Development and Comparison of Substrate-Supplied and Product-Convergent Redox-Neutral Cascade Reactions for the Sustainable Synthesis of Lactones

Hydrogen-borrowing redox-neutral cascade reactions are promising for the synthesis of lactones from the perspective of sustainable chemistry. In this study, a novel NADPH-dependent Baeyer–Villiger monooxygenase Aj BVMO was identified from Acinetobacter johnsonii with a specific activity of 0.96 U·mg –1 in the oxidation of cyclohexanone into ε-caprolactone. To achieve cofactor matching, NADP + -dependent Kp ADH T215V and Cg KR1 with high oxidative activities toward cyclohexanol and 1,6-hexanediol were constructed for developing “substrate-supplied” and “product-convergent” hydrogen-borrowing redox-neutral cascade reactions. The effects of buffer systems on the activities and spontaneous hydrolysis of ε-caprolactone and the ratios of ADHs and BVMO on the conversion rates were explored. In the “substrate-supplied” system employing Kp ADH T215V and Aj BVMO, as high as 68.6 mM ε-caprolactone could be obtained from 100 mM cyclohexanol, with a maximum TOF of 7.2 min –1 and a TTN of 337. In the “product-convergent” system employing Cg KR1 and Aj BVMO, 115.1 mM ε-caprolactone was produced from 100 mM cyclohexanone, with a maximum TOF of 5.7 min –1 and a TTN of 757. The product-convergent system is more efficient than the substrate-supplied system. Moreover, these two redox-neutral cascade systems could also be applied in the synthesis of lactones with different chain lengths such as γ-butyrolactone and δ-valerolactone. This study established efficient redox-neutral cascade systems for the synthesis of lactones featuring a high atomic economy with only H 2 O as a byproduct.