Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, October 1, 2012
Douglass F. Taber
University of Delaware

The Qin Synthesis of (+)-Gelsemine

(+)-Gelsemine (3) has no particular biological activity, but its intricate architecture continues to inspire the ingenuity of organic synthesis chemists. Yong Qin of Sichuan University devised (Angew. Chem. Int. Ed. 2012, 51, 4909. DOI: 10.1002/anie.201201736) an enantiospecific synthesis of 3, a key step of which was the cyclization of 1 to 2.

The starting material for the synthesis was the inexpensive diethyl tartrate 4, which was converted over six steps into the N-sulfonyl aziridine 5. The addition of 6 was highly regioselective, leading, after N-methylation, to the alkyne 7. After alcohol protection, the sulfonyl group was smoothly removed by sonication with Mg powder in methanol. Addition to acryonitrile then gave 8.

Semi-hydrogenation of 8 set the stage for construction of the lactone 1. The anion of 1, generated by exposure to LDA, cyclized to 2 with significant diastereoselectivity.

The lactone of 2 was selectively reduced with Dibal, to give an aldehyde that was protected as the acetal. The exposed primary alcohol was then oxidized to the aldehyde 9. Condensation of 9 with the enolate of 10 followed by dehydration delivered the alkene 11, with the stage set for a second intramolecular nitrile anion addition.

In the event, the cyclization of 11 delivered 12, the wrong diastereomer. This was corrected by selenation and oxidation to give an alkene, that was hydrogenated to 13. Exposure to acid deprotected both the MOM group of 13 and the dimethyl acetal, then promoted cyclization to 14. Reduction of the nitrile to the aldehyde followed by methylenation completed the synthesis of (+)-Gelsemine (3). It should be noted that the hydrogenation to form 13 had to be carried out carefully, to avoid premature removal of N-methoxy group. That group was critical for the successful conversion of 13 to 14.

D. F. Taber, Org. Chem. Highlights 2012, October 1.