cas 5524-05-0, (+)-DIHYDROCARVONE MIXTURE OF ISOMERS

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Novel reductase participation in the syn-addition of hydrogen to the C=C bond of enones in the cultured cells of Nicotiana tabacum
A reductase isolated from cultured cells of Nicotiana tabacum has been characterized and used in the reduction of a C=C bond adjacent to a carbonyl group. The stereochemistry of the latter reaction has been investigated by 2H NMR and mass spectroscopy. It was found that the reductase reduces stereospecifically the C=C bond of verbenone and carvone by syn addition of hydrogen from the re face at the β-position and the re face at the α-position to the carbonyl group; the hydrogen atoms participating in the enzymatic reduction at the α- and β-positions originate from the medium (H2O) and the pro-4S hydrogen of NADPH, respectively.
Shimoda, Kei,Ito, Diana I.,Izumi, Shunsuke,Hirata, Toshifumi
p. 355 - 358
(1996)
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STEREOCHEMISTRY OF REDUCTION OF THE ENDOCYCLIC DOUBLE BOND OF (-)-CARVONE WITH THE ENZYME PREPARATION FROM CULTURED CELLS OF NICOTIANA TABACUM
The stereochemistry of the reduction of the endocyclic C-C double bond of (4R)-(-)-carvone with an enzyme preparation from cultured cells of Nicotiana tabacum was investigated by (2)H NMR and mass spectroscopy.It was found that: (i) the enzyme preparation regioselectively reduces only the endocyclic double bound; (ii) the reduction occurs stereospecifically by anti addition of hydrogen from the si face at C-1 and the re face at C-6 of carvone, resulting in the formation of (1R,4R)-(+)-dihydrocarvone; (iii) the hydrogen atoms participating in the enzymatic reduction at C-1 and C-6 originate from the medium and the pro-4R hydrogen of NADH, respectively.Key Word Index - Nicotiana tabacum; Solanaceae; cultured cells; enzymatic reduction; stereochemistry; carvone.
Hirata, Toshifumi,Tang, Yixiong,Okano, Kuniko,Suga, Takayuki
p. 3331 - 3334
(1989)
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Asymmetric Reduction of (R)-Carvone through a Thermostable and Organic-Solvent-Tolerant Ene-Reductase
Ene-reductases allow regio- and stereoselective reduction of activated C=C double bonds at the expense of nicotinamide adenine dinucleotide cofactors [NAD(P)H]. Biological NAD(P)H can be replaced by synthetic mimics to facilitate enzyme screening and process optimization. The ene-reductase FOYE-1, originating from an acidophilic iron oxidizer, has been described as a promising candidate and is now being explored for applied biocatalysis. Biological and synthetic nicotinamide cofactors were evaluated to fuel FOYE-1 to produce valuable compounds. A maximum activity of (319.7±3.2) U mg?1 with NADPH or of (206.7±3.4) U mg?1 with 1-benzyl-1,4-dihydronicotinamide (BNAH) for the reduction of N-methylmaleimide was observed at 30 °C. Notably, BNAH was found to be a promising reductant but exhibits poor solubility in water. Different organic solvents were therefore assayed: FOYE-1 showed excellent performance in most systems with up to 20 vol% solvent and at temperatures up to 40 °C. Purification and application strategies were evaluated on a small scale to optimize the process. Finally, a 200 mL biotransformation of 750 mg (R)-carvone afforded 495 mg of (2R,5R)-dihydrocarvone (>95 % ee), demonstrating the simplicity of handling and application of FOYE-1.
Tischler, Dirk,G?dke, Eric,Eggerichs, Daniel,Gomez Baraibar, Alvaro,Mügge, Carolin,Scholtissek, Anika,Paul, Caroline E.
p. 1217 - 1225
(2020)
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Loop Swapping as a Potent Approach to Increase Ene Reductase Activity with Nicotinamide Adenine Dinucleotide (NADH)
The asymmetric reduction of alkenes is a widely used transformation in industry. Ene reductases (ERs) are (βα)8-barrel folded enzymes capable of catalyzing this hydrogenation reaction. At the expense of nicotinamide coenzymes, ERs can reduce a wide range of electron-deficient alkenes in an anti-specific manner and with high regio- and stereoselectivities. However, a cost-effective industrial use of these enzymes is hampered, since most ERs prefer nicotinamide adenine dinucleotide phosphate (NADPH) to the more stable and less expensive non-phosphorylated nicotinamide adenine dinucleotide (NADH) as coenzyme. Here, we demonstrate an approach to both modify the biocatalysts coenzyme selectivity and strongly increase the activity and affinity with NADH. By swapping loop regions of the cyanobacterial NostocER1 for the corresponding regions of two NADH-favoring ERs, a strong alteration of the biocatalyst's coenzyme binding was achieved. This made possible a transfer of the respective donor-ER kinetic parameters to NostocER1. Additionally, outperformance of both donors in terms of activity was achieved through combinatorial swapping of loops of both species. These findings demonstrate the high potential of loop swapping as protein engineering approach to selectively optimize the coenzyme binding of ERs. (Figure presented.).
M?hler, Christoph,Kratzl, Franziska,Vogel, Melina,Vinnenberg, Stefan,Weuster-Botz, Dirk,Castiglione, Kathrin
p. 2505 - 2513
(2019)
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Investigating the Structure-Reactivity Relationships Between Nicotinamide Coenzyme Biomimetics and Pentaerythritol Tetranitrate Reductase
Ene reductases (ERs) are attractive biocatalysts in terms of their high enantioselectivity and expanded substrate scope. Recent works have proved that synthetic nicotinamide coenzyme biomimetics (NCBs) can be used as easily accessible alternatives to natural cofactors in ER-catalyzed reactions. However, the structure-reactivity relationships between NCBs and ERs and influence factors are still poorly understood. In this study, a series of C-5 methyl modified NCBs were synthesized and tested in the PETNR-catalyzed asymmetric reductions. The physicochemical properties of these NCBs including electrochemical properties, stability, and kinetic behavior were studied in detail. The results showed that hydrophobic interaction caused by the introduced methyl group contributed to the stabilization of binding conformation in enzyme active site, resulting in comparable catalytic activity with that of NADPH. Molecular dynamics and steered molecular dynamics simulations were further performed to explain the binding mechanism between PETNR and NCBs, which revealed that stable catalytic conformation, appropriate donor-acceptor distance and angle, as well as free dissociation energy are important factors affecting the activity of NCBs. (Figure presented.).
Tan, Zhuotao,Han, Yaoying,Fu, Yaping,Zhang, Xiaowang,Xu, Mengjiao,Na, Qi,Zhuang, Wei,Qu, Xudong,Ying, Hanjie,Zhu, Chenjie
p. 103 - 113
(2021/10/07)

