Dynamic Kinetic Asymmetric Reductive Amination: Synthesis of Chiral Primary β‐Amino Lactams

Abstract

A highly efficient ruthenium-catalyzed asymmetric reductive amination (ARA) of racemic β-keto lactams with molecular hydrogen and ammonium salts is disclosed for the synthesis of enantiomerically pure primary amino lactams through dynamic kinetic resolution (DKR). By this approach, a range of syn primary β-amino lactams were obtained in high yields with high chemo-, enantio-, and diastereoselectivity (up to 98 % yield, 99 % ee, >20:1 d.r., syn products). The utility of the products has been demonstrated by rapid access to a key synthetic intermediate towards biologically active drug molecules. Meanwhile, mechanistic studies and control experiments indicate that the reaction may proceed through the hydrogenation of an iminium intermediate.

Facile Synthesis of Spirocyclic Lactams via [3+2] and [3+3] Aza‐Annulation Reactions

“…Despite moderate yields (26–44 %) of such reactions, their practical applicability is justified by the availability of starting materials and the practicability of purification of the α‐ketolactams via their Na‐salts, thus avoiding column chromatography. Alternatively, the desired ketolactams can be prepared by deprotonation of lactams with LDA at low temperatures and quenching the Li‐enolates with appropriate esters, [50] however in the latter case the yields were comparable with the NaH method (see supporting information for the details). Condensation between α‐ketolactams as well as α‐acetylbutyrolactone with primary amines proceeded readily in refluxing chloroform while using 4 Å molecular sieves as the dehydrating agent ( 3 a , c , d , h , i ).…”

β‐Keto Amides: A Jack‐of‐All‐Trades Building Block in Organic Chemistry

“…Ru‐SegPhos complex also catalyzed the reductive amination of β ‐keto lactams 439 with NH 4 OAc to give syn β ‐amino γ ‐lactams 440 in excellent ee's and dr's. However, the diastereoselectivity for β ‐keto δ ‐lactams was low (dr=1/1) (Scheme 91b) [200] . In 2021, Yamada et al [201] .…”

Ruthenium‐Catalyzed Direct Asymmetric Reductive Amination of Diaryl and Sterically Hindered Ketones with Ammonium Salts and H2

“…Ortho ‐Me‐substituted diphenyl ketone 1 was initially considered and subjected to our previously developed reaction conditions in the presence of 1 equiv of Ti(O i ‐Pr) 4 . As expected, the reaction was sluggish and only afforded a small amount of desired product 2 , with most starting material recovered.…”