- Expedient Synthesis of Bridged Bicyclic Nitrogen Scaffolds via Orthogonal Tandem Catalysis
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Bridged nitrogen bicyclic skeletons have been accessed via unprecedented site- and diastereoselective orthogonal tandem catalysis from readily accessible reactants in a step economic manner. Directed Pd-catalyzed γ-C(sp3)-H olefination of aminocyclohexane with gem-dibromoalkenes, followed by a consecutive intramolecular Cu-catalyzed amidation of the 1-bromo-1-alkenylated product delivers the interesting normorphan skeleton. The tandem protocol can be applied on substituted aminocyclohexanes and aminoheterocycles, easily providing access to the corresponding substituted, aza- and oxa-analogues. The Cu catalyst of the Ullmann-Goldberg reaction additionally avoids off-cycle Pd catalyst scavenging by alkenylated reaction product. The picolinamide directing group stabilizes the enamine of the 7-alkylidenenormorphan, allowing further product post functionalizations. Without Cu catalyst, regio- and diastereoselective Pd-catalyzed γ-C(sp3)-H olefination is achieved.
- Bheemireddy, Narendraprasad Reddy,Biswas, Sovan,Evano, Gwilherm,Maes, Bert U. W.,Van Steijvoort, Ben F.,Waeterschoot, Marjo
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p. 21988 - 21996
(2021/08/13)
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- Crossing the Border: From Keto- to Imine Reduction in Short-Chain Dehydrogenases/Reductases
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The family of NAD(P)H-dependent short-chain dehydrogenases/reductases (SDRs) comprises numerous biocatalysts capable of C=O or C=C reduction. The highly homologous noroxomaritidine reductase (NR) from Narcissus sp. aff. pseudonarcissus and Zt_SDR from Zephyranthes treatiae, however, are SDRs with an extended imine substrate scope. Comparison with a similar SDR from Asparagus officinalis (Ao_SDR) exhibiting keto-reducing activity, yet negligible imine-reducing capability, and mining the Short-Chain Dehydrogenase/Reductase Engineering Database indicated that NR and Zt_SDR possess a unique active-site composition among SDRs. Adapting the active site of Ao_SDR accordingly improved its imine-reducing capability. By applying the same strategy, an unrelated SDR from Methylobacterium sp. 77 (M77_SDR) with distinct keto-reducing activity was engineered into a promiscuous enzyme with imine-reducing activity, thereby confirming that the ability to reduce imines can be rationally introduced into members of the “classical” SDR enzyme family. Thus, members of the SDR family could be a promising starting point for protein approaches to generate new imine-reducing enzymes.
- Roth, Sebastian,Stockinger, Peter,Steff, Jakob,Steimle, Simon,Sautner, Viktor,Tittmann, Kai,Pleiss, Jürgen,Müller, Michael
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p. 2615 - 2619
(2020/07/06)
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- A Practical and Stereoselective In Situ NHC-Cobalt Catalytic System for Hydrogenation of Ketones and Aldehydes
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Homogeneous catalytic hydrogenation of carbonyl groups is a synthetically useful and widely applied organic transformation. Sustainable chemistry goals require replacing conventional noble transition metal catalysts for hydrogenation by earth-abundant base metals. Herein, we report how a practical in situ catalytic system generated by easily available pincer NHC precursors, CoCl2, and a base enabled efficient and high-yielding hydrogenation of a broad range of ketones and aldehydes (over 50 examples and a maximum turnover number [TON] of 2,610). This is the first example of NHC-Co-catalyzed hydrogenation of C=O bonds using flexible pincer NHC ligands consisting of a N-H substructure. Diastereodivergent hydrogenation of substituted cyclohexanone derivatives was also realized by fine-tuning of the steric bulk of pincer NHC ligands. Additionally, a bis(NHCs)-Co complex was successfully isolated and fully characterized, and it exhibits excellent catalytic activity that equals that of the in-situ-formed catalytic system. Catalytic hydrogenation is a powerful tool for the reduction of organic compounds in both fine and bulk chemical industries. To improve sustainability, more ecofriendly, inexpensive, and earth-abundant base metals should be employed to replace the precious metals that currently dominate the development of hydrogenation catalysts. However, the majority of the base-metal catalysts that have been reported involve expensive, complex, and often air- and moisture-sensitive phosphine ligands, impeding their widespread application. From a mixture of the stable CoCl2, imidazole salts, and a base, our newly developed catalytic system that formed easily in situ enables efficient and stereoselective hydrogenation of C=O bonds. We anticipate that this easily accessible catalytic system will create opportunities for the design of practical base-metal hydrogenation catalysts. A practical in situ catalytic system generated by a mixture of easily available pincer NHC precursors, CoCl2, and a base enabled highly efficient hydrogenation of a broad range of ketones and aldehydes (over 50 examples and up to a turnover number [TON] of 2,610). Diastereodivergent hydrogenation of substituted cyclohexanone derivatives was also realized in high selectivities. Moreover, the preparation of a well-defined bis(NHCs)-Co complex via this pincer NHC ligand consisting of a N-H substructure was successful, and it exhibits equally excellent catalytic activity for the hydrogenation of C=O bonds.
