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

Abstract

Enantiomerically-pure natural amino acids can serve as starting materials for alkaloid synthesis. In his synthesis (J. Org. Chem. 2007, 72, 10114) 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) a chiral Cu catalyst that mediated the addition of alkynyl esters and ketones to the prochiral acylated pyridine 4 in high enantiomeric excess. The dihydro-pyridines (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) 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 (Organic Lett. 2007, 9, 2763) 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.