A robust and stereocomplementary panel of ene-reductase variants for gram-scale asymmetric hydrogenation
We report an engineered panel of ene-reductases (ERs) from Thermus scotoductus SA-01 (TsER) that combines control over facial selectivity in the reduction of electron deficient C[dbnd]C double bonds with thermostability (up to 70 °C), organic solvent tolerance (up to 40 % v/v) and a broad substrate scope (23 compounds, three new to literature). Substrate acceptance and facial selectivity of 3-methylcyclohexenone was rationalized by crystallisation of TsER C25D/I67T and in silico docking. The TsER variant panel shows excellent enantiomeric excess (ee) and yields during bi-phasic preparative scale synthesis, with isolated yield of up to 93 % for 2R,5S-dihydrocarvone (3.6 g). Turnover frequencies (TOF) of approximately 40 000 h?1 were achieved, which are comparable to rates in hetero- and homogeneous metal catalysed hydrogenations. Preliminary batch reactions also demonstrated the reusability of the reaction system by consecutively removing the organic phase (n-pentane) for product removal and replacing with fresh substrate. Four consecutive batches yielded ca. 27 g L?1 R-levodione from a 45 mL aqueous reaction, containing less than 17 mg (10 μM) enzyme and the reaction only stopping because of acidification. The TsER variant panel provides a robust, highly active and stereocomplementary base for further exploitation as a tool in preparative organic synthesis.
Nett, Nathalie,Duewel, Sabine,Schmermund, Luca,Benary, Gerrit E.,Ranaghan, Kara,Mulholland, Adrian,Opperman, Diederik J.,Hoebenreich, Sabrina
(2021/01/25)

Photocontrolled Cobalt Catalysis for Selective Hydroboration of α,β-Unsaturated Ketones
Selectivity between 1,2 and 1,4 addition of a nucleophile to an α,β-unsaturated carbonyl compound has classically been modified by the addition of stoichiometric additives to the substrate or reagent to increase their “hard” or “soft” character. Here, we demonstrate a conceptually distinct approach that instead relies on controlling the coordination sphere of a catalyst with visible light. In this way, we bias the reaction down two divergent pathways, giving contrasting products in the catalytic hydroboration of α,β-unsaturated ketones. This includes direct access to previously elusive cyclic enolborates, via 1,4-selective hydroboration, providing a straightforward and stereoselective route to rare syn-aldol products in one-pot. DFT calculations and mechanistic experiments confirm two different mechanisms are operative, underpinning this unusual photocontrolled selectivity switch.
Beltran, Frédéric,Bergamaschi, Enrico,Funes-Ardoiz, Ignacio,Teskey, Christopher J.
supporting information
p. 21176 - 21182
(2020/09/17)

Total Synthesis of (?)-Rotundone and (?)-epi-Rotundone from Monoterpene Precursors
The first total synthesis of (?)-rotundone has been accomplished from (+)-(R)-limonene and therefore for the first time from an unrelated monoterpene instead of modifying structurally closely related sesquiterpene precursors such as α-guaiene. Challenges such as intermediates with stereocenters prone to epimerization by enolization were overcome by designing a β-methyl-keto route starting from (+)-(R)-limonene which finally gave (?)-rotundone by Nazarov cyclization of a precursor 13a. Diastereomer (?)-epi-rotundone was separated from (?)-rotundone chromatographically. An alternative route from rac-citronellal provided a diastereomer mixture of racemic Nazarov precursor 13 through a TRIP-catalyzed intramolecular aldolization, thus indicating that the Nazarov cyclization precursor 13a is in principle accessible from (?)-(S)-citronellal. The 11-step synthesis from (+)-(R)-limonene with ca. 1 % overall yield confirmed the absolute configuration of (?)-rotundone and provided samples of good olfactory quality.
Rüthi, Fabian,Schr?der, Fridtjof
(2020/10/30)

C3 and C6 Modification-Specific OYE Biotransformations of Synthetic Carvones and Sequential BVMO Chemoenzymatic Synthesis of Chiral Caprolactones
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.
Issa, Issa S.,Toogood, Helen S.,Johannissen, Linus O.,Raftery, James,Scrutton, Nigel S.,Gardiner, John M.
supporting information
p. 2983 - 2988
(2019/01/24)

Synthesis and Biochemical Evaluation of Nicotinamide Derivatives as NADH Analogue Coenzymes in Ene Reductase
Nicotinamide and pyridine-containing conjugates have attracted a lot of attention in research as they have found use in a wide range of applications including as redox flow batteries and calcium channel blockers, in biocatalysis, and in metabolism. The interesting redox character of the compounds’ pyridine/dihydropyridine system allows them to possess very similar characteristics to the natural chiral redox agents NAD+/NADH, even mimicking their functions. There has been considerable interest in designing and synthesizing NAD+/NADH mimetics with similar redox properties. In this research, three nicotinamide conjugates were designed, synthesized, and characterized. Molecular structures obtained through X-ray crystallography were obtained for two of the conjugates, thereby providing more detail on the bonding and structure of the compounds. The compounds were then further evaluated for biochemical properties, and it was found that one of the conjugates possessed similar functions and characteristics to the natural NADH. This compound was evaluated in the active enzyme, enoate reductase; like NADH, it was shown to help reduce the C=C double bond of three substrates and even outperformed the natural coenzyme. Kinetic data are reported.
Falcone, Natashya,She, Zhe,Syed, Jebreil,Lough, Alan,Kraatz, Heinz-Bernhard
p. 838 - 845
(2019/02/07)

Metagenomic ene-reductases for the bioreduction of sterically challenging enones
Ene-reductases (ERs) of the Old Yellow Enzyme family catalyse asymmetric reduction of activated alkenes providing chiral products. They have become an important method in the synthetic chemists' toolbox offering a sustainable alternative to metal-catalysed asymmetric reduction. Development of new biocatalytic alkene reduction routes, however needs easy access to novel biocatalysts. A sequence-based functional metagenomic approach was used to identify novel ERs from a drain metagenome. From the ten putative ER enzymes initially identified, eight exhibited activities towards widely accepted mono-cyclic substrates with several of the ERs giving high reaction yields and stereoselectivities. Two highly performing enzymes that displayed excellent co-solvent tolerance were used for the stereoselective reduction of sterically challenging bicyclic enones where the reactions proceeded in high yields, which is unprecedented to date with wild-type ERs. On a preparative enzymatic scale, reductions of Hajos-Parish, Wieland-Miescher derivatives and a tricyclic ketone proceeded with good to excellent yields.
Dobrijevic, Dragana,Benhamou, Laure,Aliev, Abil E.,Méndez-Sánchez, Daniel,Dawson, Natalie,Baud, Damien,Tappertzhofen, Nadine,Moody, Thomas S.,Orengo, Christine A.,Hailes, Helen C.,Ward, John M.
p. 36608 - 36614
(2019/11/25)

From Bugs to Bioplastics: Total (+)-Dihydrocarvide Biosynthesis by Engineered Escherichia coli
The monoterpenoid lactone derivative (+)-dihydrocarvide ((+)-DHCD) can be polymerised to form shape-memory polymers. Synthetic biology routes from simple, inexpensive carbon sources are an attractive, alternative route over chemical synthesis from (R)-carvone. We have demonstrated a proof-of-principle in vivo approach for the complete biosynthesis of (+)-DHCD from glucose in Escherichia coli (6.6 mg L?1). The pathway is based on the Mentha spicata route to (R)-carvone, with the addition of an ′ene′-reductase and Baeyer–Villiger cyclohexanone monooxygenase. Co-expression with a limonene synthesis pathway enzyme enables complete biocatalytic production within one microbial chassis. (+)-DHCD was successfully produced by screening multiple homologues of the pathway genes, combined with expression optimisation by selective promoter and/or ribosomal binding-site screening. This study demonstrates the potential application of synthetic biology approaches in the development of truly sustainable and renewable bioplastic monomers.
Ascue Avalos, Gabriel A.,Toogood, Helen S.,Tait, Shirley,Messiha, Hanan L.,Scrutton, Nigel S.
p. 785 - 792
(2019/01/29)

