An asymmetric synthesis of a chiral aryl aminopyrollidine intermediate was developed to enable multi-kilogram deliveries.  A novel cobalt-mediated opening of a meso-epoxide with trimethylsilyl azide and Jacobsen's Salen ligand was the key step in the route.  Reduction of the resulting azido silyl ether in methanol afforded the crystalline amino alcohol.  A SNAr reaction with a highly activated electrophile proceeds under mildly basic conditions.  The secondary aniline product is isolated as the HCl salt following removal of the tert-butyloxycarbonyl group.  A final reductive amination with formalin completes the synthesis in 36% overall yield from a commercially available starting material.

Asymmetric synthesis of a trisubstituted pyrollidine via <i>meso</i>-epoxide opening

246th National Meeting (2013)

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Asymmetric synthesis of a trisubstituted pyrollidine via meso-epoxide opening