Sulfonamides are profoundly important in pharmaceutical design. C-N cross-coupling of sulfonamides is an effective method for fragment coupling and SAR mining. However, cross-coupling of the important N-arylsulfonamide pharmacophore has been notably unsuccessful. Here, we present a solution to this problem via oxidative Cu-catalysis (Chan-Lam cross-coupling). Mechanistic insight has allowed the discovery and refinement of an effective cationic Cu catalyst to facilitate the practical and scalable Chan-Lam N-arylation of primary and secondary N-arylsulfonamides at room temperature. We also demonstrate utility in the large scale synthesis of a key intermediate to a clinical HCV treatment.

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An efficient asymmetric synthesis of N-[(1R)-6-chloro-2,3,4,9tetrahydro-1H-carbazol-1-yl]-2-pyridinecarboxamide 1, a potential treatment for human papillomavirus infections, is described. The key step in the synthesis of this molecule is an asymmetric reductive amination directed by chiral (phenyl)ethylamines resulting in up to 96% disastereo facial selectivity. The synthesis is also highlighted by isolation of a unique 2-picolinic acid salt of (1R)-6-chloro-2,3,4,9-tetrahydro-1Hcarbazol-1-amine (13). Subsequent application of 1-propylphosphonic acid cyclic anhydride (T3P) for convenient amide formation from the two components of the salt provides the product 1 in high yield. The process research work leading to the final synthesis includes a racemic synthesis followed by resolution with chiral supercritical fluid chromatography, and an enantioselective reductive amination via chiral transfer hydrogenation catalyzed by Ru(II) complexes of N-[(1S,2S)-2amino-1,2-diphenylethyl]-1-naphthalenesulfonamide or (R)-BI-NAP. Highlighting the practicality of the synthesis, the process has been scaled up in 200-gallon reactors for delivery of multikilograms of the target compound 1 in over 99.5% enantiomeric purity.