- Acylative kinetic resolution of racemic methyl-substituted cyclic alkylamines with 2,5-dioxopyrrolidin-1-yl (: R)-2-phenoxypropanoate
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The diastereoselective acylation of a number of racemic methyl-substituted cyclic alkylamines with active esters of 2-phenoxypropanoic acid was studied in detail. The ester of (R)-2-phenoxypropanoic acid and N-hydroxysuccinimide was found to be the most selective agent. The highest stereoselectivity was observed in the kinetic resolution of racemic 2-methylpiperidine in toluene at -40 °C (selectivity factor s = 73) with the predominant formation of (R,R)-amide (93.7% de). To explain the observed stereoselectivity, DFT modelling of the transition states in the reactions of the title acylating agent with 2-methylpiperidine and 2-methylpyrrolidine was performed. The calculated values were in good agreement with experimental data. It has been demonstrated that the acylation proceeds via a concerted mechanism, in which the addition of an amine occurs simultaneously with the elimination of the hydroxysuccinimide fragment. The high stereoselectivity of the (R,R)-amide formation is largely ensured by the lower steric hindrances in the transition states as compared to the formation of (R,S)-amide.
- Bartashevich, Ekaterina V.,Chulakov, Evgeny N.,Ezhikova, Marina A.,Gruzdev, Dmitry A.,Kodess, Mikhail I.,Korolyova, Marina A.,Krasnov, Victor P.,Levit, Galina L.,Tumashov, Andrey A.,Vakarov, Sergey A.
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supporting information
p. 862 - 869
(2022/02/03)
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- Catalytic Asymmetric Synthesis of Morpholines. Using Mechanistic Insights to Realize the Enantioselective Synthesis of Piperazines
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An efficient and practical catalytic approach for the enantioselective synthesis of 3-substituted morpholines through a tandem sequential one-pot reaction employing both hydroamination and asymmetric transfer hydrogenation reactions is described. Starting from ether-containing aminoalkyne substrates, a commercially available bis(amidate)bis(amido)Ti catalyst is utilized to yield a cyclic imine that is subsequently reduced using the Noyori-Ikariya catalyst, RuCl [(S,S)-Ts-DPEN] (η6-p-cymene), to afford chiral 3-substituted morpholines in good yield and enantiomeric excesses of >95%. A wide range of functional groups is tolerated. Substrate scope investigations suggest that hydrogen-bonding interactions between the oxygen in the backbone of the ether-containing substrate and the [(S,S)-Ts-DPEN] ligand of the Ru catalyst are crucial for obtaining high ee's. This insight led to a mechanistic proposal that predicts the observed absolute stereochemistry. Most importantly, this mechanistic insight allowed for the extension of this strategy to include N as an alternative hydrogen bond acceptor that could be incorporated into the substrate. Thus, the catalytic, enantioselective synthesis of 3-substituted piperazines is also demonstrated.
- Lau, Ying Yin,Zhai, Huimin,Schafer, Laurel L.
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p. 8696 - 8709
(2016/10/14)
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- A concise and efficient synthesis of substituted morpholines
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A simple and efficient method has been developed for the synthesis of substituted morpholines by a sequence of coupling, cyclization, and reduction reactions of easily available amino alcohols and α-halo acid chlorides. Various mono-, di-, and trisubstituted morpholines, spiro morpholines, and ring-fused morpholines, as well as morpholine homologues, were synthesized in good to excellent yields by a single methodology under similar reaction conditions. The method was also used in a multigram synthesis of (3S)-3-methylmorpholine.
- Dugar, Sundeep,Sharma, Amit,Kuila, Bilash,Mahajan, Dinesh,Dwivedi, Sandeep,Tripathi, Vinayak
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- Concerted amidation of activated esters: Reaction path and origins of selectivity in the kinetic resolution of cyclic amines via N-heterocyclic carbenes and hydroxamic acid cocatalyzed acyl transfer
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The N-heterocyclic carbene and hydroxamic acid cocatalyzed kinetic resolution of cyclic amines generates enantioenriched amines and amides with selectivity factors up to 127. In this report, a quantum mechanical study of the reaction mechanism indicates that the selectivity-determining aminolysis step occurs via a novel concerted pathway in which the hydroxamic acid plays a key role in directing proton transfer from the incoming amine. This modality was found to be general in amide bond formation from a number of activated esters including those generated from HOBt and HOAt, reagents that are broadly used in peptide coupling. For the kinetic resolution, the proposed model accurately predicts the faster reacting enantiomer. A breakdown of the steric and electronic control elements shows that a gearing effect in the transition state is responsible for the observed selectivity.
