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 Common. 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. Andr6 Charette of the Universite de Montreal found (7. Am. Chem. Soc. 2005, 727, 8966) that ylids such as 5, prepared directly from the pyridine 4, gave the highest ee s on lr -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. Common. 2005, 1327) a kinetic resolution route to piperidines. Condensation of a ketone or aldehyde ester such as 7 with an enantioinerically-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 

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. 

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