Dual-Enzyme Catalyzed Stereoselective Synthesis of Chiral Aromatic Polysubstituted γ-Butyrolactones

Chiral polysubstituted aromatic γ-butyrolactones are core structural units of many natural products and high value-added chemicals in the pharmaceutical and food industries. Currently, the precise construction of multiple chiral centers on the five-membered heterocycle substituted by bulky phenyl groups faces big challenges, such as low stereoselectivity, expensive noble metal catalysts, harsh reaction conditions and low atom economy. Herein, we report a one-pot, two-enzyme catalytic strategy for the synthesis of 18 bulky di/trisubstituted aromatic γ-butyrolactones on the α-, β- and γ-carbons with good enantioselectivities (up to >99% ee) and diastereoselectivities (up to >99:1 dr). This cascade process includes sequential two-step asymmetric reduction of α-/β-unsaturated γ-ketoesters by four ene reductases and a carbonyl reductase without intermediate isolation and catalyst removal. In particular, the large sterically hindered substrates (1p–1s) were converted to the corresponding trisubstituted γ-butyrolactones (4p–4s) with 98–99% ee and >99:1 dr. This enzymatic cascade process represents a simple, atom-economic and enantioselective method to deliver a broad of bulky polysubstituted γ-butyrolactones in a cheap and efficient manner compared to conventional methods.