Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, May 1, 2023
Douglass F. Taber
University of Delaware

The Zhao/Ma Synthesis of Napelline

Napelline (3) was isolated from Aconitum kusnezoffii, a widely-cultivated herbaceous perennial that, despite its toxicity, has long been used in traditional medicine. Xiangbo Zhao and Dawei Ma of SIOC assembled the hexacyclic ring system of 3 by the intramolecular Mannich cyclization of 1 to 2 (J. Am. Chem. Soc. 2022, 144, 15355. DOI: 10.1021/jacs.2c06738).

The convergent assembly of the diketone 1 began with the TADDOL-catalyzed addition of methacrolein 5 to the diene 4, following the procedure of Rawal, to give, after hydrolysis, the aldehyde 6. Warming with DPPH 7 converted the aldehyde 6 to the nitrile 8.

The preparation of the other half of 1 began with the acetonide 9. Benzyl ether formation and deprotection followed by selective monosilylation led to the secondary triflate 10, that was stabilized by the flanking electron-withdrawing groups. Alkylation of 11 with 10 led to 12, that was rearranged with absolute stereocontrol and then reduced and hydrolyzed, leading to the enone 13. Pd-mediated oxidative cyclization of the derived silyl enol ether gave 14. Ketalization followed by iodide formation set the stage for transmetalation and conjugate addition to 8. The product enolate was treated directly with LiAlH4, allowing selective reduction to the amine 15. Reductive ethylation followed by protection gave 16, that on deprotonation underwent intramolecular Michael addition. Deprotection and oxidation completed the preparation of the aldehyde 17.

Heat removed the Boc protecting group, so the key intramolecular Mannich cyclization could proceed. This required the formation of the seven-membered iminium salt 18, and so was reluctant. The use of the ion exchange resin Rexyn-300, that has both strong base and strong acid sites, proved effective. The cyclization of 17 to the hexacyclic 2 is a remarkable increase in molecular complexity.

With 2 in hand, allylic oxygenation led to the triketone 19. Global reduction then completed the synthesis of napelline (3).

D. F. Taber, Org. Chem. Highlights 2023, May 1.