Asymmetric photoenzymatic synthesis of chiral γ-acyloxybutenolides from 2-furoic acid in 2-methyltetrahydrofuran: from batch to flow process

Abstract

γ-Acyloxybutenolides (ABs) are building blocks for producing polymers, coatings, and bioactive compounds. In this work, we present a one-pot photoenzymatic cascade towards chiral ABs from 2-furoic acid (FCA) in biomass-based 2-methyltetrahydrofuran (2-MeTHF), where FCA is converted into γ-hydroxybutenolide (HB) via photooxygenation, followed by stereoselective enzymatic acylation. The use of 2-MeTHF as the solvent opens up a compatible “window” to allow both photocatalyst and lipase to function smoothly in a single vessel, thus eliminating the intermediate isolation step. A group of chiral ABs were synthesized in a concurrent mode by combining meso-tetra(4-carboxyphenyl)porphyrin (TCPP, a photocatalyst) and Lipozyme TL IM (a commercially available immobilized lipase) with 28–73% isolated yields and 19–73% ee. A temporal compartmentalization strategy was found to be effective at greatly reducing the mutual detrimental effects between the photocatalyst and the enzyme. As a result, a one-pot two-step cascade provided access to the target products in >90% yields in most cases. By leveraging the high stereoselectivity of lipase AK, product ee values of more than 86% were achieved. With γ-acetoxybutenolide synthesis as a model reaction, flow technology was applied to intensify the process incorporating Lipozyme TL IM and PCN-222, a stable and heterogeneous photocatalyst. The practicability of the process operating at ≥0.5 M substrate loadings was demonstrated via a gram-scale synthesis with space–time yields up to 4.1 g L⁻¹ h⁻¹ and an overall yield of 92%. This work offers an efficient and easily scalable platform for the sustainable production of biobased chiral butenolide derivatives by combining chemobiocatalysis and flow technology in a biobased solvent.