- Enantioconvergent Cu-Catalyzed Radical C-N Coupling of Racemic Secondary Alkyl Halides to Access α-Chiral Primary Amines
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α-Chiral alkyl primary amines are virtually universal synthetic precursors for all other α-chiral N-containing compounds ubiquitous in biological, pharmaceutical, and material sciences. The enantioselective amination of common alkyl halides with ammonia is appealing for potential rapid access to α-chiral primary amines, but has hitherto remained rare due to the multifaceted difficulties in using ammonia and the underdeveloped C(sp3)-N coupling. Here we demonstrate sulfoximines as excellent ammonia surrogates for enantioconvergent radical C-N coupling with diverse racemic secondary alkyl halides (>60 examples) by copper catalysis under mild thermal conditions. The reaction efficiently provides highly enantioenrichedN-alkyl sulfoximines (up to 99% yield and >99% ee) featuring secondary benzyl, propargyl, α-carbonyl alkyl, and α-cyano alkyl stereocenters. In addition, we have converted the masked α-chiral primary amines thus obtained to various synthetic building blocks, ligands, and drugs possessing α-chiral N-functionalities, such as carbamate, carboxylamide, secondary and tertiary amine, and oxazoline, with commonly seen α-substitution patterns. These results shine light on the potential of enantioconvergent radical cross-coupling as a general chiral carbon-heteroatom formation strategy.
- Cheng, Jiang-Tao,Dong, Xiao-Yang,Gu, Qiang-Shuai,Li, Zhong-Liang,Liu, Juan,Liu, Xin-Yuan,Luan, Cheng,Wang, Fu-Li,Wang, Li-Lei,Yang, Ning-Yuan,Zhang, Yu-Feng
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supporting information
p. 15413 - 15419
(2021/09/30)
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- Diastereoselective Synthesis of Nonplanar 3-Amino-1,2,4-oxadiazine Scaffold: Structure Revision of Alchornedine
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Herein, we report the diastereoselective synthesis of a 3-amino-1,2,4-oxadiazine (AOXD) scaffold. The presence of a N-O bond in the ring prevents the planar geometry of the aromatic system and induces a strong decrease in the basicity of the guanidine moiety. While DIBAL-H appeared to be the most efficient reducing agent because it exhibited high diastereoselectivity, we observed various behaviors of the Mitsunobu reaction on the resulting β-aminoalcohol, leading to either inversion or retention of the configuration depending on the steric hindrance in the vicinity of the hydroxy group. The physicochemical properties (pKa and log D) and hepatic stability of several AOXD derivatives were experimentally determined and found that the AOXD scaffold possesses promising properties for drug development. Moreover, we synthesized alchornedine, the only natural product with the AOXD scaffold. Based on a comparison of the analytical data, we found that the reported structure of alchornedine was incorrect and hypothesized a new one.
- Bihel, Frédéric,Bricard, Jacques,Garnier, Delphine,Gizzi, Patrick,Leloire, Maeva,Mohr, Julie,Schmitt, Martine,Schneider, Séverine,Tang, Shuang-Qi
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p. 15347 - 15359
(2020/11/30)
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- Chiral Phosphoric Acid Catalyzed Enantioselective Synthesis of α-Tertiary Amino Ketones from Sulfonium Ylides
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Herein we disclose a new catalytic asymmetric approach for the synthesis of chiral α-Amino ketones, which is particularly useful for the less accessible acyclic α-Tertiary cases. By a protonation-Amination sequence, our approach represents a rare asymmetric H-heteroatom bond insertion by α-carbonyl sulfonium ylides, an attractive surrogate of diazocarbonyls. The mild intermolecular C-N bond formation was catalyzed by chiral phosphoric acids with excellent efficiency and enantioselectivity. The products are precursors to other important chiral amine derivatives, including drug molecules and chiral ligands. The enantioselectivity was controlled by dynamic kinetic resolution in the amination step, rather than the initial protonation. This process opens up a new platform for the development of other related insertion reactions.
- Guo, Wengang,Li, Pingfan,Luo, Yuzheng,Sun, Jianwei,Sung, Herman H.-Y.,Williams, Ian D.
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p. 14384 - 14390
(2020/09/15)
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- Selective Nonsteroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases
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A class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft-drug strategy was implemented to ensure rapid elimination of drug candidates to minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, 15m (AZD7594), that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment.
- Hemmerling, Martin,Nilsson, Stinabritt,Edman, Karl,Eirefelt, Stefan,Russell, Wayne,Hendrickx, Ramon,Johnsson, Eskil,K?rrman M?rdh, Carina,Berger, Markus,Rehwinkel, Hartmut,Abrahamsson, Anna,Dahmén, Jan,Eriksson, Anders R.,Gabos, Balint,Henriksson, Krister,Hossain, Nafizal,Ivanova, Svetlana,Jansson, Anne-Helene,Jensen, Tina J.,Jerre, Anders,Johansson, Henrik,Klingstedt, Tomas,Lepist?, Matti,Lindsj?, Martin,Mile, Irene,Nikitidis, Grigorios,Steele, John,Tehler, Ulrika,Wissler, Lisa,Hansson, Thomas
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p. 8591 - 8605
(2017/11/03)
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- Process Development of CuI/ABNO/NMI-Catalyzed Aerobic Alcohol Oxidation
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An improved Cu/nitroxyl catalyst system for aerobic alcohol oxidation has been developed for the oxidation of functionalized primary and secondary alcohols to aldehydes and ketones, suitable for implementation in batch and flow processes. This catalyst, which has been demonstrated in a >50 g scale batch reaction, addresses a number of process limitations associated with a previously reported (MeObpy)CuI/ABNO/NMI catalyst system (MeObpy = 4,4′-dimethoxy-2,2′-bipyridine, ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl, NMI = N-methylimidazole). Important catalyst modifications include the replacement of [Cu(MeCN)4]OTf with a lower-cost Cu source, CuI, reduction of the ABNO loading to 0.05-0.3 mol%, and use of NMI as the only ligand/additive (i.e., without a need for MeObpy). Use of a high flash point solvent, N-methylpyrrolidone, enables safe operation in batch reactions with air as the oxidant. For continuous-flow applications compatible with elevated gas pressures, better performance is observed with acetonitrile as the solvent.