- Zhong, Rui,Wei, Zeyuan,Zhang, Wei,Liu, Shun,Liu, Qiang
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supporting information
p. 1552 - 1566
(2019/06/14)
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- Hydrodealkenylative C(sp3)–C(sp2) bond fragmentation
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Chemical synthesis typically relies on reactions that generate complexity through elaboration of simple starting materials. Less common are deconstructive strategies toward complexity—particularly those involving carbon-carbon bond scission. Here, we introduce one such transformation: the hydrodealkenylative cleavage of C(sp3)–C(sp2) bonds, conducted below room temperature, using ozone, an iron salt, and a hydrogen atom donor. These reactions are performed in nonanhydrous solvents and open to the air; reach completion within 30 minutes; and deliver their products in high yields, even on decagram scales. We have used this broadly functionality tolerant transformation to produce desirable synthetic intermediates, many of which are optically active, from abundantly available terpenes and terpenoid-derived precursors. We have also applied it in the formal total syntheses of complex molecules.
- Smaligo, Andrew J.,Swain, Manisha,Quintana, Jason C.,Tan, Mikayla F.,Kim, Danielle A.,Kwon, Ohyun
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p. 681 - 685
(2019/06/11)
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- Chemo-Enzymatic Oxidative Rearrangement of Tertiary Allylic Alcohols: Synthetic Application and Integration into a Cascade Process
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A chemo-enzymatic catalytic system, comprised of Bobbitt's salt and laccase from Trametes versicolor, allowed the [1,3]-oxidative rearrangement of endocyclic allylic tertiary alcohols into the corresponding enones under an Oxygen atmosphere in aqueous media. The yields were in most cases quantitative, especially for the cyclopent-2-en-1-ol or the cyclohex-2-en-1-ol substrates without an electron withdrawing group (EWG) on the side chain. Transpositions of macrocyclic alkenols or tertiary alcohols bearing an EWG on the side chain were instead carried out in acetonitrile by using an immobilized laccase preparation. Dehydro-Jasmone, dehydro-Hedione, dehydro-Muscone and other fragrance precursors were directly prepared with this procedure, while a synthetic route was developed to easily transform a cyclopentenone derivative into trans-Magnolione and dehydro-Magnolione. The rearrangement of exocyclic allylic alcohols was tested as well, and a dynamic kinetic resolution was observed: α,β-unsaturated ketones with (E)-configuration and a high diastereomeric excess were synthesized. Finally, the 2,2,6,6-tetramethyl-1-piperidinium tetrafluoroborate (TEMPO+BF4?)/laccase catalysed oxidative rearrangement was combined with the ene-reductase/alcohol dehydrogenase cascade process in a one-pot three-step synthesis of cis or trans 3-methylcyclohexan-1-ol, in both cases with a high optical purity. (Figure presented.).
