摘要：

IntroductionBaeyer–Villiger oxidation of cyclic ketones to chiral lactones allows access to highly interesting and versatile intermediates in the synthesis of bioactive or natural products.1–4The biocatalytic approach to realize this transformation with high regio- and enantioselectivity takes advantage of the high promiscuity of flavin dependent monooxygenases to accept a large diversity of non-natural substrates. Moreover, this “green chemistry” strategy utilizes molecular oxygen for the oxidation process as most sustainable oxidant. An increasing number of such Baeyer–Villiger monooxygenases (BVMOs) has become available in recent years. Due to t4While the regioselectivity of the Baeyer–Villiger oxidation is governed predominantly by electronic effects leading to preferred migration of the more nucleophilic and higher substituted carbon center, stereoelectronic effects can override this rule-of-thumb in reactions catalyzed by salen-type complexes with Zr as the central atom5or, more frequently, in enzymatic transformations.6In particular, in the series of fused bicycloketones incorporating a cyclobutanone structural motif, regiodivergent biooxidation of the antipodal substrate ketones to enantiomerically pure “normal” and “abnormal” lactone regioisomers was observed as one of the remarkable behaviors of BVMOs.7However, such a behavior was found only in a few cases of the cyclohexanone series. Alphand and Furstoss reported that wild-type cells ofAcinetobacterNCIMB 9871 or the mutant strainAcinetobacterTD63 convert (−)-trans-dihydrocarvone to the expected normal lactone, while (+)-trans-dihydrocarvone afforded abnormal lactone.8In contrast, metabolism of carveol and dihydrocarveol inRhodococcus erythropolisDCL14 displayed transformation of (+)-transand (−)-cis-dihydrocarvone to normal lactones while opposite enantiomers led to the formation of the abnormal lactones.9Normal lactones of α-substituted cyclohexanones can be also synthesized by chemical Baeyer–Villiger oxidation usingm-chloroperoxybenzoic acid, trifluoroperoxyacetic acid, peroxyacetic acid and hydrogen peroxide as oxidants. However, starting from unsaturated ketones such as dihydrocarvone, competitive oxidation of the carbon–carbon double bond can take place. Within non-chiral reactions, utilization of Sn-beta zeolites and platinum complexes in H2O2or PSA (monopersuccinic acid) in water enabled complete control of the parallel oxidation processes, ultimately giving selective Baeyer–Villiger oxidation upon reaction of bifunctional substrates.10Herein, we are reporting a preliminary study on regiodivergent and enantiocomplementary biooxidations in the cyclohexanone series. Utilizing a collection of BVMO producing recombinantE. colistrains we were able to provide access to all regio- and enantiomeric lactones for the first time starting from terpenone precursors. In particular we have studied the biooxidation of pure enantiomers oftrans- andcis-dihydrocarvone1a/b, carvomenthone1cand menthone1d(Scheme 1). We compared substrate acceptance profiles and stereopreferences of cyclohexanone (CH) and cyclopentanone (CP) monooxygenases originating fromAcinetobacter(CHMOAcineto),11Arthrobacter(CHMOArthro),12Brachymonas(CHMOBrachy),13Brevibacterium(CHMOBrevi1, CHMOBrevi2),14Rhodococcus(CHMORhodo1, CHMORhodo2),12andComamonas(CPMOComa)15species in whole-cell mediated Baeyer–Villiger oxidations with recombinantE. colias the host organism.16Baeyer–Villiger oxidations of ketones1a–dto “normal” lactones2a–dand “abnormal” lactones3a–d.

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