Chemo‐ and Enantioselective Hydrogenation of α‐Formyl Enamides: An Efficient Access to Chiral α‐Amido Aldehydes

Abstract

In order to effectively synthesize chiral a-amino aldehydes,which have awide range of potential applications in organic synthesis and medicinal chemistry,ahighly chemoand enantioselective hydrogenation of a-formyl enamides has been developed, catalyzedb yarhodium complex of aPstereogenic bisphosphine ligand. Under different hydrogen pressures,the chiral a-amido aldehydes and b-amido alcohols were obtained in high yields (97-99 %) and with excellent chemo-and enantioselectivities (up to > 99.9 %ee). The hydrogenation can be carried out on ag ram scale and with ah igh substrate/catalyst ratio (up to 20 000 S/C), and the hydrogenated products were further converted into several important chiral products.Computations of the catalytic cycle gave ac lear description for the R/S pathways, provided ar easonable explanation for the enantioselectivity,a nd revealed several other specific features. Scheme 1. Asymmetric synthesis of chiral aldehydes. Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

The role of attractive dispersion interaction in promoting the catalytic activity of asymmetric hydrogenation

“…To synthesize chiral α-amino aldehydes with high efficiency, W. Zhang and coworkers reported a highly efficient Rh-catalyzed asymmetric hydrogenation of α-formyl enamides using BenzP* as ligand, affording chiral α-amino aldehydes with up to 20 000 S/C. 11 Again, normal aryl-substituted diphosphine ligand with axial chirality like (R)-BINAP gave no desired product. Yet the reaction occurs with alkyl-substituted phosphine ligands.…”

“…Chem., describing their discoveries. [10][11][12][13][14][15][16] In these studies, weak attractive interactions have been found to play an important role by stabilizing the favorable key transition state structure formed by chiral catalysts and substrates and promoting the hydrogenation reaction. These weak attractive interactions could be found as CH⋯HC, CH⋯π, CH⋯O, and other interactions in Zhang and his coworkers' work.…”

P-Stereogenic Phosphorus Ligands in Asymmetric Catalysis

“…Another chemoselective reduction was observed in the hydrogenation of α-formyl enamides 48 using BenzP* as the chiral ligand (Schemes 21 and 22). 393 Under 10 atm H 2 pressure at room temperature for 4 h, the enamide C�C bond of substrates 48 was selectively hydrogenated to afford chiral α-amido aldehydes 49 in 98−99% yields with 92 to >99.9% ee, whereas under more forcing conditions (30 atm and 12 h), the formyl group was also reduced to furnish β-amido alcohol derivatives 50 in 97−98% yields with 92 to >99.9% ee.…”

“…Zhang, Gridnev, and co-workers have indicated, on the basis of DFT computations, that the weak attractive interaction between the catalyst and the substrate plays a significant role in controlling the catalytic activity and enantioselectivity in some Rh-, Pd-, Ni-catalyzed asymmetric hydrogenations. 393,453,480,481 Recently, Houk, Yang, and co-worker have conducted IGM (Independent Gradient Model) analysis and EDA (Energy Decomposition Analysis) for such transition-metal-catalyzed asymmetric hydrogenations using QuinoxP*, BenzP*, DTBM-SegPhos, and Ph-BPE as the chiral ligands. 484 Their IGM/ EDA analyses also show the importance of the dispersion interactions to enhance the catalytic activity and the enantioinduction ability in these asymmetric hydrogenations.…”

“…The significance of chiral amines containing functional groups for pharmaceuticals has prompted the investigations on the Rh-catalyzed asymmetric hydrogenation of functionalized enamides. The functional groups attached at the αor βposition of enamides are keto, 388−392 formyl, 393 trifluoromethyl, 394 nitro, 395 mesyl, 396 tosyl, 396 alkylthio, 397 alkenyl, 385,398,399 alkynyl, 398 pyridyl, 400 boryl, 401,402 and phosphonate. 403 In 2009, Zhang, Wu, and co-workers reported the asymmetric hydrogenation of β-ketoenamides using the Rh− DuanPhos catalyst.…”