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 through phosphine-catalyzed [3+2] annulation of allenoates or 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. 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 larger-scale synthesis of spiropenicillanates with relevant biological activity.