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Monday, April 24, 2006
Douglass Taber
University of Delaware

Stereoselective Construction of Nitrogen Heterocycles

Nitrogen heterocycles are the basis of many essential pharmaceuticals, and of many physiologically-active natural products. There is a continuing interest in the development of new methods for the construction of nitrogen heterocycles with control of relative and of absolute configuration.

Tom Livinghouse of Montana State University has developed (Org. Lett. 2005, 7, 4391. DOI: 10.1021/ol051574h) new Sc-based catalyst systems for intramolecular hydroamination. As illustrated for the conversion of 1 to 2, the Sc-based catalysts can effect cyclization with high diastereocontrol. Catalysts based on Zr (Chem. Commun. 2005, 5205. DOI: 10.1039/b505738h) are also effective, but so far show low diastereoselectivity.

P. Veeraraghavan Ramachandran of Purdue University has shown (J. Am. Chem. Soc. 2005, 127, 13450. DOI: 10.1021/ja052638m) that a catalyst derived from the Cinchona alkaloids mediates the phase transfer Michael addition to 3 with high enantio- and geometric control, giving 5. On deprotection and reduction, 5 is converted to 6 with high diastereocontrol.

Professor Ramachandran has also (J. Org. Chem. 2005, 70, 7911. DOI: 10.1021/jo0508200) taken advantage of the diastereo-and enantioselective addition of (-)-B-crotyldiisopinocampheylborane 8 to imines developed earlier by the H.C. Brown group. Alkylation of the amine 9 with a Baylis-Hillman adduct followed by cyclization with the second-generation Grubbs catalyst delivers the dehydropiperidine ester 11.

Usually, one would expect that intramolecular trapping of a carbocation would proceed with little diastereocontrol. David Crich of the University of Illinois at Chicago has observed (J. Am. Chem. Soc. 2005, 127, 9924. DOI: 10.1021/ja051657t) that the radical cations derived from the reduction of 7 and 8 cyclize predominantly with inversion of absolute configuration. The radical cation intermediate is apparently a contact ion pair, with one face blocked by the departing phosphate.

Strategies that allow the controlled construction of multiple ring systems are also important. Stephen F. Martin of the University of Texas has developed (Org. Lett. 2005, 7, 2031. DOI: 10.1021/ol050544b) a family of allyl silane reagents, represented by 16. Condensation with the protected dialdehyde 17 leads to the bicyclic amine 18 as a single diastereomer.

Many methods have been developed for the diastereoselective and enantioselective construction of aziridines. Dawei Ma of the Shanghai Institute of Organic Chemistry has devised conditions (Org. Lett. 2005, 7, 5545. DOI: 10.1021/ol0513692) for the condensation of aziridines with alkynyl esters such as 19. Ring opening and cyclization proceed with double inversion, to give 21.

The intramolecular Mannich condensation has been a workhorse of alkaloid construction. Our group found (J. Org. Chem. 2005, 70, 8739. DOI: 10.1021/jo051155y) that the strong acid-strong base ion exchange resin Rexyn-300 was effective in pushing a reluctant intramolecular Mannich condensation to completion.

D. F. Taber, Org. Chem. Highlights 2006, April 24.