Organic Chemistry Portal
Organic Chemistry Highlights

Monday, November 28, 2011
Douglass F. Taber
University of Delaware

Alkaloid Synthesis: Mearsine (Taylor), Cephalotaxine (Li), Cocaine (Shing), Quinine (Hatakeyama), Cleavamine (Bennasar), Strychnine (Vanderwal)

Richard J. K. Taylor of the University of York employed (Tetrahedron Lett. 2011, 52, 2024. DOI: 10.1016/j.tetlet.2010.08.052) the J°rgensen protocol to add 2 to 1, to give the enantiomerically-enriched cyclohexenone 3. Condensation of 3 with aqueous ammonia led directly to (-)-Mearsine (4).

Wei-Dong Z. Li of Nankai University found (Org. Lett. 2011, 13, 3538. DOI: 10.1021/ol201390r) that the intermediate from Dibal reduction of the lactone 5 underwent Nazarov cyclization, to give the α-hydroxy cyclopentenone 6. After acetylation, deprotection gave an amine that cyclized with high diastereocontrol, leading to (▒)-Cephalotaxine (7).

Tony K. M. Shing of the Chinese University of Hong Kong cyclized (Org. Lett. 2011, 13, 2916. DOI: 10.1021/ol2009686) the aldehyde 8 by exposure to 9. The product 10 was carried on to (-)-Cocaine (11), as well as several hydroxylated cocaine derivatives.

Susumi Hatakeyama of Nagasaki University found (Tetrahedron Lett. 2011, 52, 923. DOI: 10.1016/j.tetlet.2010.12.066) that exposure of the simple prochiral aldehyde 12 to catalytic proline transformed it, after reduction, into the cyclized diol 13 in high ee. The diol 13 was readily carried on to quinine (14).

M.-Llu´sa Bennasar of the University of Barcelona devised (Org. Lett. 2011, 13, 2042. DOI: 10.1021/ol200437k) Pd-catalyzed conditions for the cyclization of 15 that selectively delivered the unstable kinetic product 18. Selective hydrogenation of the more reactive bridgehead alkene then led to Cleavamine (17). The alkene 16 is also prochiral, so it is possible that a catalyst could be found that would deliver 17 in high ee.

The synthesis of the heptacyclic alkaloid Strychnine (23) would, in the past, have been a major undertaking. Christopher D. Vanderwal of the University of California, Irvine prepared (Chem. Sci. 2011, 2, 649. DOI: 10.1039/C1SC00009H) 23 in just six linear steps. The dienyl aldehyde 18 was available in two steps from tryptophyl bromide. Exposure to t-BuOK cyclized 18 to 19. N-deallylation followed by alkylation with 20 provided 21, setting the stage for a truly spectacular Brook rearrangement/conjugate addition, to give the Wieland-Gumlich aldehyde 22. The known condensation with malonic acid completed the preparation of 23.

D. F. Taber, Org. Chem. Highlights 2011, November 28.