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Monday, November 14, 2005
Douglass Taber
University of Delaware

Enantioselective Construction of N-Heterocycles

With increasing emphasis on the single-enantiomer synthesis of pharmaceuticals, there is a need for efficient methods for the preparation of enantiomerically-enriched N and O heterocycles.

Where possible, it may be most economical to effect a chiral transformation on a pre-formed, pro-chiral ring. Ben Feringa of the University of Groningen prepared (Chem. Commun. 2005, 1711. ) the enone 2 from 4-methoxypyridine (1). Cu*-catalyzed conjugate addition of dialkyl zincs to 2 proceeded in up 96% ee. Pd-mediated allylation of the intermediate zinc enolate led to 3, with the two alkyl subsituents exclusively trans to each other.

Enantiomerically-enriched piperidines can also be prepared by hydrogenation of pyridine derivatives. André Charette of the Université de Montréal found (J. Am. Chem. Soc. 2005, 127, 8966. ) that ylids such as 5, prepared directly from the pyridine 4, gave the highest ee’s on Ir*-catalyzed hydrogenation. An advantage of this approach is that the piperidine derivatives 6 are crystalline, and are easily recrystallized to higher ee.

Mercedes Amat and Joan Bosch of the University of Barcelona have been exploring (Chem. Commun. 2005, 1327. ) a kinetic resolution route to piperidines. Condensation of a ketone or aldehyde ester such as 7 with an enantiomerically pure amino alcohol such as 8 with proceeds with high (15:1) diastereoselectivity, to give 9. Reduction of 9 then delivers the piperidine 10 in high enantiomeric excess.

Polyhydroxylated piperidines such as 16 are of interest as glucosidase inhibitors. Antoni Riera, also of the University of Barcelona, has developed (J. Org. Chem. 2005, 70, 2325. ) a route to 16 from the readily available enantiomerically pure epoxide 11. Condensation with allyl isocyanate 12 followed by cyclization gave 13, which was further cyclized by a Grubb’s catalyst (unspecified) to 14. Protection set the stage for face-selective dihydroxylation, to give 15. Several other piperidines having other polyhydroxylation patterns were also prepared from 14.

Joseph P.A. Harrity of the University of Sheffield has reported (J. Org. Chem. 2005, 70, 207. ) a complementary approach to enantiomerically-pure piperidines. Alkylated azridines such as 17 are readily available from aspartic acid. Pd-catalyzed condensation of 17 with the Trost reagent 18 was found to be most effectively mediated by bis-phosphines such as “dppp”, 1,3-bis-diphenylphosphinopropane. The piperidine 19 was the key intermediate for the preparation of several of the Nuphar alkaloids, including 20.

D. F. Taber, Org. Chem. Highlights 2005, November 14.