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Monday, April 30, 2012
Douglass F. Taber
University of Delaware

Alkaloid Synthesis: (-)-α-Kainic Acid (Cohen), Hyacinthacine A2 (Fox), (-)-Agelastatin A (Hamada), (+)-Luciduline (Barbe), (+)-Lunarine (Fan), (-)-Runanine (Herzon)

The intramolecular ene cyclization is still little used in organic synthesis. Theodore Cohen of the University of Pittsburgh trapped (J. Org. Chem. 2011, 76, 7912. DOI: 10.1021/jo201341q) the cylization product from 1 with iodine to give 2, setting the stage for an enantiospecific total synthesis of (-)-α-Kainic Acid (3).

Intramolecular alkene hydroamination has been effected with transition metal catalysts. Joseph M. Fox of the University of Delaware isomerized (Chem. Sci. 2011, 2, 2162. DOI: 10.1039/C1SC00442E) 4 to the trans cyclooctene 5 with high diastereocontrol. Deprotection of the amine led to spontaneous cyclization, again with high diastereocontrol, to Hyacinathcine A2 (6).

Yasumasa Hamada of Chiba University devised (Org. Lett. 2011, 13, 5744. DOI: 10.1021/ol2023054) a catalyst system for the enantioselective aziridination of cyclopentenone 7. The product 8 was carried on to the tricyclic alkaloid (-)-Agelastatin A (9).

Guillaume Barbe, now at Novartis in Cambridge, MA, effected (J. Org. Chem. 2011, 76, 5354. DOI: 10.1021/jo200745n) the enantioselective Diels-Alder cycloaddition of acrolein 11 to the dihydropyridine 10. Ring-opening ring-closing metathesis later formed one of the carbocyclic rings of (+)-Luciduline (13), and set the stage for an intramolecular aldol condensation to form the other.

Chun-An Fan of Lanzhou University employed (Angew. Chem. Int. Ed. 2011, 50, 8161. DOI: 10.1002/anie.201103198) a Cinchona-derived organocatalyst for the enantioselective Michael addition to prepare 14. Although 14 and 15 were only prepared in 77% ee, crystallization to remove the racemic component of a later intermediate led to (+)-Lunarine (16) in high ee.

Seth B. Herzon of Yale University used (Angew. Chem. Int. Ed. 2011, 50, 8863. DOI: 10.1002/anie.201102226) the enantioselective Diels-Alder addition with 18 to block one face of the quinone 17. Reduction of 19 followed by methylation delivered an iminium salt, only one face of which was open for the addition of an aryl acetylide. Thermolysis to remove the cyclopentadiene gave an intermediate that was carried on to (+)-Runanine (20).

D. F. Taber, Org. Chem. Highlights 2012, April 30.