Organic Chemistry Portal
Organic Chemistry Highlights

Monday, November 13, 2006
Douglass Taber
University of Delaware

Stereocontrolled Construction of N-Heterocycles

Yong-Gui Zhou of the Dalian Institute of Chemical Physics (Angew. Chem. Int. Ed. 2006, 45, 2260. DOI: 10.1002/anie.200503073) and Manfred T. Reetz of the Max-Planck-Institut, Mülheim (Chem. Commun. 2006, 2159. DOI: 10.1039/b602320g) have individually reported enantioselective Ir-catalyzed hydrogenation of quinolines and, in the Zhou paper, isoquinolines. The Zhou group used this approach to prepare several enantiomerically-enriched alkaloids, including (-)-angustureine (3).

Kevin R. Campos of Merck Rahway (J. Am. Chem. Soc. 2006, 128, 3538. DOI: 10.1021/ja0605265), building on the work of Peter Beak of the University of Illinois, has shown that it is possible to enantioselectively arylate N-Boc pyrrolidine 4. Metalation in the presence of the enantiomerically-pure alkaloid sparteine gave the anion, which underwent Pd-mediated coupling with aryl halides, including 5. The enantiomeric excess of the product was independent of the aryl halide used.

Carmen Ortiz Mellet of the Universidad de Sevilla and José M. Garcia Fernández of CSIC Sevilla have been investigating the use of ortho xylylene protecting groups for carbohydrates. They have found (Org. Lett. 2006, 8, 297. DOI: 10.1021/ol052668u) that monoprotection of the fructose acetonide 7 followed by hydrolysis and cyclization gave 8. Conversion to the azide followed by hydrogenation delivered the highly-substituted pyrrolidine 10.

Ultimately, the most powerful methods for ring constuction willl be those that use chiral catalysts. Juan C. Carretero of the Universidad Autónoma de Madrid has devised (Org. Lett. 2006, 8, 1795. DOI: 10.1021/ol060314c) a Cu catalyst that effects the condensation of phenyl vinyl sulfone (11) with the dipole precursor 12. The product pyrrolidine 13 is readily recrystallized to high ee.

C-N ring construction by intramolecular alkene hydroamination is now well developed as a synthetic method. Recent developments include the observation (Angew. Chem. Int. Ed. 2006, 45, 1747. DOI: 10.1002/anie.200600052) by Ross A. Widenhoefer of Duke University that N-Boc amines such as 14 can cyclize efficiently, using a cationic Au catalyst. Using a Rh catalyst (J. Am. Chem. Soc. 2006, 128, 6042. DOI: 10.1021/ja058299e), John F. Hartwig of Yale University was able to effect anti-Markovnikov intramolecular hydroamination, converting 16 to 17. And, using a Sc catalyst (J. Am. Chem. Soc. 2006, 128, 3748. DOI: 10.1021/ja058287t), Kai C. Hultzsch of the Universität Erlangen-Nürnberg was able to effect the cyclization of 18 with high ee.

Two other developments are particularly noteworthy. Chisato Mukai of Kanazawa University has shown (Org. Lett. 2006, 8, 83. DOI: 10.1021/ol052562z) that Co-mediated cyclization of the carbodiimide 20 delivers 21, having two new rings. The enone 21 is prochiral, so there is the real possibility that chiral conjugate addition could set the absolute configuration of the ring system. Katsuhiko Tomooka of the Tokyo Institute of Technology has been studying (Org. Lett. 2006, 8, 963. DOI: 10.1021/ol053141k) the medium-ring amine 23. The sulfonylamine 22 cyclizes under Mitsunobu conditions. The amine 23 is readily resolved, and is configurationally stable - it has a half-life of optical activity in hexane at room temperature of 203 days.

D. F. Taber, Org. Chem. Highlights 2006, November 13.