Combining Photo-Organo Redox- and Enzyme Catalysis Facilitates Asymmetric C-H Bond Functionalization
In this study, we combined photo-organo redox catalysis and biocatalysis to achieve asymmetric C–H bond functionalization of simple alkane starting materials. The photo-organo catalyst anthraquinone sulfate (SAS) was employed to oxyfunctionalise alkanes to aldehydes and ketones. We coupled this light-driven reaction with asymmetric enzymatic functionalisations to yield chiral hydroxynitriles, amines, acyloins and α-chiral ketones with up to 99 % ee. In addition, we demonstrate functional group interconversion to alcohols, esters and carboxylic acids. The transformations can be performed as concurrent tandem reactions. We identified the degradation of substrates and inhibition of the biocatalysts as limiting factors affecting compatibility, due to reactive oxygen species generated in the photocatalytic step. These incompatibilities were addressed by reaction engineering, such as applying a two-phase system or temporal and spatial separation of the catalysts. Using a selection of eleven starting alkanes, one photo-organo catalyst and 8 diverse biocatalysts, we synthesized 26 products and report for the model compounds benzoin and mandelonitrile > 97 % ee at gram scale.
Zhang, Wuyuan,Fueyo, Elena Fernandez,Hollmann, Frank,Martin, Laura Leemans,Pesic, Milja,Wardenga, Rainer,H?hne, Matthias,Schmidt, Sandy
p. 80 - 84
(2019/01/04)

Asymmetric whole-cell bio-reductions of (R)-carvone using optimized ene reductases
(2R,5R)-dihydrocarvone is an industrially applied building block that can be synthesized by site-selective and stereo-selective C=C bond bio-reduction of (R)-carvone. Escherichia coli (E. coli) cells overexpressing an ene reductase from Nostoc sp. PCC7120 (NostocER1) in combination with a cosubstrate regeneration system proved to be very effective biocatalysts for this reaction. However, the industrial applicability of biocatalysts is strongly linked to the catalysts’ activity. Since the cell-internal NADH concentrations are around 20-fold higher than the NADPH concentrations, we produced E. coli cells where the NADPH-preferring NostocER1 was exchanged with three different NADH-accepting NostocER1 mutants. These E. coli whole-cell biocatalysts were used in batch operated stirred-tank reactors on a 0.7 l-scale for the reduction of 300 mM (R)-carvone. 287 mM (2R,5R)-dihydrocarvone were formed within 5 h with a diasteromeric excess of 95.4% and a yield of 95.6%. Thus, the whole-cell biocatalysts were strongly improved by using NADH-accepting enzymes, resulting in an up to 2.1-fold increased initial product formation rate leading to a 1.8-fold increased space-time yield when compared to literature.
M?hler, Christoph,Burger, Christian,Kratzl, Franziska,Weuster-Botz, Dirk,Castiglione, Kathrin
(2019/07/18)

Novel Old Yellow Enzyme Subclasses
Many drug candidate molecules contain at least one chiral centre, and consequently, the development of biocatalytic strategies to complement existing metal- and organocatalytic approaches is of high interest. However, time is a critical factor in chemical process development, and thus, the introduction of biocatalytic steps, even if more suitable, is often prevented by the limited availability of off-the-shelf enzyme libraries. To expand the biocatalytic toolbox with additional ene reductases, we screened 19 bacterial strains for double bond reduction activity by using the model substrates cyclohexanone and carvone. Overall, we identified 47 genes coding for putative ene reductases. Remarkably, bioinformatic analysis of all genes and the biochemical characterization of four representative novel ene reductases led us to propose the existence of two new Old Yellow Enzyme subclasses, which we named OYE class III and class IV. Our results demonstrate that although, on a DNA level, each new OYE subclass features a distinct combination of sequence motifs previously known from the classical and the thermophilic-like group, their substrate scope more closely resembles the latter subclass.
Peters, Christin,Frasson, David,Sievers, Martin,Buller, Rebecca
p. 1569 - 1577
(2019/05/15)

Heteropoly acid catalysis for the isomerization of biomass-derived limonene oxide and kinetic separation of the trans-isomer in green solvents
Terpenes are an abundant class of natural products, which is important for flavor and fragrance industry. Many acid catalyzed reactions used for upgrading terpenes still involve mineral acids as homogeneous catalysts and/or toxic solvents. Heteropoly acids represent a well-established eco-friendly alternative to conventional acid catalysts. As these reactions are usually performed in the liquid phase, solvents play a critical role for the process sustainability. In the present work, we developed a catalytic route to valuable fragrance ingredients, dihydrocarvone and carvenone, from limonene oxide by its isomerization using silica-supported tungstophosphoric acid as a heterogeneous catalyst and dialkylcarbonates as green solvents. The reaction pathway can be switched between dihydrocarvone and carvenone (obtained in 90% yield each) simply by changing the reaction temperature. In addition, we developed an efficient method for kinetic separation of trans-limonene oxide from commercial cis/trans-limonene oxide mixture and stereoselective synthesis of trans-dihydrocarvone.
Cotta, Rafaela F.,Martins, Rafael A.,Pereira, Matheus M.,da Silva Rocha, Kelly A.,Kozhevnikova, Elena F.,Kozhevnikov, Ivan V.,Gusevskaya, Elena V.
(2019/08/02)

Enantioselective Synthesis of the Platensimycin Core by Silver(I)-Promoted Cyclization of Δ6-α-Iodoketone
A chiral-pool-based synthesis of the platensimycin core was achieved using (S)-lactic acid as an inexpensive starting material. The cyclohexenone ring was closed in a Mukaiyama–Michael domino sequence, while the quaternary stereocenter was created by a highly stereoselective decarboxylative allylation. The spirobicyclic skeleton was constructed by a RCM reaction. A new silver(I)-promoted cyclization reaction of Δ6- and Δ7-α-iodoketones was developed and applied for the pivotal carbon–carbon bond formation. The scope and limitations of this methodology are also presented.
Trajkovic, Milos,Ferjancic, Zorana,Saicic, Radomir N.,Bihelovic, Filip
p. 4340 - 4344
(2019/02/28)

Hydrogenation of Carbonyl Derivatives Catalysed by Manganese Complexes Bearing Bidentate Pyridinyl-Phosphine Ligands
Manganese(I) catalysts incorporating readily available bidentate 2-aminopyridinyl-phosphine ligands achieve a high efficiency in the hydrogenation of carbonyl compounds, significantly better than parent ones based on more elaborated and expensive tridentate 2,6-(diaminopyridinyl)-diphosphine ligands. The reaction proceeds with low catalyst loading (0.5 mol%) under mild conditions (50 °C) with yields up to 96%. (Figure presented.).
Wei, Duo,Bruneau-Voisine, Antoine,Chauvin, Téo,Dorcet, Vincent,Roisnel, Thierry,Valyaev, Dmitry A.,Lugan, No?l,Sortais, Jean-Baptiste
supporting information
p. 676 - 681
(2017/12/26)

Enantio- A nd regioselective: Ene-reductions using F420H2-dependent enzymes
In the past decade it has become clear that many microbes harbor enzymes that employ an unusual flavin cofactor, the F420 deazaflavin cofactor. Herein we show that F420-dependent reductases (FDRs) can successfully perform enantio-, regio- A nd chemoselective ene-reductions. For the first time, we have demonstrated that F420H2-driven reductases can be used as biocatalysts for the reduction of α,β-unsaturated ketones and aldehydes with good conversions (>99%) and excellent regioselectivities and enantiomeric excesses (>99% ee). Noteworthily, FDRs typically display an opposite enantioselectivity when compared to the well established FMN-dependent Old Yellow Enzymes (OYEs).
Mathew, Sam,Trajkovic, Milos,Kumar, Hemant,Nguyen, Quoc-Thai,Fraaije, Marco W.
supporting information
p. 11208 - 11211
(2018/10/15)

