- A scalable and expedient method of preparing diastereomerically and enantiomerically enriched pseudonorephedrine from norephedrine
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Norephedrine has been efficiently converted into the corresponding diastereomer pseudonorephedrine using a three step, one-pot reaction. The three step process involves treatment of norephedrine with di-tert-butyl dicarbonate (Boc2O); cyclization by way of mesylate formation at the alcohol; and lithium hydroxide mediated hydrolysis of the oxazolidinone. The diastereomeric purity was determined by HPLC and the enantiomeric purity was determined by optical activity measurements and chiral stationary phase HPLC analysis of the pseudonorephedrine oxazolidinone derivatives.
- Groeper, Jonathan A.,Hitchcock, Shawn R.,Ferrence, Gregory M.
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- 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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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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- Asymmetric Transfer Hydrogenation: Dynamic Kinetic Resolution of α-Amino Ketones
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A series of α-amino ketones were reduced using asymmetric transfer hydrogenation (ATH) through a dynamic kinetic resolution (DKR). The protecting group was matched to the reducing agent, and following optimization, a series of substrates were investigated, giving products in high diastereoselectivity, over 99% ee in several cases and full conversion. The methodology was applied to the enantioselective synthesis of an MDM2-p53 inhibitor precursor.
- Gediya, Shweta K.,Clarkson, Guy J.,Wills, Martin
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p. 11309 - 11330
(2020/10/12)
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- FACTOR XIIa INHIBITORS
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The present invention provides a compound of Formula (I) and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing thromboses, embolisms, hypercoagulability or fibrotic changes. The compounds are selective Factor XIIa inhibitors.
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Page/Page column 30-31
(2018/06/06)
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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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- Discovery of a PCAF Bromodomain Chemical Probe
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The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)-(?)-norephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co-crystal structure of L-45 with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L-45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell-permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use.
- Moustakim, Moses,Clark, Peter G. K.,Trulli, Laura,Fuentes de Arriba, Angel L.,Ehebauer, Matthias T.,Chaikuad, Apirat,Murphy, Emma J.,Mendez-Johnson, Jacqui,Daniels, Danette,Hou, Chun-Feng D.,Lin, Yu-Hui,Walker, John R.,Hui, Raymond,Yang, Hongbing,Dorrell, Lucy,Rogers, Catherine M.,Monteiro, Octovia P.,Fedorov, Oleg,Huber, Kilian V. M.,Knapp, Stefan,Heer, Jag,Dixon, Darren J.,Brennan, Paul E.
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supporting information
p. 827 - 831
(2017/01/14)
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- Synthesis of chiral aminophosphines from chiral aminoalcohols via cyclic sulfamidates
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(Chemical Equation Presented) Protic aminophosphines with multiple chiral centers were synthesized in good yields and high purity by the nucleophilic ring-opening of N-protected cyclic sulfamidates with metal phosphides, followed by hydrolysis and deprote
- Guo, Rongwei,Lu, Shuiming,Chen, Xuanhua,Tsang, Chi-Wing,Jia, Wenli,Sui-Seng, Christine,Amoroso, Dino,Abdur-Rashid, Kamaluddin
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supporting information; experimental part
p. 937 - 940
(2010/05/02)
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- METHOD FOR THE PREPARATION OF AMINOPHOSPHINE LIGANDS AND THEIR USE IN METAL CATALYSTS
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The present application is directed to i) a two-step method for synthesizing phosphme-ammophosphme (P,N,P) ligands, ii) the use of such ligands in the preparation of metal complexes as hydrogenation catalysts, and iii) ammophosphme (P,N) and phosphme-ammo
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Page/Page column 36
(2009/01/24)
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- METHOD OF PREPARING PSEUDONOREPHEDRINE
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A method of making high diastereoselective and enantiomerically pure pseudonorephedrine and the hitherto unknown compound (1R,2R) pseudonorephedrine.
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Page/Page column 4
(2008/06/13)
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- A Lewis acid-mediated protocol for the protection of aryl amines as their Boc-derivatives
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A new protocol of protection of poorly reactive aryl amines and functionalized amines with Boc2O in the presence of Zn(ClO 4)2·6H2O as the catalyst is reported. The catalytic action of Zn(ClO4)2·6H2O is specific for the activation of the pyrocarbonates, thus acid sensitive functionalities and stereochemical configurations of the starting materials remain unaltered in the protection process.
- Bartoli, Giuseppe,Bosco, Marcella,Locatelli, Manuela,Marcantoni, Enrico,Massaccesi, Massimo,Melchiorre, Paolo,Sambri, Letizia
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p. 1794 - 1798
(2007/10/03)
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- Efficient synthesis of enantiomerically pure 2-acylaziridines: Facile syntheses of N-Boc-safingol, N-Boc-D-erythro-sphinganine, and N-Boc-spisulosine from a common intermediate
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Various enantiomerically pure 2-acylaziridines were prepared efficiently from the corresponding aziridine-2-carboxylate via Weinreb's amide and the subsequent treatment of organometallic compounds. The carbonyl group of those 2-acylaziridines was stereose
- Yun, Jung Min,Sim, Tae Bo,Hahm, Heung Sik,Lee, Won Koo,Ha, Hyun-Joon
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p. 7675 - 7680
(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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- Heterocyclizations of N-Boc derivatives of β-amino alcohols and thio analogs: an unusual case of the Thorpe-Ingold effect
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Enantiopure oxazolidin-2-ones were synthesized from chiral N-Boc β-aminoalcohols which underwent a cyclization upon treatment with tosyl chloride.This reaction was strongly accelerated in the case of carbamates derived from N-methylated amines.A similar heterocyclization was observed with dithiocarbamates, ie sulfur analogs of carbamates.The rate enhancement due to the nitrogen substitution was studied by AM1 calculations. - Keywords: carbamate; dithiocarbamate; oxazolidinone; thiazolidinone; AM1 calculations
- Agami, Claude,Couty, Francois,Hamon, Louis,Venier, Olivier
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p. 808 - 814
(2007/10/02)
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- Chiral oxazolidinones from N-Boc derivatives of β-amino alcohols. Effect of a N-methyl substituent on reactivity and stereoselectivity
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Treatment of N-tert-butoxycarbonyl derivatives of homochiral β-amino alcohols with p-toluenesulfonyl chloride affords 2-axazolidinones. These heterocycles were produced by intramolecular nucleophilic attack of the carbamate moiety in an intermediate tosylate. The presence of a N-methyl substituent enhanced the cyclization rate and this effect was studied by AMI calculations.
- Agami, Claude,Couty, Francois,Hamon, Louis,Venier, Olivier
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p. 4509 - 4512
(2007/10/02)
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- MILD RECOVERY OF β-AMINO ALCOHOLS FROM THE CORRESPONDING 2-OXAZOLIDINONES
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A mild ring cleavage of N-tert-butoxycarbonyl-2-oxazolidinones (N-BOC-2-oxazolidinones) 5a-5d and the recovery of β-amino alcohols 7a-7d from the corresponding N-BOC-derivatives are reported.
- Jommi, Giancarlo,Ripa, Alberto,Ripa, Giorgio,Sisti, Massimo
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