Silver-Catalyzed Asymmetric Aldol Reaction of Nonactivated Ketones with α-Isocyanocarboxylic Acid Derivatives Enabled by Prolinol-phosphine-<i>sec</i>-amine Chiral Ligand
Satoshi Sakai, Kei Uchiyama, Koji Imai, Kazuna Yato, Mai Onizawa, Kosuke Higashida, Hiroyasu Sato, Yoshitaka Aoyama, Y. Shimizu, Masaya Sawamura
Abstract
The catalytic asymmetric aldol reaction of nonactivated ketones is a formidable challenge in asymmetric catalysis. To this end, we designed and synthesized a prolinol-phosphine- sec -amine P,N,N,O-tetradentate chiral ligand that enabled a highly diastereo- and enantioselective silver(I)-catalyzed aldol reaction of nonactivated ketones with isocyanoacetamides, affording enantioenriched α-amino acid derivatives with a tertiary alcohol at the β-position. This stereoselective reaction allowed extremely challenging molecular transformations with sterically demanding dialkyl ketones and alkyl aryl ketones, such as tert -alkyl methyl ketones, sec -alkyl primary alkyl ketones, and sec -alkyl aryl ketones. The silver(I) catalyst system was also effective in the enantiocontrolled construction of consecutive tetrasubstituted stereogenic carbon centers through the aldol reaction between simple aryl alkyl ketones and α-alkyl-α-isocyanoaetates. Spectroscopic and microED analysis combined with computational investigations showed that P,N,N,O-tetradentate metal binding of the chiral ligand allows the creation of a metal/organo cooperative asymmetric catalytic space that provides densely accumulated classical and nonclassical hydrogen bonds and complementary London dispersion interactions, stabilizing the transition state of the stereochemistry-determining ring-closing reaction of the oxyanion intermediate.