Piperidines are frequently
found in natural products and are of
importance to the pharmaceutical industry. A generally useful asymmetric
route to enantiomerically enriched 3-substituted piperidines remains
elusive. Here we report a cross-coupling approach to enantioenriched
3-piperidines from pyridine- and sp2-hybridized boronic
acids. The key step involves a Rh-catalyzed asymmetric reductive Heck
reaction of aryl, heteroaryl, or vinyl boronic acids and phenyl pyridine-1(2H)-carboxylate to provide 3-substituted tetrahydropyridines
in high yield and excellent enantioselectivity with a wide functional
group tolerance. A three-step process involving i) partial reduction
of pyridine, ii) Rh-catalyzed asymmetric carbometalation, and then
iii) another reduction provides access to a wide variety of enantioenriched
3-piperidines, including clinically used materials such as Preclamol
and Niraparib.