A Short and Versatile Approach for the Synthesis of Pyrrolizidinones

Abstract

Herein we describe a novel 3-step synthesis of pyrrolizidinone derivatives with good overall yield. This sequence relies on first a [2 + 2] cycloaddition between a keteniminium salt intermediate, bearing an alkyl chloride side chain, and an alkene partner furnishing the corresponding cyclobutanone after hydrolysis of the resulting cyclobutaniminium. Then ring expansion towards the γ-lactam using a Beckmann-type rearrangement followed by intramolecular S N 2 reaction in the presence of a base triggers the second ring formation of the process. This approach, which is particularly straightforward, allows a broad diversification of pyrrolizidinones by changing the nature of the substituents on the starting alkene and on the keteniminium precursor. Additionally, a computational study was conducted to assess the activation barrier of the S N 2 step on different intermediates as well as the nitrogen pyramidalization of the resulting pyrrolizidinones adducts.

Stereospecific Nitrogen Insertion Using Amino Diphenylphosphinates: An Aza-Baeyer–Villiger Rearrangement

“…We hypothesized that nitrogen insertion into cyclobutanone ( 1a ) should be feasible by a Baeyer–Villiger-related mechanism via Criegee-like intermediate 2a , a pathway that has been postulated in related settings before . Promising candidates for this aza-Baeyer–Villiger pathway are amines bearing a good leaving group at nitrogen such as commercial amino benzoate 3 and diphenylphosphinate 4a as well as Tamura’s reagent ( 5 ) (Scheme ).…”