- Preparation of Optically Pure (R)-(+)-Nicotine. Studies on the Microbial Degradation of Nicotinoids
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(R)-(+)-Nicotine (1a) of high optical purity (average 99.6percent) has been obtained from (R,S)-nicotine by stereoselective microbial degradation of the (S)-(-)-nicotine with use of the microorganism Pseudomonas putida.Liquid culture results indicated that the organism growing on (S)-(-)-nicotine can utilize 1a but at a slower rate.Studies on related nicotinoids showed the microorganism to be primarily specific for (S)-(-)-nicotine.
- Edwards, William B.,McCuen, R.
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Read Online
- Enantioselective Hydrosilylation and Hydrogenation of Alkaloid Precursors
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Enantioselective hydrosilylations of the 3,4-dihydropyrrole derivatives 1a-c and 5 with in-situ catalysts consisting of 2 and optically active phosphines yield the N-silyl compounds 2a-c and 6 in up to 66.1percent ee.The N-silyl derivatives were treated with acetic formic anhydride or trifluoroacetic anhydride to give the N-formyl and N-trifluoroacetyl compounds 3a-c, 4a-c, 7, and 8.The alkaloids nicotine and macrostomine were synthesized with 63.3 and 33percent ee by reduction of the N-formyl compounds 8 and 12.Enantioselective hydrogenations of the N-formyl and N-trifluoroacetyl-2-phenylpyrrolines 14 and 15 with the same in-situ catalysts produce the cyclic amides 3a and 4a in up to 36.1percent ee.
- Brunner, Henri,Kuerzinger, Alfred,Mahboobi, Siavosh,Wiegrebe, Wolfgang
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- The pyrolysis of (-)-(S)-nicotine: Racemization and decomposition
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The pyrolytic behaviour of (1)-(S)-nicotine in methanol was investigated using on-line pyrolysis GC/MS to establish whether racemization to the R(+) antipode occurs and to identify other products of pyrolysis. The conditions used included pyrolysing the sample for 15 seconds in an atmosphere of 9% oxygen in nitrogen (275ml/min total flow) across the temperature range of 200°C-1000°C. A chiral Cyclodex-B analytical column (30m × 0.25mm i.d. × 0.25 μm film thickness) was used to separate the enantiomers of nicotine, although the two enantiomer peaks were not baseline resolved. The results of the experiment shows that there is no increase in (+)-(R)-nicotine levels across a wide temperature range. This suggests that the elevated levels of (+)-R-nicotine observed in tobacco smoke (compared to tobacco leaf material) are not due to the pyrolytic auto-racemization of (1)-(S)-nicotine but are a result of more complex interactions between (-)-(S)-nicotine and other smoke components. The pyrolysis of isotopically labelled nicotine established that nicotine undergoes thermal decomposition to β-nicotyrine which in turn may decompose to other products. Chirality 22:442-446, 2010.
- Clayton, Peter,Lu, Annhelen,Bishop, Louise
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Read Online
- Asymmetric preparation method of nicotine
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The invention relates to a preparation method of nicotine, in particular to a preparation method of nicotine from nicotinic acid ester as a starting material through five-step reaction. The method comprises the following specific steps: (1) a condensation reaction of the nicotinate with N - methylpyrrolidinone in a suitable reaction vessel, and adding a strong acid to react to obtain 4 - methylamino -1 - (3 - pyridine) - butanone hydrochloride after the reaction is finished. (2) The amino group is protected with a suitable amino protecting reagent to give an intermediate (4). (3) The chiral alcohol intermediate (5) is obtained by asymmetric reduction. (4) The chiral alcohol intermediate can be converted into nicotine through two-step conversion. The asymmetric reduction reaction of metal catalysis is a key step of the method, so that the chiral alcohol intermediate with high optical activity can be obtained, and nicotine can be prepared through two-step conversion. The nicotine preparation method provided by the invention is simple to operate, low in cost, mild in reaction condition and suitable for industrial production.
