Biocatalytic Reductive Amination by Native Amine Dehydrogenases to Access Short Chiral Alkyl Amines and Amino Alcohols

Small optically active molecules, and more particularly short-chain chiral amines, are key compounds in the chemical industry and precursors of various pharmaceuticals. Their chemo-biocatalytic production on a commercial scale is already established, mainly through lipase-catalyzed resolutions leading to ChiPros™ products among others. Nevertheless, their biocatalytic synthesis remains challenging for very short-chain C4 to C5 amines due to low enantiomeric excess. To complement the possibilities recently offered by transaminases, this work describes alternative biocatalytic access using amine dehydrogenases (AmDHs). Without any protein engineering, some of the already described wild-type AmDHs (CfusAmDH, MsmeAmDH, MicroAmDH, and MATOUAmDH2) were shown to be efficient for the synthesis of hydroxylated or unfunctionalized small 2-aminoalkanes. Conversions up to 97.1% were reached at 50 mM, and moderate to high enantioselectivities were obtained, especially for (S)-1-methoxypropan-2-amine (98.1%), (S)-3-aminobutan-1-ol (99.5%), (3S)-3-aminobutan-2-ol (99.4%), and the small (S)-butan-2-amine (93.6%) with MsmeAmDH. Semi-preparative scale-up experiments were successfully performed at 150 mM substrate concentrations for the synthesis of (S)-butan-2-amine and (S)-1-methoxypropan-2-amine, the latter known as “(S)-MOIPA”. Modeling studies provided some preliminary results explaining the basis for the challenging discrimination between similarly sized substituents in the active sites of these enzymes.

Nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts enabled by NN2 pincer ligand

Alkynes are amongst the most valuable functional groups in organic chemistry and widely used in chemical biology, pharmacy, and materials science. However, the preparation of alkyl-substituted alkynes still remains elusive. Here, we show a nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts. Key to the success of this coupling is the development of an easily accessible and bench-stable amide-type pincer ligand. This ligand allows naturally abundant alkyl amines as alkylating agents in Sonogashira reactions, and produces diverse alkynes in excellent yields under mild conditions. Salient merits of this chemistry include broad substrate scope and functional group tolerance, gram-scale synthesis, one-pot transformation, versatile late-stage derivatizations as well as the use of inexpensive pre-catalyst and readily available substrates. The high efficiency and strong practicability bode well for the widespread applications of this strategy in constructing functional molecules, materials, and fine chemicals.

Site-Selective Allylic C-H Amination with Aliphatic Amines

The direct coupling of olefins and alkyl amines represents the most efficient and atom-economical approach to prepare aliphatic allylamines which are fundamental building blocks. However, the method that achieves this goal while exhibiting exquisite control over the site at which the amine is introduced remains elusive. Herein, we report that the combination of a photocatalyst and a cobaloxime enables site-selective allylic C–H amination of olefins with secondary alkyl amines to afford allylic amines, eliminating the need for oxidants. This reaction proceeds by a radical-based mechanism distinct from those of existing allylic amination reactions. It affords the product resulting from cleavage of the stronger, primary allylic C–H bonds over other weaker allylic C–H bond options. DFT calculations reveal that this selectivity originates from a cobaloxime-promoted hydrogen atom transfer (HAT) process. Our method is compatible with a broad scope of alkenes, and can be extended to achieve a site- and diastereoselective amination of natural terpenes.

Diversification of α–Ketoamides via Transamidation Reactions with Alkyl and Benzyl Amines at Room Temperature

A wide range of N-tosyl α–ketoamides underwent transamidation with various alkyl amines in the absence of catalyst, base, or additives. On the other hand, transamidation in N-Boc α–ketoamides is achieved...