Regiodivergent enantioselective C-H functionalization of Boc-1,3-oxazinanes for the synthesis of beta(2)- and beta(3)-amino acids

beta(2)- and beta(3)-amino acids are important chiral building blocks for the design of new pharmaceuticals and peptidomimetics. Here, we report a straightforward regio- and enantiodivergent access to these compounds using a one-pot reaction composed of sparteine-mediated enantioselective lithiation of a Boc-1,3-oxazinane, transmetallation to zinc and direct or migratory Negishi coupling with an organic electrophile. The regioselectivity of the Negishi coupling was highly ligand-controlled and switch-able to obtain the C4- or the C5-functionalized product exclusively. High enantioselectivities were achieved on a broad range of examples, and a catalytic version in chiral diamine was developed using the (+)-sparteine surrogate. Selected C4- and C5-functionalized Boc-1,3-oxazinanes were subsequently converted to highly enantioenriched beta(2)- and beta(3)-amino acids with the (R) or (S) configuration, depending on the sparteine enantiomer employed in the lithiation step.