Lactonization reactions through hydrolase-catalyzed peracid formation. Use of lipases for chemoenzymatic Baeyer–Villiger oxidations of cyclobutanones

Highlights

• A one-pot chemoenzymatic cascade is described for the formation of γ-butyrolactones.

• This approach is based on a lipase-catalyzed perhydrolysis and a chemical oxidation.

• Baeyer–Villiger reaction has been successfully applied to 3-substituted cyclobutanones.

• Lactones have been achieved in excellent isolated yields under mild conditions.

• Purification of the final products was possible after a simple extraction protocol.

Abstract

A one-pot chemoenzymatic method has been described for the synthesis of γ-butyrolactones starting from the corresponding ketones through a Baeyer–Villiger reaction. The approach is based on a lipase-catalyzed perhydrolysis for the formation of peracetic acid, which is the responsible for the ketone oxidation. Optimization studies have been performed in the oxidation of cyclobutanone, finding Candida antarctica lipase type B, ethyl acetate and urea-hydrogen peroxide complex as the best system. The relative ratio of these reagents has also been analyzed in depth. This synthetic approach has been successfully extended to a family of 3-substituted cyclobutanones in high substrate concentration, yielding the corresponding lactones with excellent isolated yields and purities, under mild reaction conditions and after a simple extraction protocol.

Introduction

Hydrolases are enzymes capable to naturally catalyze hydrolytic reactions for a vast number of organic compounds such as peptides, esters or amides [1], [2]. Alternatively, and depending on the reaction conditions, they can also accelerate the reverse transformations leading to the corresponding esterification, aminolysis, ammonolysis, perhydrolysis, hydrazynolysis or thiolysis products, specially when working in non-aqueous media [3], [4]. Within this class of enzymes, perhydrolases are able to efficiently catalyze perhydrolysis reactions for the formation of peracids [5], [6], but the unusual participation of lipases for global oxidative process has attracted the attention of different research groups in the last decade [5], [7], [8]. Thus, examples of lipase-mediated epoxidation [9], [10], [11], [12], [13], [14], Baeyer–Villiger reactions [15], [16], [17], [18], [19], perhydrolysis of carboxylic acid and esters [20], sequential Baeyer–Villiger reaction and ring-opening polymerization [21], and also consecutive esterification and Baeyer–Villiger cascade reactions [22] have appeared in the literature, giving access to synthetically useful oxygenated heterocycles through clean and selective transformations under mild reaction conditions.

In this context, the synthesis of lactones is highly appealing because of their interesting properties as subunits for polymer industry, and their applications in medicinal chemistry, fragrance and food industry. Lipases provide useful possibilities for the synthesis of lactones by the proper combination of a peracid precursor, solvent and an oxidizing agent in mild reaction conditions [7], avoiding the use and storage of peracids that are usually associated with explosion risks. This in situ formation of a peracid, commonly large aliphatic linear peracids or peracetic acid, provides an environmentally friendly alternative route to the desired oxygenated heterocyles [23].

Examples described in the literature have been mainly focused on the oxidation of cyclopentanones and cyclohexanones [15], [16], [17], [18], [19], [24], [25]. Herein we have explored the possibility of using a cascade chemoenzymatic strategy for the production of γ-butyrolactones from cyclobutanones. With that purpose, different enzymes have been tested in order to find adequate oxidizing conditions, paying special attention to the oxygen source and the substrate concentration.