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Monday, May 12, 2008
Douglass F. Taber
University of Delaware

Adventures in Alkaloid Synthesis: (+)-α-Kainic Acid (Jung), 223AB (Ma), Pumiliotoxin 251F (Jamison), Spirotryprostatin B (Trost), (-)-Drupacine (Stoltz)

Enantiomerically-pure natural amino acids can serve as starting materials for alkaloid synthesis. In his synthesis (J. Org. Chem. 2007, 72, 10114. DOI: 10.1021/jo701988j) of (-)-α-kainic acid (3), Kyung Woon Jung of the University of Southern California prepared the diazo sulfone 1 from (L)-glutamic acid. Rh-mediated intramolecular C-H insertion proceeded with the predicted high diastereoselectivity, to give the lactam 2, containing seven of the ten carbon atoms and two of the three stereogenic centers of (-)-α-kainic acid (3).

The absolute configuration of the nitrogen ring system(s) can also be established by chiral catalysis. Dawei Ma of the Shanghai Institute of Organic Chemistry has developed (J. Am. Chem. Soc. 2007, 129, 9300. DOI: 10.1021/ja0734849) a chiral Cu catalyst that mediated the addition of alkynyl esters and ketones to the prochiral acylated pyridine 4 in high enantiomeric excess. The dihydropyridines (e.g. 5) so produced will be versatile starting materials both for alkaloid synthesis, as illustrated by the preparation of the Dendrobatid alkaloid 223AB (6), and for the production of pharmaceuticals.

In his synthesis of the Dentrobatid alkaloid pumiliotoxin 251D (9), Timothy F. Jamison took (J. Org. Chem. 2007, 72, 7451. DOI: 10.1021/jo071132e) as his starting material another amino acid, proline. Ni-mediated cyclization of the epoxide 8 proceeded with high geometric and regiocontrol, to give 9. The chemistry to convert 7 into 8 with high diastereocontrol and without racemization is a substantial contribution that will have many other applications.

In his synthesis (Org. Lett. 2007, 9, 2763. DOI: 10.1021/ol070971k) of spirotryprostatin B (12), Barry M. Trost of Stanford University also started with proline, which was readily elaborated to the oxindole 10. The question was, could the Pd-catalyzed decarboxylation of 10 be induced to provide specifically 11? Counting geometric isomers of the trisubstituted alkene, and allylic regioisomers, as well as diastereomers, there were sixteen possible products from this prenylation. Using chiral Pd control, the rearrangement proceeded with 14:1 regiocontrol, and 16:1 diasterocontrol. Oxidative cyclization of 11 then delivered spirotryprostatin B (12).

The Cephalotaxus alkaloid (-)-drupacine (19) has five stereogenic centers, including four of the five positions on the cyclopentane ring. Remarkably, Brian M. Stoltz of the California Institute of Technology was able (J. Org. Chem. 2007, 72, 7352. DOI: 10.1021/jo0710883) to prepare enantiomerically-pure 19 by initially controlling just the single stereogenic center of 15. Reductive amination of 15 with racemic 14 led to a separable 1:1 mixture of diastereomers. Acid-mediated equilibration converted the wrong diastereomer 17 (as well as the correct diastereomer, not shown) to a 2:1 mixture favoring the desired diastereomer 18.

This column is dedicated to the memory of the late John W. Daly, who contributed so much to our knowledge of alkaloid chemistry.

D. F. Taber, Org. Chem. Highlights 2008, May 12.