Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, September 2, 2013
Douglass F. Taber
University of Delaware

The Carreira Synthesis of (±)-Gelsemoxonine

The traditional Chinese pharmacopeia includes Gelsemium elegans benth, from which the alkaloid Gelsemoxonine (3) was isolated. Erick M. Carreira of the Eidgenössische Technische Hochschule Zürich envisioned (J. Am. Chem. Soc. 2013, 135, 8500. DOI: 10.1021/ja403823n) that the unusual azetidine ring of 3 could be established by Brandi contraction of 1 to give 2.

Following Brandi and Salaün (Eur. J. Org. Chem. 1999, 2725. DOI: 10.1002/(SICI)1099-0690(199911)1999:11<2725::AID-EJOC2725>3.0.CO;2-0), the hemiketal 4 was carried on to the aldehyde 9. Condensation with nitromethane followed by dehydration gave the unsaturated nitrile oxide, that cyclized to 10. Epoxidation of 10 across the more open face gave an intermediate epoxide. Addition of 11 to the epoxide, promoted by InBr3, delivered 12 with good stereocontrol. CeCl3-mediated addition of 1-propynyl lithium completed the assembly of 1.

A cyclopropanone could be seen as the addition product of carbon monoxide to an alkene. On exposure of 1 to acid, this formal addition was reversed, leading to the β-lactam 2. A computational study of this cleavage was recently reported (Eur. J. Org. Chem. 2011, 5608. DOI: 10.1002/ejoc.201100621). Conceptually, one can imagine protonation activating the C-N bond for cleavage, leading to an intermediate such as 14, which then fragments to the acylium ion, leading to cyclization. It is unlikely that 14 would have any real lifetime.

On warming with the Petasis reagent, the Boc-protected β-lactam was converted to the alkene 15. Hydroboration proceeded to give the alcohol 16 as a single diastereomer. Reduction followed by oxidation to 17 then set the stage for intramolecular aldol reaction to give 18.

The last challenge was the diastereoselective assembly of the N-methoxy oxindole. To this end, oxidation and dehydration of 18 led to the bromo amide 20. As hoped, Heck reductive cyclization proceeded across the more open face of the alkene, leading to 21. Hydroxyl-directed hydrosilylation of the pendant alkyne to give the ethyl ketone then completed the synthesis of Gelsemoxonine (3).

Twice in this synthesis, advantage was taken of the preparation and reactivity of heteroatom-substituted alkenes. Dimethyl dioxirane, generated as a solution in acetone, was sufficiently water-free that the epoxide derived from 10 could survive long enough to react in a bimolecular sense with the ketene silyl acetal 11. Later in the synthesis, the Petasis reagent was sufficiently oxophilic to convert the β-lactam carbonyl to the methylenated product 15, setting the stage for face-selective hydroboration.

D. F. Taber, Org. Chem. Highlights 2013, September 2.