- Allen, Scott E.,Hsieh, Sheng-Ying,Gutierrez, Osvaldo,Bode, Jeffrey W.,Kozlowski, Marisa C.
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p. 11783 - 11791
(2014/11/08)
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- NOVEL HEPATITIS C VIRUS INHIBITORS
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The invention provides compounds of formula (I): wherein Rings A and A' are independently 5-membered optionally substituted aromatic heterocycles; Q is C(=O)NR1R1' or formula U is C(R4)2, O, S, S(=O)2, C(R4)2C(R4)2, CH2O, OCH2, CH2S, SCH2, CH2S(=O)2, S(=O)CH2 or C=C(Ru )2; X is CH2, CHR12, CR12R12, O, S, S(=O)2 or NRx; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; the other variables are as defined in the claims, which are of use in the treatment or prophylaxis of hepatitis C virus infection, and related aspects.
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Page/Page column 39; 40
(2013/07/05)
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- Catalytic asymmetric synthesis of substituted morpholines and piperazines
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Under two conditions: Hydroamination catalyzed by group 4 metals is featured in the modular and enantioselective synthesis of 3-substituted morpholines and the diastereoselective synthesis of 2,5-substituted piperazines. Copyright
- Zhai, Huimin,Borzenko, Andrey,Lau, Ying Yin,Ahn, Shin Hye,Schafer, Laurel L.
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supporting information
p. 12219 - 12223
(2013/02/23)
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- 2-AMINOBENZOXAZOLE CARBOXAMIDES AS 5HT3 MODULATORS
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Compounds of formulae I, II and III: are disclosed as 5-HT3 inhibitors. The compounds are useful in treating CINV, IBS-D and other diseases and conditions.
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Page/Page column 21
(2008/12/04)
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- PYRAZOLE DERIVATIVE
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A compound represented by Formula (I): wherein Ar1 represents Formula (II): Ar2 represents a 5- or 6-membered aromatic heterocyclic group which may be substituted; and X represents Formula (III): a salt thereof, or a solvate of the compound or the salt. A potent platelet aggregation suppressant which does not inhibit COX-1 and COX-2 is provided.
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Page/Page column 149
(2010/11/27)
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- Phthalazine, aza- and diaza-phthalazine compounds and methods of use
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The present invention comprises a new class of compounds useful for the prophylaxis and treatment of protein kinase mediated diseases, including inflammation and related conditions. The compounds have a general Formula I wherein A1, A2, B, R1, R2, R3 and R4 are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula I, uses of such compounds and compositions for treatment of kinase mediated diseases including rheumatoid arthritis, psoriasis and other inflammation disorders, as well as intermediates and processes useful for the preparation of compounds of Formula I.
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Page/Page column 45
(2008/06/13)
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- Quinoxaline compounds
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Certain amidophenyl-sulfonylamino-quinoxaline compounds are CCK2 modulators useful in the treatment of CCK2 mediated diseases.
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Page/Page column 19
(2008/06/13)
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- SYNTHESIS AND ABSOLUTE CONFIGURATION OF SUBSTITUTED MORPHOLINES
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We studied methods of stereospecific synthesis that enabled us to obtain variously substituted morpholinic compounds and to determine their absolute configuration.From a study of the chiroptical properties of synthetic N-(2-pyridyl-N-oxide) derivatives of optically active morpholines, it was possible to correlate the sign of the Cotton effect with the absolute configuration.This correlation agrees with that previously established for derivatives of the piperidine type.By evaluating the various contributions to the Cotton effect of substituents in positions 2 and 3, we established the absolute configuration of bicyclic compounds condensed in the two positions mentioned above.
- Bettoni, Giancarlo,Franchini, Carlo,Perrone, Roberto,Tortorella, Vincenzo
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p. 409 - 415
(2007/10/02)
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