- Brenna, Elisabetta,Crotti, Michele,De Pieri, Matteo,Gatti, Francesco G.,Manenti, Gabriele,Monti, Daniela
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p. 3677 - 3686
(2018/06/04)
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- Exploiting the Catalytic Diversity of Short-Chain Dehydrogenases/Reductases: Versatile Enzymes from Plants with Extended Imine Substrate Scope
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Numerous short-chain dehydrogenases/reductases (SDRs) have found biocatalytic applications in C=O and C=C (enone) reduction. For NADPH-dependent C=N reduction, imine reductases (IREDs) have primarily been investigated for extension of the substrate range. Here, we show that SDRs are also suitable for a broad range of imine reductions. The SDR noroxomaritidine reductase (NR) is involved in Amaryllidaceae alkaloid biosynthesis, serving as an enone reductase. We have characterized NR by using a set of typical imine substrates and established that the enzyme is active with all four tested imine compounds (up to 99 % conversion, up to 92 % ee). Remarkably, NR reduced two keto compounds as well, thus highlighting this enzyme family's versatility. Using NR as a template, we have identified an as yet unexplored SDR from the Amaryllidacea Zephyranthes treatiae with imine-reducing activity (≤95 % ee). Our results encourage the future characterization of SDR family members as a means of discovering new imine-reducing enzymes.
- Roth, Sebastian,Kilgore, Matthew B.,Kutchan, Toni M.,Müller, Michael
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p. 1849 - 1852
(2018/09/10)
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- Ruthenium-catalyzed asymmetric transfer hydrogenation of allylic alcohols by an enantioselective isomerization/transfer hydrogenation mechanism
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Reducing hazards: A asymmetric transfer hydrogen reaction was developed to reduce prochiral allylic alcohols in high yield and excellent enantioselectivity (see example). Mechanistic studies indicate a novel enantioselective isomerization/transfer hydrogenation mechanism. This new reaction is much safer than high-pressure hydrogenation using H2 gas. Copyright
- Wu, Ruoqiu,Beauchamps, Marie G.,Laquidara, Joseph M.,Sowa Jr., John R.
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experimental part
p. 2106 - 2110
(2012/04/11)
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- Miniaturizing biocatalysis: Enzyme-catalyzed reactions in an aqueous/organic segmented flow capillary microreactor
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A segmented flow capillary microreactor was used to perform the enzyme-catalyzed conversion of 1-heptaldehyde to 1-heptanol in a two liquid-liquid phase system. These reactor formats are established for chemical reactions but so far data describing the relevant system parameters for enzymatic catalysis are lacking. This work now addresses the impact of important parameters such as capillary diameter, flow velocity, phase ratio, and enzyme as well as substrate concentration on the performance of the enzymatic reaction under segmented flow conditions. All key parameters governing reaction performance have been correlated in a novel operational window for an easy assessment of the various system constraints. Such systems are characterized by high productivities and easy phase separation facilitating downstream processing. This work underscores the importance of segmented flow systems as a promising tool to perform multiphasic enzymatic catalysis. Abbreviations/ Nomenclature: Da: Damkoehler number; kcat: turnover number (s-1); eo: enzyme concentration (mM); I?: phase ratio; kL: mass transfer coefficient (m s-1); a: interfacial area per volume (m-1); CAe: equilibrium substrate concentration in the aqueous phase (mM); CAL: substrate concentration in the bulk aqueous phase (mM); rA: rate of reaction in the aqueous phase; mA: substrate mass transfer into the aqueous phase; STY: space time yield. Copyright
- Karande, Rohan,Schmid, Andreas,Buehler, Katja
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experimental part
p. 2511 - 2521
(2011/11/07)
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- Electroenzymatic asymmetric reduction of rac-3-methylcyclo-hexanone to (1S,3S)-3-methyleyclohexanol in organic/aqueous media catalyzed by a thermophilic alcohol dehydrogenase
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Electrochemical regeneration of nicotinamide cofactors has been discussed as a promising, clean, and sustainable technology since the 1980s. However, most concepts for the coupling of this technology to enzymes suffer from low productivities, insufficient
- Hoellrigl, Volker,Otto, Katja,Schmid, Andreas
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p. 1337 - 1340
(2008/03/28)
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- Coupled chemoenzymatic transfer hydrogenation catalysis for enantioselective reduction and oxidation reactions
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Stereoselective reductions of prochiral ketones were performed using a new thermophilic, NAD-dependent alcohol dehydrogenase from Thermus sp. (TADH). The enzyme was produced on 2L-scale from recombinant Escherichia coli and purified by a simple, one-step heat treatment procedure yielding 220 mg of pure enzyme. Regeneration of NADH was catalyzed by the organometallic complex [Cp*Rh(bpy)(H2O)]2+ using formate as a reducing agent. The catalytic performance of [Cp*Rh(bpy)(H2O)] 2+ in terms of total number of catalytic cycles and number of catalytic cycles per hour achieved herein (up to 1500 and more than 400 h -1, respectively), are the highest reported for a non-enzymatic nicotinamide regeneration system so far. Chemoenzymatic reduction reactions in a two liquid phase setup were performed on a gramme-scale, for example, 1.3 g of enantiopure (1S,3S)-3-methylcyclohexanol was obtained after purification. The volumetric productivity reached up to 3.9 mM h-1 with an average of 2.6 mM h-1 (5.3 g L-1 d-1) over 10 h. In addition, chemoenzymatic oxidations utilizing the same catalyst set and molecular oxygen as a terminal electron acceptor were performed. Thus, the preparative value of chemoenzymatic transfer hydrogenations with [Cp*Rh(bpy)(H2O)]2+ as a regeneration catalyst coupled especially to thermophilic ADHs was demonstrated.