- Steves, Janelle E.,Preger, Yuliya,Martinelli, Joseph R.,Welch, Christopher J.,Root, Thatcher W.,Hawkins, Joel M.,Stahl, Shannon S.
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p. 1548 - 1553
(2015/12/01)
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- Copper(I)/ABNO-catalyzed aerobic alcohol oxidation: Alleviating steric and electronic constraints of Cu/TEMPO catalyst systems
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Cu/TEMPO catalyst systems promote efficient aerobic oxidation of sterically unhindered primary alcohols and electronically activated substrates, but they show reduced reactivity with aliphatic and secondary alcohols. Here, we report a catalyst system, consisting of (MeObpy)CuI(OTf) and ABNO (MeObpy =4,4′-dimethoxy-2,2′-bipyridine; ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl), that mediates aerobic oxidation of all classes of alcohols, including primary and secondary allylic, benzylic, and aliphatic alcohols with nearly equal efficiency. The catalyst exhibits broad functional group compatibility, and most reactions are complete within 1 h at room temperature using ambient air as the source of oxidant.
- Steves, Janelle E.,Stahl, Shannon S.
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p. 15742 - 15745
(2013/11/06)
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- A highly stereoselective synthesis of optically active trisubstituted 1,2-ethylenediamines: The first example of Grignard addition to N-diphenylphosphinoyl ketimines derived from amino acids
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The efficient synthesis of optically active trisubstituted 1,2-ethylenediamines is described. Addition of aryl and/or alkyl Grignard reagents to α-amino N- diphenylphosphinoyl ketimines derived from α-amino acids was demonstrated to afford the desired tri
- Kohmura, Yoshinori,Mase, Toshiaki
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p. 6329 - 6334
(2007/10/03)
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- Synthesis of optically active N-protected α-aminoketones and α-amino alcohols
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A series of optically active N-protected α-aminoketones were synthesized via the Grignard reaction of the Weinreb amides of the N-tert-butoxycarbonyl amino acids. Reduction of the α-aminoketones by sodium borohydride resulted in the corresponding 1,2-amino alcohols.
- Zhou, Zheng Hong,Tang, Yi Long,Li, Kang Ying,Liu, Bing,Tang, Chu Chi
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p. 603 - 606
(2007/10/03)
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- Improved syntheses of α-BOC-aminoketones from α-BOC-amino-Weinreb amides using a pre-deprotonation protocol
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A general procedure was developed to prepare α-BOC-aminoketones in good yields from α-BOC-amino Weinreb amides containing an exchangeable amino proton. By first deprotonating this amino group using 1 equiv. of a simple alkyl Grignard base, only a stoichio
- Liu, Jinchu,Ikemoto, Norihiro,Petrillo, Daniel,Armstrong III, Joseph D.
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p. 8223 - 8226
(2007/10/03)
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- An efficient synthesis of both enantiomers of Cathinone by regioselective reductive ring opening of substituted aziridines
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Both enantiomers of Cathinone were prepared as HCl salts from N-(R)-α-methylbenzylaziridine-2(S)-carboxaldehyde 2c and its enantiomer N-(S)-α-methyl-benzylaziridine-2(R)-carboxaldehyde 3c in high yield. This process makes it possible to prepare other aromatic and heteroaromatic analogs of Cathinone efficiently.
- Hwang, Gweon Il,Chung, Jae-Ho,Lee, Won Koo
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p. 12111 - 12116
(2007/10/03)
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- α-Amino Acids as Chiral Educts for Asymmetric Products. Amino Acylation with N-Acylamino Acids
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α-N-Acylamino acids have been developed as useful reagents for the preparation of optically pure α-aminoalkylaryl ketones.Protection of the amino group as either the ethoxycarbonyl or benzenesulfonyl derivative allows alanine to serve as an effective educt for the chirally specific synthesis of a variety of structures containing the phenylethylamine backbone.Benzene undergoes Friedel-Crafts acylation with the N-acylalanine acid chloride.Catalyst complexation with oxagenated aromatics, however, prohibits acylation of aryl ethers.An arylmetallo reaction scheme overcomes this problem and also affords regiospecificity not attainable in conventional acylations.As examples, optically pure ephedrines and amphetamines were directly synthesized without recourse to resolution since the chirality of the amino acid educt was entirely conserved throughout the process.
- Buckley, Thomas F.,Rapoport, Henry
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p. 6157 - 6163
(2007/10/02)
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