Poly-ε-caprolactone (PCL) is chemically produced on an industrial scale in spite of the need for hazardous peracetic acid as an oxidation reagent. Although Baeyer-Villiger monooxygenases (BVMO) in principle enable the enzymatic synthesis of ε-caprolactone (ε-CL) directly from cyclohexanone with molecular oxygen, current systems suffer from low productivity and are subject to substrate and product inhibition. The major limitations for such a biocatalytic route to produce this bulk chemical were overcome by combining an alcohol dehydrogenase with a BVMO to enable the efficient oxidation of cyclohexanol to ε-CL. Key to success was a subsequent direct ring-opening oligomerization of in situ formed ε-CL in the aqueous phase by using lipase A from Candida antarctica, thus efficiently solving the product inhibition problem and leading to the formation of oligo-ε-CL at more than 20 g L(-1) when starting from 200 mM cyclohexanol. This oligomer is easily chemically polymerized to PCL.
The overlapping clinical features of relapsing remitting multiple sclerosis (RRMS), aquaporin-4 (AQP4)-antibody (Ab) neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein (MOG)-Ab disease mean that detection of disease specific serum antibodies is the gold standard in diagnostics. However, antibody levels are not prognostic and may become undetectable after treatment or during remission. Therefore, there is still a need to discover antibody-independent biomarkers. We sought to discover whether plasma metabolic profiling could provide biomarkers of these three diseases and explore if the metabolic differences are independent of antibody titre. Plasma samples from 108 patients (34 RRMS, 54 AQP4-Ab NMOSD, and 20 MOG-Ab disease) were analysed by nuclear magnetic resonance spectroscopy followed by lipoprotein profiling. Orthogonal partial-least squares discriminatory analysis (OPLS-DA) was used to identify significant differences in the plasma metabolite concentrations and produce models (mathematical algorithms) capable of identifying these diseases. In all instances, the models were highly discriminatory, with a distinct metabolite pattern identified for each disease. In addition, OPLS-DA identified AQP4-Ab NMOSD patient samples with low/undetectable antibody levels with an accuracy of 92%. The AQP4-Ab NMOSD metabolic profile was characterised by decreased levels of scyllo-inositol and small high density lipoprotein particles along with an increase in large low density lipoprotein particles relative to both RRMS and MOG-Ab disease. RRMS plasma exhibited increased histidine and glucose, along with decreased lactate, alanine, and large high density lipoproteins while MOG-Ab disease plasma was defined by increases in formate and leucine coupled with decreased myo-inositol. Despite overlap in clinical measures in these three diseases, the distinct plasma metabolic patterns support their distinct serological profiles and confirm that these conditions are indeed different at a molecular level. The metabolites identified provide a molecular signature of each condition which is independent of antibody titre and EDSS, with potential use for disease monitoring and diagnosis.Electronic supplementary materialThe online version of this article (10.1186/s40478-017-0495-8) contains supplementary material, which is available to authorized users.
A novel concept for the direct oxidation of cycloalkanes to the corresponding cyclic ketones in a one‐pot synthesis in water with molecular oxygen as sole oxidizing agent was reported recently. Based on this concept we have developed a new strategy for the double oxidation of n‐heptane to enable a biocatalytic resolution for the direct synthesis of heptanone and (R)‐heptanols in a one‐pot reaction. The bicatalytic cascade employs an NADH driven P450 BM3 monooxygenase variant (WTNADH, 19A12NADH or CM1NADH) and an (S)‐enantioselective alcohol dehydrogenase (RE‐ADH). In the initial step n‐heptane is hydroxylated under consumption of NADH to produce (R/S)‐heptanol. In the second oxidation step the (S)‐heptanol enantiomers are transformed to the corresponding ketones, reducing and thereby regenerating the cofactor. Characterization of initial hydroxylation step revealed high turnover frequencies (TOF) of up to 600 min−1, as well as high coupling efficiencies using NADH as cofactor (up to 44%). In the cascade reaction a nearly 2‐fold improved product formation was achieved, compared to the single hydroxylation reaction. The total product concentration reached 1.1 mM, corresponding to a total turnover number (TTN) of 2500. Implementation of an additional cofactor regeneration system (D‐glucose/glucose dehydrogenase) enabled a further enhancement in product formation with a total product concentration of 1.8 mM and a TTN of 3500.
The enantioselective preparation of a-substituted nitroalkanes of type 1 is of high interest due to the use of the corresponding amines 2 in the synthesis of pharmaceuticals. [1] Representative examples for commercial drugs based on such amines are Tamsulosin and Selegiline (Scheme 1). Due to the lack of suitable enantioselective catalytic synthetic methodologies, these drugs are produced in a laborious fashion either by chiral resolution (at the final stage of a suitable amine) or by a reaction relying on a chiral auxiliary (used in stoichiometric amount and not recyclable). [1,2] An attractive alternative synthetic approach would be based on the enantioselective reduction of a-methylated nitroalkenes of type 5 as a key step. The concept of this process as well as its integration in the preparation of amines and related derivatives is shown in Scheme 2. The trans substrates 5 are easily accessible starting from economically attractive and readily available industrial chemicals (aldehydes, nitroethane), and methods have been reported for the final transformation of the nitro group into an amino group with retention of the absolute configuration. [3] However, hitherto reported processes for the enantioselective reduction of nitroalkenes 5 in the presence of chemocatalysts as well as enzymes only led to low to moderate and in a few cases good enantioselectivities. For instance, in the presence of metalcontaining hydrogenation catalysts maximum enantioselectivities of 58 % ee are obtained for the nitroalkanes 1. [4] Alternatively, due to the achievements in the enzymatic reduction of activated C=C bonds of a multitude of substrate classes, [5] the enantioselective reduction of a-methylated nitroalkenes 5 using ene reductases was also studied. [5,6] Despite intensive efforts, however, until recently such enzyme-catalyzed processes for these substrates have given only enantioselectivities of 0-48 % ee in most cases and 70 % ee at best. [6a-g] In a current study, the enantioselectivity has been increased up to 84 % ee.[6h] A range of reasons for this were identified, such as the high CH acidity and the resulting sensitivity of nitroalkanes 1 towards racemization, [7] as well as the general low enantioselectivity of enzymes in the reduction of substrates of type 5. [6] One difficulty may arise from the fact that the stereogenic center is not formed in the initial addition of the hydride, but in the subsequent protonation of the resulting carbanion; [8] the control of enantioselectivity in such asymmetric protonations is generally considered to be difficult. A further demanding task is avoiding the competing enzymatic Nef reaction, [9] which transforms nitroalkenes 5 into the corresponding ketones. Accordingly (and independent of the type of catalyst), the development of a highly enantioselective C = C reduction of nitroalkenes of type 5 is still regarded as a challenge. Herein we report the first highly enantioselective process for the reduction of amethylated trans-nitroalkenes 5 to provide nitroalkanes 1 with enantio...
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