Manchester Institute of Biotechnology and the School of Chemistry, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.
BBSRC/EPSRC Manchester Synthetic Biology Research Centre, for Fine and Specialty Chemicals (SYNBIOCHEM), Manchester Institute of Biotechnology and the School of Chemistry, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.
Chemistry. 2019 Feb 26;25(12):2983-2988. doi: 10.1002/chem.201805219. Epub 2019 Jan 15.
The scope for biocatalytic modification of non-native carvone derivatives for speciality intermediates has hitherto been limited. Additionally, caprolactones are important feedstocks with diverse applications in the polymer industry and new non-native terpenone-derived biocatalytic caprolactone syntheses are thus of potential value for industrial biocatalytic materials applications. Biocatalytic reduction of synthetic analogues of R-(-)-carvone with additional substituents at C3 or C6, or both C3 and C6, using three types of OYEs (OYE2, PETNR and OYE3) shows significant impact of both regio-substitution and the substrate diastereomer. Bioreduction of (-)-carvone derivatives substituted with a Me and/or OH group at C6 is highly dependent on the diastereomer of the substrate. Derivatives bearing C6 substituents larger than methyl moieties are not substrates. Computer docking studies of PETNR with both (6S)-Me and (6R)-Me substituted (-)-carvone provides a model consistent with the outcomes of bioconversion. The products of bioreduction were efficiently biotransformed by the Baeyer-Villiger monooxygenase (BVase) CHMO_Phi1 to afford novel trisubstituted lactones with complete regioselectivity to provide a new biocatalytic entry to these chiral caprolactones. This provides both new non-native polymerization feedstock chemicals, but also with enhanced efficiency and selectivity over native (+)-dihydrocarvone Baeyer-Villigerase expansion. Optimum enzymatic reactions were scaled up to 60-100 mg, demonstrating the utility for preparative biocatalytic synthesis of both new synthetic scaffold-modified dihydrocarvones and efficient biocatalytic entry to new chiral caprolactones, which are potential single-isomer chiral polymer feedstocks.
迄今为止，非天然香芹酮衍生物的生物催化修饰用于特种中间体的范围一直受到限制。此外，己内酰胺是一种重要的原料，在聚合物工业中有多种应用，因此新型非天然萜烯衍生的生物催化己内酰胺合成具有潜在的工业生物催化材料应用价值。使用三种 OYE（OYE2、PETNR 和 OYE3）对 C3 或 C6 或 C3 和 C6 处具有额外取代基的 R-(-)-香芹酮的合成类似物进行生物催化还原，表明区域取代和底物非对映异构体都有显著影响。C6 位取代有 Me 和/或 OH 基团的（-）-香芹酮衍生物的生物还原高度依赖于底物的非对映异构体。取代基大于甲基部分的 C6 取代衍生物不是底物。PETNR 与（6S）-Me 和（6R）-Me 取代的（-）-香芹酮的计算机对接研究提供了与生物转化结果一致的模型。生物还原产物可通过 Baeyer-Villiger 单加氧酶（BVase）CHMO_Phi1 有效地进行生物转化，得到具有完全区域选择性的新型三取代内酯，为这些手性己内酰胺提供了新的生物催化途径。这不仅提供了新的非天然聚合原料化学品，而且相对于天然（+）-二氢香芹酮 Baeyer-Villigerase 扩展，提高了效率和选择性。最佳酶反应放大到 60-100mg，证明了新型合成支架修饰的二氢香芹酮的制备性生物催化合成和新型手性己内酰胺的高效生物催化入口的实用性，它们是潜在的单异构体手性聚合物原料。
