindoline

The Vinca-derived vinblastine (2a) and vincristine (2b) are still mainstays of cancer chemotherapy. The more complex half of these dimeric alkaloids, vindoline (1), has in the past presented a formidable challenge for total synthesis. Dale L. Boger of Scripps, La Jolla has developed (Org. Lett. 2005, 7, 4539. DOI: 10.1021/ol051975x) a strikingly simple solution to this problem, based on sequential cycloaddition.

The starting point for the synthesis was N-methyl 6-methoxytryptamine (3), an improved preparation of which is described by the authors. This was extended to 4, which was then cyclized to 5, and acylated with 6 to give 7. 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! The precursor 7 was flat, so it offered no opportunity for chiral synthesis. Fortunately, 10 and ent-10 proved to be very easy to resolve by chiral chromatography.

To complete the synthesis, the δ-lactam 11 was oxygenated to 12. Conditions for desulfurization of the derived thiolactam also effected debenzylation, to give, after acetylation, the ether 13. Pt-mediated hydrogenolysis gave 14, which was dehydrated to vindoline (1).

A complementary synthetic route, based on the E isomer of 6, and so leading through the ether 15, is also described. Although slightly longer, this approach was about as efficient as the route via 11.

D. F. Taber, Org. Chem. Highlights 2006, June 5.