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Monday, May 11, 2009
Douglass F. Taber
University of Delaware

Alkaloid Synthesis: (-)-Aurantioclavine (Stoltz), (-)-Esermethole (Nakao/Hiyama/Ogoshi), (-)-Kainic Acid (Tomooka), Dasycarpidone (Bennasar), (-)-Cephalotaxine (Ishibashi) and Lysergic Acid (Fujii/Ohno)

Intriguing strategies have been developed for the stereocontrolled assembly of complex alkaloid structures. Brian M. Stoltz of Caltech prepared (J. Am. Chem. Soc. 2008, 130, 13745 ) the enantiomerically-pure alcohol precursor to the secondary amine 1 by enantioselective oxidation of the racemic alcohol. Intramolecular Mitsunobu coupling of 1 then led to (-)-Aurantioclavine (3).

Yoshiaki Nakao and Tamejiro Hiyama of Kyoto University and Sensuke Ogoshi of Osaka University developed (J. Am. Chem. Soc. 2008, 130, 12874 ) an enantioselective Ni catalyst for the cyclization of 4 to 5. Oxidation and cyclization then delivered (-)-Esermethole (6).

Although the sulfonamide 7 appears to be prochiral, in fact its two most stable conformations are bent, and enantiomers of each other, with a significant barrier for interconversion. Katsuhiko Tomooka of Kyushu University separated (Tetrahedron Lett. 2008, 49, 6327 ) the enantiomers of 7, then carried the enantiomercially-pure 7 on, by Pd-catalyzed Cope rearrangement, to 8 and so to (-)-Kainic Acid (9).

M.-Llu´sa Bennasar of the University of Barcelona prepared (J. Org. Chem. 2008, 73, 9033 ) the acyl selenide 11 from the indole 10. While the radical derived from 11 might have been expected to undergo 5-exo cyclization, in the event the 6-endo mode dominated, to give Dasycarpidone (12) and its diastereomer.

Hiroyuki Ishibashi of Kanazawa University showed (Org. Lett. 2008, 10, 4129 ) that the radical cascade cyclization of the enamine 13, derived from diethyl tartrate, proceeded with remarkable diastereocontrol, to give 14. The amide 14 was converted to (-)-Cephalotaxine (15).

Nobutaka Fujii and Hiroaki Ohno, also of Kyoto University, used (Org. Lett. 2008, 10, 5239 ) a Pd catalyst to mediate the cascade cyclization of 16 to 17. Although 16 has two stereogenic centers, including the allene, it is the aminated stereogenic center of 17 that sets the absolute configuration of the product Lysergic Acid (18). One intermediate in the conversion of 16 to the tetracyclic 17 is the tricyclic π-allyl Pd complex. If all the material could be channeled through that pathway, there is a good chance that the chiral Trost catalyst could effectively control the absolute configuration of the aminated stereogenic center as it is formed, leading to the enantiomerically enriched product 18.

D. F. Taber, Org. Chem. Highlights 2009, May 11.
URL: https://www.organic-chemistry.org/Highlights/2009/11May.shtm