A practical chemoenzymatic process to access (R)-quinuclidin-3-ol on scale

Nomoto, Fumiki; Hirayama, Yoshihiko; Ikunaka, Masaya; Inoue, Toru; Otsuka, Koutaro

doi:10.1016/s0957-4166(03)00363-x

Cited by 32 publications

(22 citation statements)

References 12 publications

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“…The production of (R)-3-quinuclidinol has been achieved by chemical and biochemical methods based on the optical resolution of a racemic mixture. [12][13][14] However, the stereoselective production of (R)-3-quinuclidinol simplifies the synthetic processes without the requirement of several modifications of precursor compounds. The (R)-selective reduction of 3-quinuclidinone is catalyzed by two quinuclidinone reductases from Rhodotorula rubra (RrQR) and Agrobacterium tumefaciens (AtQR), 15,16) which belong to the short-chain dehydrogenases/reductases (SDR) family.…”

Section: Structural Basis For the Stereoselectivity Of Quinuclidinmentioning

confidence: 99%

Structural analysis of enzymes used for bioindustry and bioremediation

Tanokura

Miyakawa

Guan

et al. 2015

Bioscience, Biotechnology, and Biochemistry

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Microbial enzymes have been widely applied in the large-scale, bioindustrial manufacture of food products and pharmaceuticals due to their high substrate specificity and stereoselectivity, and their effectiveness under mild conditions with low environmental burden. At the same time, bioremedial techniques using microbial enzymes have been developed to solve the problem of industrial waste, particularly with respect to persistent chemicals and toxic substances. And finally, structural studies of these enzymes have revealed the mechanistic basis of enzymatic reactions, including the stereoselectivity and binding specificity of substrates and cofactors. The obtained structural insights are useful not only to deepen our understanding of enzymes with potential bioindustrial and/or bioremedial application, but also for the functional improvement of enzymes through rational protein engineering. This review shows the structural bases for various types of enzymatic reactions, including the substrate specificity accompanying cofactor-controlled and kinetic mechanisms.

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Section: Structural Basis For the Stereoselectivity Of Quinuclidinmentioning

confidence: 99%

Structural analysis of enzymes used for bioindustry and bioremediation

Tanokura

Miyakawa

Guan

et al. 2015

Bioscience, Biotechnology, and Biochemistry

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“…This implies that part of the neomenthol has been selectively epimerized at the alcohol group. Finally, Raney Co has been proposed as a catalyst for racemization of quinuclidin-3-ol by the Nagase Company [24]. The Raney catalyst is used under hydrogen atmosphere at 140°C.…”

Section: Heterogeneous Catalysts For Alcohol Racemizationmentioning

confidence: 99%

Heterogeneous Catalysts for Racemization and Dynamic Kinetic Resolution of Amines and Secondary Alcohols

et al. 2010

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This paper gives an overview of the available heterogeneous catalysts for racemization of chirally stable secondary alcohols and amines, and of the combination of these catalysts with immobilized enzymes in dynamic kinetic resolution (DKR) for production of enantiopure esters or amides. For the one-pot DKR process, compatibility of enzyme and heterogeneous catalyst is a major issue, and in some cases the combination fails because of (mutual) deactivation. Heterogeneous catalysts of various types, such as zeolites or oxides effect alcohol racemization; they function either via acid catalysis and carbenium chemistry, or via a redox pathway via the ketone. Dynamic kinetic resolution of aliphatic alcohols using a heterogeneous catalyst in mild conditions is however an open challenge. Heterogeneous amine racemization catalysts invariably operate using a redox mechanism via the imine. In this case, the scope encompasses benzylic and aliphatic amines. The practicality of the approach is illustrated with the production of enantiopure N-acylated homoserine lactones, which are signalling compounds in microbial communities.

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“…The metal catalysts are expensive, toxic, and the transition metal may contaminate the product. An alternative access to (R)-3-quinuclidinol in 42% overall yield and 96% ee is Aspergillus melleus protease-catalyzed kinetic resolution of (dl)-3-quinuclidinol esters [12]. Nevertheless, no chemical or resolution of racemic compounds can compare with the biocatalytic asymmetric reduction of 3-quinuclidinone, in which biocatalysts produce the products in 100% theoretical conversion yield and exceptionally high ee value.…”

Section: Introductionmentioning

confidence: 99%

Magnetic Combined Cross-Linked Enzyme Aggregates of Ketoreductase and Alcohol Dehydrogenase: An Efficient and Stable Biocatalyst for Asymmetric Synthesis of (R)-3-Quinuclidinol with Regeneration of Coenzymes In Situ

et al. 2018

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Enzymes are biocatalysts. In this study, a novel biocatalyst consisting of magnetic combined cross-linked enzyme aggregates (combi-CLEAs) of 3-quinuclidinone reductase (QNR) and glucose dehydrogenase (GDH) for enantioselective synthesis of (R)-3-quinuclidinolwith regeneration of cofactors in situ was developed. The magnetic combi-CLEAs were fabricated with the use of ammonium sulfate as a precipitant and glutaraldehyde as a cross-linker for direct immobilization of QNR and GDH from E. coli BL(21) cell lysates onto amino-functionalized Fe 3 O 4 nanoparticles. The physicochemical properties of the magnetic combi-CLEAs were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and magnetic measurements. Field emission scanning electron microscope (FE-SEM) images revealed a spherical structure with numerous pores which facilitate the movement of the substrates and coenzymes. Moreover, the magnetic combi-CLEAs exhibited improved operational and thermal stability, enhanced catalytic performance for transformation of 3-quinuclidinone (33 g/L) into (R)-3-quinuclidinol in 100% conversion yield and 100% enantiomeric excess (ee) after 3 h of reaction. The activity of the biocatalysts was preserved about 80% after 70 days storage and retained more than 40% of its initial activity after ten cycles. These results demonstrated that the magnetic combi-CLEAs, as cost-effective and environmentally friendly biocatalysts, were suitable for application in synthesis of (R)-3-quinuclidinol essential for the production of solifenacin and aclidinium with better performance than those currently available.

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A practical chemoenzymatic process to access (R)-quinuclidin-3-ol on scale

Cited by 32 publications

References 12 publications

Structural analysis of enzymes used for bioindustry and bioremediation

Structural analysis of enzymes used for bioindustry and bioremediation

Heterogeneous Catalysts for Racemization and Dynamic Kinetic Resolution of Amines and Secondary Alcohols

Magnetic Combined Cross-Linked Enzyme Aggregates of Ketoreductase and Alcohol Dehydrogenase: An Efficient and Stable Biocatalyst for Asymmetric Synthesis of (R)-3-Quinuclidinol with Regeneration of Coenzymes In Situ

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