Investigating: Saccharomyces cerevisiae alkene reductase OYE 3 by substrate profiling, X-ray crystallography and computational methods
Saccharomyces cerevisiae OYE 3 shares 80% sequence identity with the well-studied Saccharomyces pastorianus OYE 1; however, wild-type OYE 3 shows different stereoselectivities toward some alkene substrates. Site-saturation mutagenesis of Trp 116 in OYE 3 followed by substrate profiling showed that the mutations had relatively little effect, opposite to that observed previously for OYE 1. The X-ray crystal structures of unliganded and phenol-bound OYE 3 were solved to 1.8 and 1.9 ? resolution, respectively. Both structures were nearly identical to that of OYE 1, with only a single amino acid difference in the active site region (Ser 296 versus Phe 296, part of loop 6). Despite their essentially identical static X-ray structures, molecular dynamics (MD) simulations revealed that loop 6 conformations differed significantly in solution between OYE 3 and OYE 1. In OYE 3, loop 6 remained nearly as open as observed in the crystal structure; by contrast, loop 6 closed over the active site of OYE 1 by ca. 4 ?. Loop closure likely generates a greater number of active site protein contacts for substrate bound to OYE 1 as compared to OYE 3. These differences provide an explanation for the differing stereoselectivities of OYE 3 and OYE 1, despite their nearly identical X-ray crystal structures.
Powell, Robert W.,Buteler, M. Pilar,Lenka, Sunidhi,Crotti, Michele,Santangelo, Sara,Burg, Matthew J.,Bruner, Steven,Brenna, Elisabetta,Roitberg, Adrian E.,Stewart, Jon D.
p. 5003 - 5016
(2018/10/17)

Novel concurrent redox cascades of (R)- and (S)-carvones enables access to carvo-lactones with distinct regio- and enantioselectivity
Within this study, we investigated a one-pot enzymatic redox cascade composed of different enoate reductases (5 EREDs from diverse bacterial origins) and various Baeyer-Villiger monooxygenases (4 BVMOs) with complementary regioselectivity that enabled access to six out of eight carvo-lactone stereoisomers starting from readily available natural carvones. Applicability of this two-step cascade was demonstrated by preparative scale experiments yielding up to 76% of the desired chiral carvolactone.
Iqbal, Naseem,Stewart, Jon D.,Macheroux, Peter,Rudroff, Florian,Mihovilovic, Marko D.
p. 7389 - 7394
(2018/11/23)

Stereodivergent Synthesis of Carveol and Dihydrocarveol through Ketoreductases/Ene-Reductases Catalyzed Asymmetric Reduction
Chiral carveol and dihydrocarveol are important additives in the flavor industry and building blocks in the synthesis of natural products. Despite the remarkable progress in asymmetric catalysis, convenient access to all possible stereoisomers of carveol and dihydrocarveol remains a challenge. Here, we present the stereodivergent synthesis of carveol and dihydrocarveol through ketoreductases/ene-reductases catalyzed asymmetric reduction. By directly asymmetric reduction of (R)- and (S)-carvone using ketoreductases, which have Prelog or anti-Prelog stereopreference, all four possible stereoisomers of carveol with medium to high diastereomeric excesses (up to >99 %) were first observed. Then four stereoisomers of dihydrocarvone were prepared through ene-reductases catalyzed diastereoselective synthesis. Asymmetric reduction of obtained dihydrocarvone isomers by ketoreductases further provide access to all eight stereoisomeric dihydrocarveol with up to 95 % de values. In addition, the absolute configurations of dihydrocarveol stereoisomers were determined by using modified Mosher's method.
Guo, Jiyang,Zhang, Rui,Ouyang, Jingping,Zhang, Feiting,Qin, Fengyu,Liu, Guigao,Zhang, Wenhe,Li, Hengyu,Ji, Xiaohong,Jia, Xian,Qin, Bin,You, Song
p. 5496 - 5504
(2018/11/30)

Transfer hydrogenation of ketones catalyzed by iridium-bulky phosphine complexes
The complexes [Ir(COD)(PR3)2]PF6 (R = PPh3 (1); R = PBn3 = tribenzylphosphine (2)), [Ir(COD)(PBn3)(PAn3)]PF6 (3) (PAn3 = Tri-orthoanisyl-phosphine) and cis-(P,P)-[IrH(COD)(PBn3){η2-P,C-(C6H4CH2)PBn2}]PF6 (4) are active in the transfer hydrogenation of ketones. However, complex (3) gives the best results in conversion toward the alcohol. Interestingly, commercial isopropanol was used as hydrogen source, without any drying treatment. In situ generated isopropoxide was used as base. An efficient conversion of a variety of ketones, aromatic or aliphatic, cyclic or linear, including molecules with conjugated or isolated C[dbnd]C moieties was achieved, thus reporting 12 examples of hydrogenated substrates. Ketones of higher steric hindrance could not be converted under the studied conditions. The experimental evidence indicates that the steric and electronic properties of the substrates are determinant in the observed conversions and performance of the system. For α,β-unsaturated ketones, preference toward the reduction of the C[dbnd]C bond was observed. However, the system shows chemoselectivity toward the carbonyl group in molecules which also bear an isolated C[dbnd]C moiety. With the results obtained, a pseudo first-order dependence of the reaction rate on the concentration of ketone was determined. Also, stoichiometric as well as in situ tests were performed to shed light into the reaction pathways possibly involved in the catalytic TH of ketones described herein (precursor 3, base and isopropyl alcohol as hydrogen source).
Landaeta, Vanessa R.,Rosa, Abel D. Salazar-La,Rodríguez-Lugo, Rafael E.
p. 303 - 311
(2017/09/06)

Mild Chemoenzymatic Oxidation of Allylic sec-Alcohols. Application to Biocatalytic Stereoselective Redox Isomerizations
The design of catalytic oxidative methodologies in aqueous medium under mild reaction conditions and using molecular oxygen as final electron acceptor represents a suitable alternative to the traditional oxidative transformations. These methods are especially relevant if other functionalities that can be oxidized are present within the same molecule, as in the case of allylic alcohols. Herein we apply a simple chemoenzymatic system composed of the laccase from Trametes versicolor and 2,2,6,6-tetramethylpiperidinyloxy radical (TEMPO) to oxidize a series of racemic allylic sec-alcohols into the corresponding α,β-unsaturated ketones. Afterward, these compounds react with different commercially available ene-reductases to afford the corresponding saturated ketones. Remarkably, in the case of trisubstituted alkenes, the bioreduction reaction occurred with high stereoselectivity. Overall, a bienzymatic one-pot two-step sequential strategy has been described with respect to the synthesis of saturated ketones starting from racemic allylic alcohols, thus resembling the metal-catalyzed redox isomerizations of these derivatives that have been previously reported in the literature.
Martínez-Montero, Lía,Gotor, Vicente,Gotor-Fernández, Vicente,Lavandera, Iván
p. 2413 - 2419
(2018/03/13)

Iron-Catalyzed Chemoselective Reduction of α,β-Unsaturated Ketones
An iron-catalyzed chemo- and diastereoselective reduction of α,β-unsaturated ketones into the corresponding saturated ketones in mild reaction conditions is reported herein. DFT calculations and experimental work underline that transfer hydride reduction is a more facile process than hydrogenation, unveiling the fundamental role of the base.
Lator, Alexis,Gaillard, Sylvain,Poater, Albert,Renaud, Jean-Luc
supporting information
p. 5770 - 5774
(2018/03/26)

