Modular synthesis of chiral 1,2-dihydropyridines via Mannich/Wittig/cycloisomerization sequence that internally reuses waste
Bo‐Shuai Mu, Xiao‐Yuan Cui, Xing‐Ping Zeng, Jin‐Sheng Yu, Jian Zhou
Abstract
Abstract 1,2-Dihydropyridines are valuable and reactive synthons, and particularly useful precursors to synthesize piperidines and pyridines that are among the most common structural components of pharmaceuticals. However, the catalytic enantioselective synthesis of structurally diverse 1,2-dihydropyridines is limited to enantioselective addition of nucleophiles to activated pyridines. Here, we report a modular organocatalytic Mannich/Wittig/cycloisomerization sequence as a flexible strategy to access chiral 1,2-dihydropyridines from N -Boc aldimines, aldehydes, and phosphoranes, using a chiral amine catalyst. The key step in this protocol, cycloisomerization of chiral N -Boc δ-amino α,β-unsaturated ketones recycles the waste to improve the yield. Specifically, recycling by-product water from imine formation to gradually release the true catalyst HCl via hydrolysis of SiCl 4 , whilst maintaining a low concentration of HCl to suppress side reactions, and reusing waste Ph 3 PO from the Wittig step to modulate the acidity of HCl. This approach allows facile access to enantioenriched 2-substituted, 2,3- or 2,6- cis -disubstituted, and 2,3,6- cis -trisubstituted piperidines.