Highly Enantioselective Direct Asymmetric Reductive Amination of 2-Acetyl-6-Substituted Pyridines

Abstract

A highly direct asymmetric reductive amination of a variety of ketone substrates, including 2-acetyl-6-substituted pyridines, β-keto esters, β-keto amides, and 1-(6-methylpyridin-2-yl)­propan-2-one, has been disclosed for the first time (94.6% to >99.9% ee). With ammonium trifluoroacetate as the nitrogen source, various chiral corresponding primary amines were prepared in excellent enantioselectivity and conversion in the presence of a commercially available and inexpensive chiral catalyst, Ru­(OAc)2{(S)-binap}, under 0.8 MPa of hydrogen gas pressure.

Impact of aqueous micellar media on biocatalytic transformations involving transaminase (ATA); applications to chemoenzymatic catalysis

“…Substituted acylpyridines ( 8 and 26 ) were also responsive under standard aqueous conditions at 50 °C. By contrast, as discussed recently, 23 acylated 2-bromopyridine can be converted to the same primary amine 26 under hydrogenation conditions using a Ru/BINAP catalyst in 87% yield (96% ee). Reductions such as these, however, require high pressures (8 atm H 2 ), organic solvents (THF), and high temperatures (90 °C).…”

“…Rather than screening surfactants for every substrate, TPGS-750-M was selected as a representative amphiphile for evaluation of the scope of ketones amenable to conversion to the derived nonracemic primary amines with various ATAs in aqueous buffer under optimized conditions (Figure 2). Acetophenones varying in substituent and location on the ring were all readily accommodated, including highly lipophilic cases (14 and 19) and for one case bearing ortho-substitution (20). Cyclic ketones such as a Cbz-protected 4-oxoazepane (21), and N-Boc and N-Cbz-protected 3-pyrrolidinones, afforded the corresponding amines (22 and 23) in reasonable yields and, with the exception of 21, high ee's.…”

Direct Asymmetric Reductive Amination of Alkyl (Hetero)Aryl Ketones by an Engineered Amine Dehydrogenase

“…(4a), Scheme 1]. [9] Albeit effective, the substrate scope is limited to special 6-substituted 2-pyridinyl ketones, which greatly restricted its applications. As a complementary/alternative asymmetric synthesis route, biocatalytic conversion for the synthesis of chiral primary amines have also been well developed, including kinetic resolution using hydrolases, [10] deracemization using monoamine oxidases, [11] and CÀ H amination using an engineered iron-haem enzyme.…”

Direct Asymmetric Reductive Amination of Alkyl (Hetero)Aryl Ketones by an Engineered Amine Dehydrogenase

“…(4a), Scheme 1]. [9] Albeit effective, the substrate scope is limited to special 6‐substituted 2‐pyridinyl ketones, which greatly restricted its applications.…”