Revealing Additional Stereocomplementary Pairs of Old Yellow Enzymes by Rational Transfer of Engineered Residues
Every year numerous protein engineering and directed evolution studies are published, increasing the knowledge that could be used by protein engineers. Here we test a protein engineering strategy that allows quick access to improved biocatalysts with very little screening effort. Conceptually it is assumed that engineered residues previously identified by rational and random methods induce similar improvements when transferred to family members. In an application to ene-reductases from the Old Yellow Enzyme (OYE) family, the newly created variants were tested with three compounds, revealing more stereocomplementary OYE pairs with potent turnover frequencies (up to 660 h?1) and excellent stereoselectivities (up to >99 %). Although systematic prediction of absolute enantioselectivity of OYE variants remains a challenge, “scaffold sampling” was confirmed as a promising addition to protein engineers' collection of strategies.
Nett, Nathalie,Duewel, Sabine,Richter, Alexandra Annelis,Hoebenreich, Sabrina
p. 685 - 691
(2017/04/11)

Kinetics of the Aqueous Phase Reactions of Atmospherically Relevant Monoterpene Epoxides
Laboratory and field measurements have demonstrated that an isoprene-derived epoxide intermediate (IEPOX) is the origin of a wide range of chemical species found in ambient secondary organic aerosol (SOA). In order to explore the potential relevance of a similar mechanism for the formation of monoterpene-derived SOA, nuclear magnetic resonance techniques were used to study kinetics and reaction products of the aqueous-phase reactions of several monoterpene epoxides: β-pinene oxide, limonene oxide, and limonene dioxide. The present results, combined with a previous study of α-pinene oxide, indicate that all of these epoxides will react more quickly than IEPOX with aqueous atmospheric particles, even under low-acidity conditions. As for α-pinene oxide, the observed products can be mainly rationalized with a hydrolysis mechanism, and no long-lived organosulfate or nitrate species nor species that retain the β-pinene bicyclic carbon backbone are observed. As bicyclic ring-retaining organosulfate and nitrate species have been previously observed in monoterpene-derived SOA, it appears that monoterpene-derived epoxides may not be as versatile as IEPOX in producing a range of SOA species, and other mechanisms are needed to rationalize organosulfate and nitrate formation.
Cortés, DIego A.,Elrod, Matthew J.
p. 9297 - 9305
(2017/12/18)

Kinetic Modeling of an Enzymatic Redox Cascade In Vivo Reveals Bottlenecks Caused by Cofactors
We describe the development of a kinetic model for the simulation and optimization of an in vivo redox cascade in E. coli in which a combination of an alcohol dehydrogenase, an enoate reductase, and a Baeyer–Villiger monooxygenase is used for the synthesis of lactones. The model was used to estimate the concentrations of active enzyme in the sequential biotransformations to identify bottlenecks together with their reasons and how to overcome them. We estimated adapted Michaelis–Menten parameters from in vitro experiments with isolated enzymes and used these values to simulate the change in the concentrations of intermediates and products during the in vivo cascade reactions. Remarkably, the model indicated that the fastest enzyme was rate-determining because of the unexpectedly low concentration of the active form, which opens up reversible reaction channels towards byproducts. We also provide substantial experimental evidence that a low intracellular concentration of flavin and nicotinamide cofactors drastically decreased the performance of the in vivo cascade drastically.
Milker, Sofia,Fink, Michael J.,Oberleitner, Nikolin,Ressmann, Anna K.,Bornscheuer, Uwe T.,Mihovilovic, Marko D.,Rudroff, Florian
p. 3420 - 3427
(2017/09/06)

Selective one-pot carvone oxime hydrogenation over titania supported gold catalyst as a novel approach for dihydrocarvone synthesis
It was shown for the first time that dihydrocarvone can be selectively produced by gold-catalyzed one-pot transformation of carvone oxime. This reaction was carried out at 100 °C under hydrogen pressure of 9 bar over 1.9 wt.% Au/TiO2 catalyst using methanol as a solvent. Dihydrocarvone synthesis was shown to occur via carvone formation with the subsequent hydrogenation of its conjugated C=C double bond. Application of Au/TiO2 catalyst for both deoximation and selective hydrogenation of olefinic C=C functional group is reported for the first time. The combination of these steps provides optimization of the synthetic method for dihydrocarvone production from carvone oxime which is a key intermediate in carvone synthesis from limonene. Despite a lower reaction rate than in the case of carvone, a significant increase in the stereoselectivity towards trans-dihydrocarvone was observed in the case of carvone oxime hydrogenation. The ratio between trans- and cis-dihydrocarvone was close to 4.0 compared to 1.8 achieved in the case of carvone hydrogenation.
Demidova, Yu. S.,Suslov,Simakova,Volcho,Salakhutdinov,Simakova,Murzin, D. Yu.
p. 142 - 148
(2016/06/13)

Cell-free protein engineering of Old Yellow Enzyme 1 from Saccharomyces pastorianus
In protein engineering, cell-free transcription/translation of linear mutagenic DNA templates can tremendously accelerate and simplify the screening of enzyme variants. Using the RApid Parallel Protein EvaluatoR (RAPPER) protocol, we have evaluated the impact of amino acid substitutions and loop truncations on substrate specificity and stereoselectivity of Old Yellow Enzyme 1 from Saccharomyces pastorianus. Our study demonstrates the benefit of systematically assessing amino acid variations including substrate profiling to explore sequence-function space.
Quertinmont, Leann T.,Lutz, Stefan
p. 7282 - 7287
(2016/10/29)

New biobased tetrabutylphosphonium ionic liquids: Synthesis, characterization and use as a solvent or co-solvent for mild and greener Pd-catalyzed hydrogenation processes
Phosphonium-based Ionic Liquids (PhosILs) with natural organic derived anions (l-lactate, l-tartrate, malonate, succinate, l-malate, pyruvate, d-glucuronate, d-galacturonate, ferulate, p-coumarate) were easily prepared by acid-base method from tetrabutylphosphonium hydroxide and an excess of the corresponding acid with good yields. Their characterization was realized through classical NMR, IR and elemental analysis techniques; their viscosity and ATG parameters were also determined. These ionic liquids showed good performance and recyclability in the selective Pd-catalyzed hydrogenation of alkenes, polyenes like linoleic acid and enantioselective hydrogenation of unsaturated ketones such as isophorone at room temperature under atmospheric H2 pressure. Furthermore, NMR studies leading to computational calculations were performed to establish easily the composition of the resulting mixture obtained through the hydrogenation of linoleic acid.
Hayouni, Safa,Robert, Anthony,Ferlin, Nadège,Amri, Hassen,Bouquillon, Sandrine
p. 113583 - 113595
(2016/12/16)

Method for synthesizing dihydrocarvone by use of epoxy limonene
The invention discloses a method for synthesizing dihydrocarvone by use of epoxy limonene. The method comprises the following steps: step 1, mixing epoxy limonene with a main catalyst A or an aided catalyst B, and heating to trigger a ring-opening rearrangement reaction, so as to generate dihydrocarvone; step 2, after the reaction is finished, adding white oil into the reaction liquid, and carrying out rectification to obtain a finished product of dihydrocarvone, wherein the main catalyst A is divalent-zinc lewis acid, and the aided catalyst B comprises one or two of organic alkali, ester or acyl ketone compounds. The method has the following advantages: the raw materials are easy to synthesize, cheap, and easy to obtain; no solvent is needed in the reaction process, so that the synthesis technology is environmentally friendly; post-processing purification can be achieved only through rectification, therefore the post-processing purification technology is simple; the selected catalyst can be recycled, and the method is suitable for industrialized production.
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Paragraph 0018