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- Preparation method of nicotine with optical activity
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The invention discloses a preparation method of nicotine with optical activity, which comprises the following steps: adding a nitrogen-containing or phosphorus-containing chiral ligand and a metal catalyst into an organic solvent, preparing a catalyst, sequentially adding an imine salt and a reducing agent to carry out a reduction reaction, and adding an extracting agent to extract the nicotine compound. According to the preparation method disclosed by the invention, the imine salt derivative is used as a precursor, the initial raw material cost is low, the reaction conditions are mild (for example, catalysis and reduction reactions occur in a temperature range near normal temperature), the catalyst and the reducing agent are common chemical substances, the synthesis yield and the chemicalpurity of the final product nicotine are high, and large-scale industrial production is convenient to realize.
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Paragraph 0061-0063; 0095-0097
(2020/06/20)
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- Enantioselective Synthesis of Nicotine via an Iodine-Mediated Hofmann-L?ffler Reaction
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An iodine-mediated Hofmann-L?ffler reaction has been developed that enables the first enantioselective synthesis of nicotine based on this synthetic methodology. The effect of the free pyridine core on the involved electrophilic iodine reagents was explored in detail. The final synthesis proceeds under moderate reaction conditions that tolerate the free pyridine core. The same synthetic sequence is also applicable to a number of derivatives with higher substituted pyridine cores, including bipyridine derivatives.
- Del Castillo, Estefanía,Mu?iz, Kilian
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supporting information
p. 705 - 708
(2019/02/07)
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- ENANTIOMERIC SEPARATION OF RACEMIC NICOTINE BY ADDITION OF AN O,O'-DISUBSTITUTED TARTARIC ACID ENANTIOMER
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The present invention relates to a method of separating racemic nicotine of Formula (l-a) as a mixture of the (R)- and (S)-enantiomers into the enantiomerically pure (S)- and (R)-nicotine represented by Formula (l-b) and (l-c), by adding a mixture of the L- and the D-enantiomer of a O,O'-disubstituted tartaric acid, wherein the molar ratio of the L- to the D-enantiomer is from 80:20 to 95:5, and obtaining the (S)-nicotine of formula (l-b), or by adding O,O'-dibenzoyl-D-tartaric acid and obtaining the (R)-nicotine of formula (l-c).
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- PREPARATION OF RACEMIC NICOTINE BY REACTION OF ETHYL NICOTINATE WITH N-VINYLPYRROLIDONE IN THE PRESENCE OF AN ALCOHOLATE BASE AND SUBSEQUENT PROCESS STEPS
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The present invention relates to a method of preparing racemic nicotine comprising: (i) reacting ethyl nicotinate and N-vinylpyrrolidone in the presence of an alcoholate base to 3-nicotinoyl-1-vinylpyrrolidin-2-one; (ii) reacting the 3-nicotinoyl-1-vinylpyrrolidin-2-one with an acid to myosmine; (iii) reducing the myosmine to nornicotine using a reducing agent; and (iv) methylating the nornicotine to obtain the racemic nicotine.
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- Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase
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A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.
- Hellinghausen, Garrett,Lopez, Diego A.,Lee, Jauh T.,Wang, Yadi,Weatherly, Choyce A.,Portillo, Abiud E.,Berthod, Alain,Armstrong, Daniel W.
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p. 1067 - 1078
(2018/08/01)
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- SYNTHESIS AND RESOLUTION OF NICOTINE
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The present disclosure generally relates to methods of preparing nicotine and resolving R,S nicotine to enrich the (S)(?) enantiomer. The method may comprise combining N-methyl-2-pyrrolidone or a salt thereof with a nicotinate compound in the presence of a solvent and a strong base to form 1-methyl-3-nicotinoyl-2-pyrrolidone or a salt thereof; and reducing the 1-methyl-3-nicotinoyl-2-pyrrolidone or salt thereof in solution with Na2S2O4 to produce racemic nicotine or salt thereof. Resolving the racemic nicotine (or other enantiomeric mixture) may comprise combining the nicotine with (?)-O,O′-di-p-toluoyl-L-tartaric acid (L-PTTA).