- Hollmann, Frank,Kleeb, Andreas,Otto, Katja,Schmid, Andreas
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p. 3512 - 3519
(2007/10/03)
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- Trifluoromethyl vs. methyl ability to direct enantioselection in microbial reduction of carbonyl substrates
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The stereoselective reduction of 3-trifluoromethylcyclohexanone (1a), (E)-1.1.1-(trifluoro-4-phenyl-3-buten-2-one (3a), and their unfluorinated analogues 1b and 3b has been performed with some growing microorganisms. Differences in the electronic and steric properties of the trifluoromethyl and methyl residues result in different chemo- and stereoselectivities in the microbial reduction of phenylbutenones 3a and 3b while cyclohexanones 1a and 1b showed strictly similar stereoselectivities. A new protocol based oil 13C NMR spectra of 2-phenylpropionic acid esters]has been used to assign the absolute configuration of the obtained secondary alcohols.
- Arnone, Alberto,Bernardi, Rosanna,Blasco, Francesca,Cardillo, Rosanna,Resnati, Giuseppe,Gerus, Igor I.,Kukhar, Valery P.
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p. 2809 - 2818
(2007/10/03)
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- Potential application of Sulfolobus solfataricus as catalyst in organic synthesis
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Sulfolobus solfataricus, a thermoacidophilic archaeon, has been utilized as catalyst for several enzymatic transformations such as carbonyl-alcohol oxidoreductions, synthesis of glycosides, kinetic resolution of aminoacid esters, etc.All these reactions have been carried out at 75 deg C in accordance with the thermophilic nature of the enzymes present in the organisms.
- Trincone, Antonio,Nicolaus, Barbara,Lama, Licia,Gambacorta, Agata
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- A Concise Synthesis of Enantiomerically Pure Taxane C-Ring via the Wittig Rearrangement
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An efficient, stereoselective synthesis of an enantiomerically pure C-ring precursor 14-S of O-cinnamoyltaxicins-I and -II has been achieved from 3-methyl-2-cyclohexen-1-ol, using a Wittig rearrangement as the key step.
- Kress, Michael H.,Kaller, Brian F.,Kishi, Yoshito
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p. 8047 - 8050
(2007/10/02)
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- Transfer Hydrogenation of Ketones with (1-) as the Precatalyst
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The cluster 1a has been found to be an efficient precatalyst for the transfer hydrogenations of ketones and α,β-unsaturated ketones.With substrates such as (5S)-carvone , (3R)-methylcyclopentanone and (3R)-methylcyclohexanone, moderate to high diastereoselectivities were observed for reduction of the conjugated olefinic and ketonic functionalities respectively.Aromatisation of carvone to 5-isopropyl-2-methylphenol and disproportionation of cyclohex-2-en-1-one to phenol and cyclohexanone have also been found to be catalysed by 1a.Studies with radical inhibitors and other evidence suggest a radical mechanism for the transfer-hydrogenation and aromatisation reactions.In the transfer hydrogenation of cyclohex-2-en-1-one, the rate of conversion of 1a into other soluble species can be modelled accurately if autocatalysis is assumed.The time-dependent concentration profiles of cyclohex-2-en-1-one, cyclohexanone and cyclohexanol are simulated well if autocatalytic formation of an active intermediate followed by consecutive reactions leading to the formation of products is assumed.Such a model is also consistent with the proposed radical mechanism.