(2016/11/09)

Ene Reductase Enzymes for the Aromatisation of Tetralones and Cyclohexenones to Naphthols and Phenols
Ene reductases (EREDs) have great potential as oxidation biocatalysts, as demonstrated by their efficient conversion of a number of tetralones to the corresponding naphthols. Of 96 enzymes tested, 57 were able to produce 2-naphthol in this way. Further tests with substituted tetralones revealed typically high conversions up to >99%. The reactions were performed under mild conditions in aqueous buffer with only co-solvent, biocatalyst and oxidation substrate required for conversion. Production of a methoxy-substituted naphthol was also successfully performed on a gram scale, with 91% yield. This methodology provides a new avenue to produce substituted naphthols as valuable building blocks, with the possibility to extend the approach to the production of phenols also being demonstrated.
Kelly, Paul P.,Lipscomb, David,Quinn, Derek J.,Lemon, Ken,Caswell, Jill,Spratt, Jenny,Kosjek, Birgit,Truppo, Matthew,Moody, Thomas S.
supporting information
p. 731 - 736
(2016/03/09)

Natural-Product-Derived Transient Receptor Potential Melastatin 8 (TRPM8) Channel Modulators
A library of novel structural hybrids of menthol and cubebol was tested for each derivative's ability to interact with the transient receptor potential subfamily melastatin member 8 (TRPM8) channel. This structure-activity relationship study revealed three potent modulators of the TRPM8 ion channel: a novel agonist (4) with an EC50 value of 11 ± 1 μM, an antagonist (15) with an IC50 value of 2 ± 1 μM, and an allosteric modulator (21) that minimized channel desensitization toward menthol. Each of these novel exocyclic olefin analogues of menthol is readily accessible by synthesis and was tested using Ca2+ assays and electrophysiology.
Legay, Christina M.,Gorobets, Evgueni,Iftinca, Mircea,Ramachandran, Rithwik,Altier, Christophe,Derksen, Darren J.
supporting information
p. 2746 - 2749
(2016/06/15)

Selective carvone hydrogenation to dihydrocarvone over titania supported gold catalyst
Selective hydrogenation of natural carvone to industrially valuable dihydrocarvone was carried out at 100°C under hydrogen pressure over a 1.9wt.% Au/TiO2 catalyst. The gold catalyst has demonstrated high activity as well as stereo- and chemoselectivity in conjugated C=C double bond hydrogenation with predominant formation of trans-dihydrocarvone. The catalytic activity and trans-to cis-isomers ratio were shown to strongly depend on the solvent. In a range of C1 - C3 alcohol solvents both catalytic activity and trans-to cis-dihydrocarvone ratio increased following the order: 2-propanol a nearly complete carvone conversion (90%) after 13h in the case of methanol, with the trans-to cis-dihydrocarvone ratio being about 1.8. Based on the transition state theory a quantitative description of trans-to cis-dihydrocarvone ratio variations in different solvents was made.
Demidova,Suslov,Simakova,Simakova,Volcho,Salakhutdinov,Murzin
p. 189 - 194
(2015/03/14)

Structural insights into stereospecific reduction of α, β-unsaturated carbonyl substrates by old yellow enzyme from Gluconobacter oxydans
We report the crystal structure of old yellow enzyme (OYE) family protein Gox0502 (a.a 1-315) in free form at 3.3 ?. Detailed structural analysis revealed the key residues involved in stereospecific determination of Gox0502, such as Trp66 and Trp100. Structure-based computational analysis suggested the bulky side chains of these tryptophan residues may play important roles in product stereoselectivity. The introduction of Ile or Phe or Tyr mutation significantly reduced the product diastereoselectivity. We hypothesized that less bulky side chains at these critical residues could create additional free space to accommodate intermediates with different conformations. Notably, the introduction of Phe mutation at residue Trp100 increased catalytic activity compared to wild-type Gox0502 toward a set of substrates tested, which suggests that a less bulky Phe side chain at residue W100F may facilitate product release. Therefore, Gox0502 structure could provide useful information to generate desirable OYEs suitable for biotechnological applications in industry.
Yin, Bo,Deng, Jian,Lim, Lirong,Yuan, Y. Adam,Wei, Dongzhi
p. 410 - 421
(2015/08/11)

Microwave assisted bi-functional activation of β-bromo-tert-alcohols
Microwave-assisted dehydration-oxidation of β-bromo-tert-alcohols to afford 2,3-unsaturated ketones in good yield is reported. The reaction of substrates with DMSO in 1:1 ratio (w/v) is promoted by ZnS in a solvent-free condition. A concurrent bi-functional activation of trans-vicinal bromo- and hydroxyl groups with ZnS is elucidated. This is a new observation under microwave and applies to β-bromo-tert-alcohols derived from 1,4-disubstitued-1-cyclohexenes. It is very useful in the synthesis of 2,3-unsaturated ketones derived from monoterpenes which are valuable flavour compounds. [Figure not available: see fulltext.]
Kannan, Nandini,Rangaswamy, Manjunatha Javagal,Kemapaiah, Bettadaiah Bheemanakere
p. 1405 - 1410
(2015/11/09)

Identification, characterization, and application of three enoate reductases from Pseudomonas putida in in vitro enzyme cascade reactions
Enoate reductases are versatile enzymes for the enantio- and regioselective addition of hydrogen to double bonds. We identified three EREDs (XenA, XenB, NemA) from Pseudomonas putida ATCC 17453 through a sequence motif search. In addition to cloning, functional expression, and biochemical characterization of these enzymes, the enoate reductases were also applied in enzyme cascade reactions in combination with a Baeyer-Villiger monooxygenase and an alcohol dehydrogenase to produce lactones. Good things come in threes: The identification, cloning, expression, and characterization of three enoate reductases from Pseudomonas putida reveal broad substrate scope and high stereoselectivities. Furthermore, the enoate reductases could be integrated into cascade reactions together with an alcohol dehydrogenase and a Baeyer-Villiger monooxygenase.
Peters, Christin,Koelzsch, Regina,Kadow, Maria,Skalden, Lilly,Rudroff, Florian,Mihovilovic, Marko D.,Bornscheuer, Uwe T.
p. 1021 - 1027
(2014/05/06)

Heterologous expression and characterization of the ene-reductases from Deinococcus radiodurans and Ralstonia metallidurans
The Old Yellow Enzyme (OYE) homologues or ene-reductases (ER) from Deinococcus radiodurans (DrER) and Ralstonia metallidurans (RmER) were cloned and characterized. Sequence and phylogenetic analysis revealed both these enzymes to belong to the YqjM-like or "thermophilic-like" group of OYEs, both sharing more than 60% sequence similarity to the ER from Thermus scotoductus. This group of OYEs is characterized by a conserved cysteine residue modulating the redox potential of the flavin cofactor as well as a conserved tyrosine residue located at the N-terminus region involved in binding certain ligands. The genes were recombinantly expressed in Escherichia coli as functional soluble proteins. Both ERs have monomer molecular weights of approximately 40 kDa, with DrER a homodimer in solution and RmER a monomer. DrER and RmER are optimally active at pH 7-7.5 at 30 C and 35 C respectively. Although the enzymes showed comparable affinities towards the ubiquitous ER substrate 2-cyclohexenone, the specific activity and catalytic efficiency of DrER were more than twice those observed for RmER. Similar to other members of this subclass of ERs, no conversion was detected with cyclic Cβ substituted enones, and only DrER was able to convert citral. Both DrER and RmER were highly active at reducing N-phenyl substituted maleimides. The selectivity of the ERs was assessed using both the isomers of carvone, which were converted with high diastereomeric excesses. Ketoisophorone and 2-methylcyclopentenone were converted to their (R)- and (S)-enantiomeric products respectively. Finally, a light-driven cofactor regeneration system was used to drive enzymatic reduction in the absence of NAD(P)H.
Litthauer,Gargiulo,Van Heerden,Hollmann,Opperman
p. 89 - 95
(2014/01/06)