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Paragraph 0039-0044
(2016/11/28)
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- Ring Opening of Donor-Acceptor Cyclopropanes with the Azide Ion: A Tool for Construction of N-Heterocycles
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A general method for ring opening of various donor-acceptor cyclopropanes with the azide ion through an SN2-like reaction has been developed. This highly regioselective and stereospecific process proceeds through nucleophilic attack on the more-substituted C2 atom of a cyclopropane with complete inversion of configuration at this center. Results of DFT calculations support the SN2 mechanism and demonstrate good qualitative correlation between the relative experimental reactivity of cyclopropanes and the calculated energy barriers. The reaction provides a straightforward approach to a variety of polyfunctional azides in up to 91% yield. The high synthetic utility of these azides and the possibilities of their involvement in diversity-oriented synthesis were demonstrated by the developed multipath strategy of their transformations into five-, six-, and seven-membered N-heterocycles, as well as complex annulated compounds, including natural products and medicines such as (-)-nicotine and atorvastatin. A new world of opportunities: Stereospecific ring opening of donor-acceptor cyclopropanes with the azide ion gives rise to densely functionalized building blocks that are valuable for the assembly of a diverse range of N-heterocycles (see scheme; EDG=electron donating group; EWG=electron withdrawing group). These synthetic opportunities are provided by the simultaneous presence of the N3 group, which reacts as a latent amine or 1,3-dipole, easily modifiable donor and acceptor substituents, as well as the activated CH fragment.
- Ivanov, Konstantin L.,Villemson, Elena V.,Budynina, Ekaterina M.,Ivanova, Olga A.,Trushkov, Igor V.,Melnikov, Mikhail Ya.
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supporting information
p. 4975 - 4987
(2015/03/18)
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- Synthetic cascades are enabled by combining biocatalysts with artificial metalloenzymes
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Enzymatic catalysis and homogeneous catalysis offer complementary means to address synthetic challenges, both in chemistry and in biology. Despite its attractiveness, the implementation of concurrent cascade reactions that combine an organometallic catalyst with an enzyme has proven challenging because of the mutual inactivation of both catalysts. To address this, we show that incorporation of a d 6 -piano stool complex within a host protein affords an artificial transfer hydrogenase (ATHase) that is fully compatible with and complementary to natural enzymes, thus enabling efficient concurrent tandem catalysis. To illustrate the generality of the approach, the ATHase was combined with various NADH-, FAD- and haem-dependent enzymes, resulting in orthogonal redox cascades. Up to three enzymes were integrated in the cascade and combined with the ATHase with a view to achieving (i) a double stereoselective amine deracemization, (ii) a horseradish peroxidase-coupled readout of the transfer hydrogenase activity towards its genetic optimization, (iii) the formation of L-pipecolic acid from L-lysine and (iv) regeneration of NADH to promote a monooxygenase-catalysed oxyfunctionalization reaction.
- Koehler,Wilson,Duerrenberger,Ghislieri,Churakova,Quinto,Knoerr,Haeussinger,Hollmann,Turner,Ward
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- A process for the resolution of (R,S)-nicotine
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(R,S)-Nicotine was resolved through diastereomeric salt formation using dibenzoyl-d-tartaric acid and dibenzoyl-l-tartaric acid to obtain enantiomerically pure (S)-nicotine and (R)-nicotine.
