Catalytic asymmetric reductive hydroalkylation of enamides and enecarbamates to chiral aliphatic amines

Abstract

To increase the reliability and success rate of drug discovery, efforts have been made to increase the C(sp3) fraction and avoid flat molecules. sp3-Rich enantiopure amines are most frequently encountered as chiral auxiliaries, synthetic intermediates for pharmaceutical agents and bioactive natural products. Streamlined construction of chiral aliphatic amines has long been regarded as a paramount challenge. Mainstream approaches, including hydrogenation of enamines and imines, C–H amination, and alkylation of imines, were applied for the synthesis of chiral amines with circumscribed skeleton structures; typically, the chiral carbon centre was adjacent to an auxiliary aryl or ester group. Herein, we report a mild and general nickel-catalysed asymmetric reductive hydroalkylation to effectively convert enamides and enecarbamates into drug-like α-branched chiral amines and derivatives. This reaction involves the regio- and stereoselective hydrometallation of an enamide or enecarbamate to generate a catalytic amount of enantioenriched alkylnickel intermediate, followed by C–C bond formation via alkyl electrophiles.

Enantioselective access to chiral aliphatic amines and alcohols via Ni-catalyzed hydroalkylations

“…6b ). The reaction of ( E )-acyl enamine was slightly slower and delivered a lower yield and higher enantioselectivity of 9 in comparison to the generation of 8 from ( Z )-acyl enamine 50 , 51 . These results indicated that Ni–H insertion onto acyl enamines to form alkyl-Ni species might be irreversible and enantio-determining.…”

“…In 2021, Hu group reported a hydroalkylation of vinyl boronates to give chiral secondary alkyl boronates enabled by the anchoring effect of boron 49 . These examples showcased the feasibility of building a stereogenic carbon center originating from alkenes via Ni-catalyzed hydroarylation [36][37][38] and hydroalkylation [48][49][50][51] of alkenes.…”

“…1c). Here, we report the Ni-H-catalyzed regio-and enantioselective hydroalkylation of acyl enamines and enol esters with alkyl iodides to forge a stereogenic carbon center next to nitrogen or oxygen originating from alkenes in high enantioselectivity, providing a unified protocol for rapid access to chiral secondary alkyl-substituted amine and alcohol derivatives which are difficult to access otherwise [50][51][52] .…”

Gene mining, codon optimization and analysis of binding mechanism of an aldo-keto reductase with high activity, better substrate specificity and excellent solvent tolerance

“…The synthesis of chiral alcohols and their derivatives has great significance and great market demand as they are key intermediates in many important drugs, such as the anti-tumor drug Irutinib, the anti-depression drug Duloxetine, and the lipid-lowering drug Atorvastatin [ 1 – 12 ]. Biocatalysis has shown advantages and concerns due to its high chiral selectivity, stereoscopic and regional selectivity, environmental friendliness, mild conditions and so on.…”

SOMOphilic Alkynylation of Unreactive Alkenes Enabled by Iron-Catalyzed Hydrogen Atom Transfer

“…Recently, metal (Fe, Co, Mn)-catalyzed hydrofunctionalization of alkenes has been established as an attractive and robust strategy for the construction of structural skeletons via the metal hydride hydrogen atom transfer (MHAT) process [ 40 , 41 ]. The alkenes interact with the metal hydride in situ generated from the metal catalyst with hydrogen sources to form carbon radical species, which were involved in varieties of chemical bonds formation such as C–H [ 42 , 43 , 44 ], C–C [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ], C–O [ 54 , 55 , 56 , 57 , 58 ], C–S [ 59 , 60 ], C–N [ 61 , 62 , 63 , 64 , 65 ], and C–F [ 66 , 67 ] bond coupling. However, hydrogen atom transfer-triggered the hydrofunctionalization of alkenes, leading to internal alkynes using acetylenic sulfones as alkyne source was less explored.…”