Enzymatic hydrogenation of diverse activated alkenes. Identification of two Bacillus old yellow enzymes with broad substrate profiles
By whole cell transformation, 32 out of 71 strains showed OYEs activity toward maleimide in the first round screening. Among them, a Bacillus strain was identified to be active toward a selection of substrates with different electron-withdrawing groups. Two OYE homologous genes, bac-oye1 and bac-oye2 were cloned from this strain and overexpressed in Escherichia coli BL21(DE3). The recombinant enzyme Bac-OYE2 showed a broader pH range (6.0-10.5), while Bac-OYE1 was so sensitive to pH that it lost most of the enzyme activity below pH 6.0 or above pH 9.0. The reaction temperature exerted similar effects on the activities of both enzymes, but the stability of Bac-OYE2 was more sensitive to the temperature than Bac-OYE1. In addition to α,β-unsaturated aldehydes, ketones, nitroalkenes, and the double activated carboxylic acids, esters, nitriles and cyclic imides, Bac-OYE1 and Bac-OYE2 also exhibited activities toward the "borderline" substrates such as unsaturated lactones, mono carboxylic esters, showing their broader substrate scopes. These enzymes also had excellent enantioselectivity as evidenced by the reductions of several α,β-unsaturated cyclic ketones, α-substituted α,β-unsaturated carboxylic esters and 2-methyl maleimide. For example, methyl 2-acetamidoacrylate was reduced by Bac-OYE1 with >99% conversion and >99% ee.
Zhang, Hailing,Gao, Xiuzhen,Ren, Jie,Feng, Jinhui,Zhang, Tongcun,Wu, Qiaqing,Zhu, Dunming
p. 118 - 125
(2014/05/20)

Production of flavours and fragrances via bioreduction of (4R)-(-)-carvone and (1R)-(-)-myrtenal by non-conventional yeast whole-cells
As part of a program aiming at the selection of yeast strains which might be of interest as sources of natural flavours and fragrances, the bioreduction of (4R)-(-)-carvone and (1R)-(-)-myrtenal by whole-cells of non-conventional yeasts (NCYs) belonging to the genera Candida, Cryptococcus, Debaryomyces, Hanseniaspora, Kazachstania, Kluyveromyces, Lindnera, Nakaseomyces, Vanderwaltozyma and Wickerhamomyces was studied. Volatiles produced were sampled by means of headspace solid-phase microextraction (SPME) and the compounds were analysed and identified by gas chromatography-mass spectroscopy (GC-MS). Yields (expressed as % of biotransformation) varied in dependence of the strain. The reduction of both (4R)-(-)-carvone and (1R)-(-)-myrtenal were catalyzed by some ene-reductases (ERs) and/or carbonyl reductases (CRs), which determined the formation of (1R,4R)-dihydrocarvone and (1R)-myrtenol respectively, as main flavouring products. The potential of NCYs as novel whole-cell biocatalysts for selective biotransformation of electron-poor alkenes for producing flavours and fragrances of industrial interest is discussed.
Goretti, Marta,Turchetti, Benedetta,Cramarossa, Maria Rita,Forti, Luca,Buzzini, Pietro
p. 5736 - 5748
(2013/07/19)

Heteropoly acid catalysts for the synthesis of fragrance compounds from biorenewables: Isomerization of limonene oxide
The liquid-phase isomerization of limonene oxide was studied in the presence of heteropoly acid catalysts in aprotic solvents in homogeneous and heterogeneous systems. Among the catalysts were bulk and silica-supported tungstophosphoric acid H3PW12O40 and its acidic Cs salt Cs0.5H0.5PW12O40 (CsPW). The reaction gave dihydrocarvone, a valuable fragrance intermediate, as the main product with turnover numbers of up to 8000. The nature of the solvent had a strong effect on reaction rate and selectivity. CsPW (0.1 mol%) was found to be a highly efficient and truly heterogeneous catalyst for this reaction, providing 82% yield of dihydrocarvone in 1,4-dioxane as a solvent under ambient conditions. This simple catalytic method represents economically attractive route to industrially important compounds starting from bio-renewable substrates easily available from essential oils. The Royal Society of Chemistry 2013.
Costa, Vinicius V.,Da Silva Rocha, Kelly A.,Kozhevnikov, Ivan V.,Kozhevnikova, Elena F.,Gusevskaya, Elena V.
p. 244 - 250
(2013/04/10)

Asymmetric reduction of (4R)-(-)-carvone catalyzed by Baker's yeast in aqueous mono- and biphasic systems
(1R,4R)-dihydrocarvone (2), an important renewable building block, was prepared with good conversions and excellent diastereoisomeric excess through the reduction of the α,β-unsatured carbon-carbon double bond of (4R)-(-)-carvone (1) mediated by Baker's yeast (BY) in aqueous mono- and biphasic systems. Some parameters that may alter this bioreduction reaction, such as the concentrations of yeast and substrate, temperature, and pH, were evaluated. The effect of the addition of different additives on the course of 1 biotransformation was also investigated. The results showed that the conversion and diastereoisomeric excesses were strongly dependent on these variables. The optimum reaction conditions were 100 g L-1 of BY, 16.6 mM of substrate, and pH 7.5 at 26 °C in the presence of DMSO, trehalose, or sucrose as additives. Under the optimum conditions, the (1R,4R)-dihydrocarvone was recovered with diastereoisomeric excesses of 92-99% and with conversions of 70-74%.
Silva, Vanessa Dutra,Stambuk, Boris Ugarte,Nascimento, Maria Da Graa
experimental part
p. 98 - 104
(2012/06/30)

Use of immobilized transition metal complexes as recyclable catalysts for oxidation reactions with hydrogen peroxide as oxidant
A tetradentate Schiff base (teta), obtained from triethylenetetramine and salicylaldehyde, has been covalently bonded to divinylbenzene cross-linked chloromethylated polystyrene. This chelating ligand, abbreviated as PS-teta (PS = polymeric support), reacts with metal chlorides (Cu2+, Co 2+, and Ni2+) in methanol to give polymerbound transition metal complexes, PS-Cu(II)teta/(Cat-1), PS-Ni(II)teta/(Cat-2), and PS-Co(II)teta/(Cat-3), formation of which has been established by various physiochemical methods and spectroscopic techniques. The catalytic potential of these materials has been tested for the oxidation of various alkenes, alkanes, alcohols, and thioethers in the presence of 30% H2O2 as an oxidant. At the same time, these catalysts are very stable and could be reused in oxidation reactions for more than five times without noticeable loss of their catalytic activity. Springer Science+Business Media B.V. 2011.
Islam, Sk Manirul,Mobarok, Manir,Mondal, Paramita,Roy, Anupam Singha,Salam, Noor,Hossain, Dildar,Mondal, Sanchita
experimental part
p. 97 - 107
(2012/09/22)

