Continuous Flow Spirocyclization Reactions: Towards Efficient Synthesis of Chiral Spiropenicillanates

Abstract

Herein, we describe the development of a continuous flow approach to chiral spiropenicillanates with remarkable bioactive properties from 6‐alkylidenepenicillanates via phosphine‐catalyzed [3+2] annulation of allenoates or via 1,3‐dipolar cycloaddition with diphenyldiazomethane. Model reactions were carried out using simple alkenes, such as methyl vinyl ketone and N‐substituted maleimides, leading to the corresponding products in excellent yields (up to 96%). The [3+2] annulation reaction was subsequently extended to the reactivity of 6‐alkylidenepenicillanates, a more complex 2π‐component with an exocyclic carbon‐carbon double bond, allowing the synthesis of spirocyclic compounds. Two regioisomeric chiral spirocyclopentene‐β‐lactams were obtained, in moderate to good overall yields (31‐84%). The 1,3‐dipolar cycloaddition reactions between 6‐alkylidenepenicillanates and diphenyldiazomethane under continuous flow conditions gave the corresponding spiro‐1‐pyrazolinepenicillanates in high yields (up to 81%). Thermal ring contraction, via N2 extrusion, of spiro‐1‐pyrazolinepenicillanates under continuous flow conditions led to spirocyclopropanepenicillanates in quantitative yields. The continuous flow proved to be an efficient methodology for the synthesis of spiropenicillanates and represents a more sustainable approach for the scale‐up synthesis of spiropenicillanates with relevant biological activity.