Direct Synthesis of Chiral NH Lactams via Ru-Catalyzed Asymmetric Reductive Amination/Cyclization Cascade of Keto Acids/Esters

Abstract

Lactams with a stereogenic center adjacent to the N atom have existed in many medicinal agents and bioactive alkaloids. Herein we report a broadly applicable synthesis of enantioenriched NH lactams through a one-pot asymmetric reductive amination/cyclization sequence of easily available keto acids/esters. Such cascade processes alleviate the demand for protecting group manipulations as well as intermediate purification. This strategy is capable of constructing enantioenriched lactams and benzo-lactams of a five-, six-, or seven-membered ring in generally high yield and with excellent enantioselectivities (up to 97% ee). Scalable and concise syntheses of key drug intermediates have further displayed the importance of this methodology.

The serendipitous effect of KF in Ritter reaction: Photo-induced amino-alkylation of alkenes

“…After completion of reaction as checked by TLC, the solvent was evaporated and the residue was purified directly by flash column chromatograph (petroleum ether/ethyl acetate, 1:1 v/v) to give 5-phenylpyrrolidin-2-one 11 (13.1 mg, 81%) as white solid ( Zheng and Studer, 2019 ). Known compound ( Shi et al., 2020 ), 1 H NMR (400 MHz, CDCl 3 ) δ 7.39–7.35 (m, 2H), 7.31–7.29 (m, 3H), 6.37 (s, 1H), 4.75 (t, J = 7.1 Hz, 1H), 2.62–2.53 (m, 1H), 2.51–2.36 (m, 2H), 2.02–1.95 (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 178.5, 142.5, 128.9, 127.9, 125.6, 58.0, 31.3, 30.3.…”

Efficient preparation of (R)‐2‐(2,5‐difluorophenyl)pyrrolidine via a recycle process of resolution

“…Larotrectinib (Scheme 1), a highly selective tropomyosin receptor kinases (TRK) inhibitor, was approved in 2018 by Food and Drug Administration (FDA) for treating cancer harboring neurotrophin receptor (NTRK) gene fusions due to its striking efficacy toward 17 different kinds of tumors 1 . ( R )‐2‐(2,5‐Difluorophenyl)pyrrolidine (( R ) ‐1 ) is the key chiral intermediate for synthesis of Larotrectinib, and most of approaches to synthesize ( R ) ‐1 focus on the asymmetric synthesis by the chiral catalyst, 2–5 chiral auxiliary, 6,7 or biocatalyst 8 . However, these methods suffer some deficiencies such as requirement for high‐pressure of hydrogen, using and subsequent removal of costly catalysts, harsh reaction conditions, or (and) complex protection/de‐protection of the active functional groups.…”

“…Meanwhile, most of catalytic asymmetric methods gave insufficient stereoselectivity (75%–87% ee ), which cannot meet the requests of practical application. Additional recrystallization was needed to improve the chiral purity of ( R ) ‐1 2–5 …”

Chemoenzymatic Stereoselective Synthesis of Substituted γ‐ or δ‐lactams with Two Chiral Centers via Transaminase‐catalysed Dynamic Kinetic Resolution

“…Recently, a Ru-catalysed asymmetric reductive amination and cyclization cascade furnished enantioenriched lactams with up to 97 % enantiomeric excess (Scheme 1C). [9] However, most cases still suffer from several drawbacks, including multiple steps, costly transition metal catalysts, or scope limitations. Biocatalysis provides an alternative for the production of this important class of compounds, [10] traditionally using lipase, [11] or acylase [12] via kinetic resolutions (KR) of racemic lactams.…”