A base-promoted deprotection of 1,3-dioxolanes to ketones
An effective deprotection methodology of dioxolanes was developed, affording moderate to excellent yield via a LTMP-promoted reaction in THF, which displays admirable chemoselectivity in the presence of dimethylketal, 1,3-dioxane, 1,3-dithiane, or other acid-sensitive protective groups.
Yuan, Changchun,Yang, Li,Yue, Guizhou,Yu, Tianzi,Zhong, Weiming,Liu, Bo
supporting information
p. 6972 - 6976
(2013/01/15)

Synthesis of optically active dihydrocarveol via a stepwise or one-pot enzymatic reduction of (R)- and (S)-carvone
A recombinant enoate reductase LacER from Lactobacillus casei catalyzed the reduction of (R)-carvone and (S)-carvone to give (2R,5R)-dihydrocarvone and (2R,5S)-dihydrocarvone with 99% and 86% de, respectively, which were further reduced to dihydrocarveols by a carbonyl reductase from Sporobolomyces salmonicolor SSCR or Candida magnolia CMCR. For (R)-carvone, (1S,2R,5R)-dihydrocarveol was produced as the sole product with >99% conversion, while (1S,2R,5S)-dihydrocarveol was obtained as the major product, but with a lower de when (S)-carvone was used as the substrate. The one-pot reduction was performed at a 0.1 M substrate concentration, indicating that it might provide an effective synthetic route to this type of chiral compound.
Chen, Xi,Gao, Xiuzhen,Wu, Qiaqing,Zhu, Dunming
experimental part
p. 734 - 738
(2012/08/29)

Asymmetric bioreduction of activated carbon-carbon double bonds using Shewanella yellow enzyme (SYE-4) as novel enoate reductase
Shewanella yellow enzyme (SYE-4), a novel recombinant enoate reductase, was screened against a variety of different substrates bearing an activated double bond, such as unsaturated cyclic ketones, diesters, and substituted imides. Dimethyl- and ethyl esters of 2-methylmaleic acid were selectively reduced to (R)-configured succinic acid derivatives and various N-substituted maleimides furnished the desired (R)-products in up to >99% enantiomeric excess. Naturally occurring (+)-carvone was selectively reduced to (-)-cis- dihydrocarvone and (-)-carvone was converted to the diastereomeric product, respectively. Overall SYE-4 proved to be a useful biocatalyst for the selective reduction of activated CC double bonds and complements the pool of synthetic valuable enoate reductases.
Iqbal, Naseem,Rudroff, Florian,Brigé, Ann,Van Beeumen, Jozef,Mihovilovic, Marko D.
experimental part
p. 7619 - 7623
(2012/09/07)

A novel ene-reductase from Synechococcus sp. PCC 7942 for the asymmetric reduction of alkenes
The increasing demand for enantiopure molecules in the pharmaceutical and fine-chemical industry requires the availability of well-characterized and efficient biocatalysts for asymmetric syntheses. Thereby, asymmetric reduction of alkenes represents one of the most employed reactions for the production of chiral molecules. Here, we present a novel ene-reductase from the cyanobacterium Synechococcus sp. PCC 7942, a member of the old yellow enzyme family, capable of reducing CC bonds in a anti-specific fashion. We evaluated its biocatalytic potential by characterizing the substrate spectrum, cofactor preference, stereoselectivity and biochemical properties. This NADPH-dependent flavoprotein accepted a wide range of activated alkenes and displayed a pH optimum between pH 7.6 and pH 8.6. A C-terminal His6-tag decreased the enzyme activity 2.7-fold, but did not influence the stereoselectivity. The reduction of (R)-carvone and 2-methylmaleimide yielded (R)-products with high optical purities (98% de and >99% ee, respectively), pointing out the applicability of this new biocatalyst in the stereoselective production of chiral compounds.
Fu, Yilei,Hoelsch, Kathrin,Weuster-Botz, Dirk
p. 1988 - 1997
(2013/02/25)

A Site-Saturated Mutagenesis Study of Pentaerythritol Tetranitrate Reductase Reveals that Residues 181 and 184 Influence Ligand Binding, Stereochemistry and Reactivity
We have conducted a site-specific saturation mutagenesis study of H181 and H184 of flavoprotein pentaerythritol tetranitrate reductase (PETN reductase) to probe the role of these residues in substrate binding and catalysis with a variety of α,β-unsaturated alkenes. Single mutations at these residues were sufficient to dramatically increase the enantiopurity of products formed by reduction of 2-phenyl-1-nitropropene. In addition, many mutants exhibited a switch in reactivity to predominantly catalyse nitro reduction, as opposed to C=C reduction. These mutants showed an enhancement in a minor side reaction and formed 2-phenylpropanal oxime from 2-phenyl-1-nitropropene. The multiple binding conformations of hydroxy substituted nitro-olefins in PETN reductase were examined by using both structural and catalytic techniques. These compounds were found to bind in both active and inhibitory complexes; this highlights the plasticity of the active site and the ability of the H181/H184 couple to coordinate with multiple functional groups. These properties demonstrate the potential to use PETN reductase as a scaffold in the development of industrially useful biocatalysts. Divergent evolution: A site-saturation study of PETN reductase was performed at conserved substrate binding residues H181 and H184. These residues were shown to dramatically alter the ratio of alkene versus nitro-group reduction in favour of oxime by-product formation, as summarised in the picture.
Toogood, Helen S.,Fryszkowska, Anna,Hulley, Martyn,Sakuma, Michiyo,Mansell, David,Stephens, Gill M.,Gardiner, John M.,Scrutton, Nigel S.
scheme or table
p. 738 - 749
(2012/02/01)

(R)-(-)-carvone and (1R, 4R)-trans-(+)-dihydrocarvone from Poiretia latifolia vogel
The essential oils of Poiretia latifolia Vogel, native and cultivated leaves (Samples A and B, respectively) and native flowers (sample C), were obtained by hydrodistillation and analyzed by GC, GC/MS and chiral phase gas chromatography (CPGC). Twenty-four compounds were identified, representing 99.25, 99.26 and 99.23percent of the oils, respectively. The major constituents of the oils were the monoterpenes (S)-(-)-limonene (16.05, 27.60, 15.60percent, respectively), (1R, 4R)-trans-(+)-dihydrocarvone (18.05, 0.66 and 77.80percent, respectively) and (R)-(-)-carvone (61.05, 64.20 and 4.50percent, respectively). The essential oils were evaluated against some strains of Gram (+) and Gram (-) bacteria, and yeast, but displayed only modest antimicrobial activity.
Porto, Carla,Stu?ker, Caroline Z.,Mallmann, Anderson S.,Simionatto, Euclesio,Flach, Adriana,Do Canto-Dorow, Tais,Da Silva, Ubiratan F.,Dalcol, Ionara I.,Morel, Ademir F.
scheme or table
p. 782 - 786
(2010/11/17)

Studies towards the taming of the 'carbocation' in the regioselective ring opening of epoxides to allylic alcohols
Regioselective isomerisation of epoxides to allylic alcohols can be achieved using p-toluenesulfonic acid in the presence of 1,3- dimethylimidazolidin-2-one. Georg Thieme Verlag Stuttgart.
Chapman, Helen A.,Herbal, Karim,Motherwell, William B.
experimental part
p. 595 - 598
(2010/09/15)

Synthesis of a key intermediate for the total synthesis of pseudopteroxazole
A facile synthesis of a key intermediate for the total synthesis of anti-mycobacterial compound pseudopteroxazole is described employing an intramolecular Diels-Alder cyclization and an iodine-mediated oxidative aromatization step.
Yadav,Bhasker, E. Vijaya,Srihari
experimental part
p. 1997 - 2004
(2010/04/29)