Direct synthesis of 4-arylpiperidines via palladium/copper(I)-cocatalyzed Negishi coupling of a 4-piperidylzinc iodide with aromatic halides and triflates.

A general procedure for the synthesis of 4-arylpiperidines via the coupling of 4-(N-BOC-piperidyl)zinc iodide with aryl halides and triflates is presented. The reaction requires cocatalysis with both Cl(2)Pd(dppf) and a copper(I) species. An improved, safer procedure for the activation of zinc dust is also presented.

Highly Chemoselective Trichloroacetimidate-Mediated Alkylation of Ascomycin: A Convergent, Practical Synthesis of the Immunosuppressant L-733,725.

L-733,725, a new immunosuppressant drug candidate, was prepared by a highly chemoselective alkylation of the macrolide ascomycin at the C32 hydroxy position with the imidazolyl trichloroacetimidate 16. The trichloroacetimidate-activated side chain 16 was prepared by an efficient four-step sequence in 42% overall yield. The high chemoselectivity in the alkylation of the C32 hydroxy group of the unprotected ascomycin was the result of the synergetic effects of the electron-donating protecting group on the imidazole 16, the polar, moderately basic solvent, and the strong acid catalyst. N,N-Dimethylpivalamide mixed with acetonitrile was found to be the best solvent and trifluromethanesulfonic acid the best catalyst. This synthesis coupled with a resin column purification of L-733,725 followed by crystallization of its tartrate salt has been used to make multi-kilogram quantities of the bulk drug with consistent and high purity.