New and Expeditious Tandem Sequence Aza-Michael/Intramolecular Nucleophilic Substitution Route to Substituted γ-Lactams: Synthesis of the Tricyclic Core of (±)-Martinellines

Abstract

A new and highly diastereoselective tandem reaction aza-Michael/intramolecular nucleophilic substitution is presented. This unprecedented tandem reaction between N-substituted alpha-bromoacetamides and Michael acceptors proceeds with good yields and excellent diastereoselectivity to provide the corresponding trisubstituted gamma-lactam systems. An application to the concise synthesis of the tricyclic core of (+/-)-martinelline alkaloids is also described.

The Fascinating Chemistry of α‐Haloamides

“…An aza-Michael initiated ring closure (aza-MIRC) was envisioned by Comesse and co-workers as a straightforward way for achieving γ-lactams C from N-substituted α-bromoacetamides A and Knoevenagel substrates B (Scheme 183). [193] Thus, the amidate anion addition onto substrates B followed by intramolecular alkylation afforded compounds C through a formal [3 + 2] cycloaddition reaction. The one-pot tandem process provided diastereoselectively polysubstituted pyrrolidin-2-ones in moderate to good yields (49 to 69 %).…”

α-Halogenoacetamides: versatile and efficient tools for the synthesis of complex aza-heterocycles

“…It should be noted that a soft base such as a carbonate is mandatory to promote this reaction with good yields (Scheme 22). 90 After the deprotonation of the nitrogen atom with NaH, the domino sequence starts with an aza-Michael addition leading to the anionic intermediate A. This step is followed by a carbocyclization furnishing the desired -lactam 59 in yields ranging from 49 to 69% and excellent diastereoselectivity when E ≠ E'.…”

Synthesis and Characterization of New Thiazolidinones and 2-Oxopyrrolidines Derived From Schiff Bases

“…4 Substituted γ-lactams, in particular, have potential application in drug synthesis, but the development of the stereoselective synthesis of chiral γlactams remains a challenge. 5,6 Various γ-lactams are components of natural products, 7 and some biologically important lactams 8 are obtained from the reaction of imines with phenylsuccinic anhydride.…”