- Bhaduri, Sumit,Sharma, Krishna,Mukesh, Doble
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p. 1191 - 1200
(2007/10/02)
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- Kinetic Resolution of Racemic Allylic Alcohols by BINAP-Ruthenium(II)-Catalyzed Hydrogenation
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Chiral allylic secondary alcohols have been resolved efficiently by homogeneous hydrogenation catalyzed by (R)- or (S)-BINAP-Ru diacetate complex.The combined effects of intramolecular and intermolecular asymmetric induction give up to 76:1 differentiation between the enantiomeric unsaturated alcohols.
- Kitamura, Masato,Kasahara, Isamu,Manabe, Kenji,Noyori, Ryoji,Takaya, Hidemasa
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p. 708 - 710
(2007/10/02)
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- ENZYMATIC "IN VITRO" REDUCTION OF KETONES. Part 10. Study of 3-Acetylpyridine Adenine Dinucleotide in a Co-enzyme Recycling System Ethanol-Ketone-3-AcPyAD+-HLAD
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The NAD+ analogue 3-acetylpyridine adenine dinucleotide (3-AcPyAD+) has been studied in the co-enzyme recycling system ethanol-ketone-3-AcPyAD+-HLAD.All reaction parameters are tested in analogous conditions as for the NAD+-recycling system.The stereospecificity of the new system is investigated for the reduction of 4-, 3- and 2-alkylcyclohexanones.The new recycling system is kinetically and stereochemically very similar to the NAD+ system, but 3.2 times slower.
- Lemiere, Guy L.,Jaco, Jan,Merckx, Erik M.,Lepoivre, Josef A.,Alderweireldt, Frank C.
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p. 747 - 752
(2007/10/02)
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- Use of Shift Reagent with MTPA Derivatives in 19F NMR Spectroscopy IV - Determination of Enantiomeric Composition for a Variety of Secondary Cycloalkanols. A Survey
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Chiral secondary cycloalkanols (monpocyclic alcohols) are derivatized to the corresponding (R)-α-methoxy-α-trifluoromethyl-α-phenylacetic acid esters and analysed by 19F NMR in the presence of tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium(III) .Using this method the enantiomeric composition can be measured for severak cyclopentanols, cyclohexanols and cycloheptanols, with a variety of substitution patterns.It is shown that a mixture of four stereoisomeric cycloalkanols, such as cis and trans disubstituted alcohols, can be analysed simultaneously.
- Merckx, E. M.,Lepoivre, J. A.,Lemiere, G. L.,Alderweireldt, F. C.
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p. 380 - 387
(2007/10/02)
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- Microbiological Reduction of α,β-Unsaturated Ketones by Beauveria sulfurescens
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Microbiological reduction of α,β-unsaturated ketones was studied.Variously substituted cyclopentenones, cyclohexenones, and methylalkenones were reduced by Beauveria sulfurescens under low-aeration conditions.The reaction takes place only with a small substituent in the α-position and hydrogen in the β-position.The saturated ketone is always obtained, sometimes accompanied by saturated alcohol.Yields and optical purities of the products are excellent.
- Kergomard, A.,Renard, M. F.,Veschambre, H.
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p. 792 - 798
(2007/10/02)
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- ENZYMATIC "IN VITRO" REDUCTION OF KETONES. VI.(1) Reduction rates and stereochemistry of the HLAD-catalyzed reduction of 3-alkyl- and 4-alkylcyclohexanones.
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Reaction rate constants for the catalytic step HLAD-NADH + ketone * HLAD-NAD+ + alcohol in the HLAD-catalyzed reduction of 3-alkyl- and 4-alkylcyclohexanones are determined from initial rate measurements in the coenzyme recycling system ketone-ethanol-NAD+-HLAD.By rate measurements at several temperatures, activation parameters were determined and isokinetic relationships tracked down.Two different isokinetic relationships show that the 3-alkylcyclohexanones pass through an other type of transition state than cyclohexanone and the 4-alkylcyclohexanones, which means that they have a different arrangement on the HLAD-NADH complex.The results are rationalized in view of the most recent principles on nucleophilic additions to carbonyl functions.The resulting model for the HLAD-catalyzed reduction adequately explains the observed rate accelerating and decelerating effects and the stereochemistry of the reduction as well.
- Osselaer, T. A. Van,Lemiere, G. L.,Lepoivre, J. A.,Alderweireldt, F. C.
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p. 133 - 150
(2007/10/02)
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