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Page/Page column 6
(2012/08/14)
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- Enantioselective, palladium-catalyzed α-arylation of N-Boc pyrrolidine: In situ react IR spectroscopic monitoring, scope, and synthetic applications
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A comprehensive study of the enantioselective Pd-catalyzed α-arylation of N-Boc pyrrolidine has been carried out. The protocol involves deprotonation of N-Boc pyrrolidine using s-BuLi/(-)-sparteine in TBME or Et2O at -78 °C, transmetalation with ZnCl2 and Negishi coupling using Pd(OAc)2, t-Bu3P-HBF4 and the aryl bromide. This paper reports several new features including in situ React IR spectroscopic monitoring of the process; use of (-)-sparteine and the (+)-sparteine surrogate to access products with opposite configuration; development of a catalytic asymmetric lithiation-Negishi coupling reaction; extension to a wide range of heteroaromatic bromides; total synthesis of (R)-crispine A, (S)-nicotine and (S)-SIB-1508Y via short synthetic routes; and examples of α-vinylation of N-Boc pyrrolidine using vinyl bromides exemplified by the total synthesis of naturally occurring (+)-maackiamine (thus establishing its configuration as (R)). In this way, the full scope and limitations of the methodology are delineated.
- Barker, Graeme,McGrath, Julia L.,Klapars, Artis,Stead, Darren,Zhou, George,Campos, Kevin R.,O'Brien, Peter
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experimental part
p. 5936 - 5953
(2011/10/09)
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- Esters of pyromellitic acid. Part II. Esters of chiral alcohols: Para pyromellitate diesters as a novel class of resolving agents and use of pyromellitates as duplicands for chiral purification
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(Chemical Equation Presented) Methods are presented for the preparation of pyromellitate esters of chiral terpene alcohols, including d-(3) or l-menthol (4), d-isomenthol (7), l-borneol (8), or d- (5) or l-isopinocampheol (6). Alcoholysis of PMDA in CH2Cl2/Et3N led to the formation of monoesters (e.g., 18) or diesters (11, 12), as needed, relying on the differential reactivity of the two anhydride groups. The easily isolated para diester (11) crystallized before the meta diester (12) from HOAc. Nicotine (1, 14) was efficiently resolved as 1:1 salts with the menthyl (11a, 11b) or bornyl (11f) para diesters, prototypes of what promises to be a large class of novel resolving agents. Recrystallization of para-di-d-menthyl pyromellitate (11a) greatly improved the chiral purity of the contained d-menthol (3), an example of purification by "duplication". An alternative synthesis of specific diesters took advantage of the easily separated benzyl diesters and their derived acid chlorides (19, 21), with the benzyl esters serving as temporary blocking groups removable by catalytic hydrogenolysis. Pyromellitate tetraesters (26) were prepared by base-catalyzed transesterification of the tetraethyl ester (25). Tri-l-menthyl pyromellitate (27b) was obtained by catalytic hydrogenolysis of benzyl tri-l-menthyl pyromellitate (31b), itself prepared from the alcoholysis of benzyl pyromellitate triacid chloride (30) with l-menthol (4).
- Paine III, John B.
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p. 4939 - 4948
(2008/12/21)
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- A chemo-enzymatic route to enantiomerically pure cyclic tertiary amines
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Deracemization of racemic chiral tertiary amines has been achieved by combination of an enantioselective amine oxidase, obtained through directed evolution, and ammonia borane in a one-pot process. Copyright
- Dunsmore, Colin J.,Carr, Reuben,Fleming, Toni,Turner, Nicholas J.
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p. 2224 - 2225
(2007/10/03)
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- A short and efficient synthesis of unnatural (R)-nicotine
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A short and efficient synthesis of unnatural (R)-nicotine is described, in which the key step is an intramolecular hydroboration-cycloalkylation of an azido-olefin intermediate. The synthesis is achieved in only four steps, with an overall yield of 51% (or in six steps with an overall yield of 65%). (C) 2000 Elsevier Science Ltd.
- Girard,Robins,Villieras,Lebreton
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p. 9245 - 9249
(2007/10/03)
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