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1.
J Org Chem ; 87(4): 2120-2128, 2022 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-34582192

RESUMO

Two scalable and efficient synthetic routes for the synthesis of a T-type calcium channel antagonist MK-8998 were developed from a simple pyridine building block. The key step to set the stereochemistry relied on either chiral rhodium catalyst-mediated asymmetric hydrogenation of an enamide or transamination of an arylketone that provided the corresponding product in high enantioselectivity and high yield.


Assuntos
Bloqueadores dos Canais de Cálcio , Ródio , Aminação , Bloqueadores dos Canais de Cálcio/farmacologia , Catálise , Hidrogenação , Estereoisomerismo
2.
J Org Chem ; 85(7): 4807-4812, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32167764

RESUMO

The therapeutic application of nitric oxide, an endogenous cellular signaling molecule, has been limited due to the difficulty of developing stable pro-drugs with slow kinetics of NO release. Diazeniumdiolates are valuable NO donors; however, synthetic challenges have hampered their use. O2-alkylation or arylation of diazeniumdiolates form stable pro-drugs which have found application in hypertension, cancer, and as antimicrobial agents. The synthesis of sodium diazeniumdiolates has proven to be challenging due to hazardous reaction conditions (high N2O concentrations, and flammable solvents), which can lead to detonation and suffered from limited scope. We have previously disclosed that synthesis of calcium diazeniumdiolate salts are a safer and more scalable alternative. Herein, we report the expanded scope of calcium diazeniumdiolates from benzylic amines, amides, and sterically bulky amines hitherto inaccessible and a comparison of their reactivity in comparison to sodium diazeniumdiolate.

3.
J Org Chem ; 84(8): 4780-4795, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30475616

RESUMO

An asymmetric synthesis of HCV NS5B nucleoside polymerase inhibitor (1) is described. This novel route features several remarkably diastereoselective and high-yielding transformations, including construction of the all-carbon quaternary stereogenic center at C-2 via a thermodynamic aldol reaction. A subsequent glycosylation reaction with activated uracil via C-1 phosphate and installation of the cyclic phosphate group using an achiral phosphorus(III) reagent followed by oxidation provides 1.


Assuntos
Antivirais/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Humanos , Estrutura Molecular , Estereoisomerismo , Proteínas não Estruturais Virais/metabolismo
4.
J Org Chem ; 77(7): 3297-310, 2012 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-22423625

RESUMO

An efficient, new, and scalable semisynthesis of glucan synthase inhibitors 1 and 2 from the fermentation product enfumafungin 3 is described. The highlights of the synthesis include a high-yielding ether bond-forming reaction between a bulky sulfamidate 17 and alcohol 4 and a remarkably chemoselective, improved palladium(II)-mediated Corey-Yu allylic oxidation at the highly congested C-12 position of the enfumafungin core. Multi-hundred gram quantities of the target drug candidates 1 and 2 were prepared, in 12 linear steps with 25% isolated yield and 13 linear steps with 22% isolated yield, respectively.


Assuntos
Álcoois/química , Antifúngicos/síntese química , Antifúngicos/farmacologia , Crisenos/química , Crisenos/síntese química , Equinocandinas/química , Glucosiltransferases/antagonistas & inibidores , Glicosídeos/química , Paládio/química , Triterpenos/química , Catálise , Estrutura Molecular , Estereoisomerismo
5.
Org Lett ; 24(17): 3254-3258, 2022 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-35467884

RESUMO

A highly efficient enantioselective synthesis for the potent G-protein-coupled receptor 40 agonist MK-2305 was developed. The key tetrasubstituted olefin was prepared via a stereoselective Mukaiyama aldol reaction/elimination sequence. The highly enantioselective rhodium-catalyzed transfer hydrogenation of the tetrasubstituted olefin afforded the target compound MK-2305 in excellent optical and chemical purity. The key asymmetric transfer hydrogenation proceeds in excellent yields and enantioselectivities for a variety of substrates. The superior reactivity of the tethered catalysts was revealed by NMR studies.


Assuntos
Ródio , Alcenos/química , Benzopiranos , Catálise , Hidrogenação , Estrutura Molecular , Ródio/química , Estereoisomerismo , Tiazolidinedionas
6.
Org Lett ; 21(11): 4072-4076, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31117703

RESUMO

Determining the configuration of proton-deficient molecules is challenging using conventional NMR methods including nuclear Overhauser effect (NOE) and the proton-dependent J-based configuration analysis (JBCA). The problem is exacerbated when only one stereoisomer is available. Alternative methods based on the utilization of 13C NMR chemical shifts, 13C-13C homonuclear couplings measured at natural abundance, and residual chemical shift anisotropy measurements in conjunction with density functional theory calculations are illustrated with a proton-deficient model compound.

7.
Org Lett ; 21(11): 4210-4214, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31117712

RESUMO

Synthetic diazeniumdiolate (DAZD)-based nitric oxide is utilized to modulate the nitric oxide (NO) concentration in cellular environments and to control physiological processes, yet chemists are still struggling to find efficient and scalable methodologies that will enable them to access sufficient quantities of the high-energy diazeniumdiolate intermediates for biological studies. Now, a general, scalable, safer, and high-yielding new methodology adaptable to the large-scale synthesis of DAZDs has been developed.

8.
Org Lett ; 19(21): 5880-5883, 2017 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-29052413

RESUMO

A practical and asymmetric synthesis of a functionalized trans-cyclopropoxy building block for the preparation of the HCV NS3/4a protease inhibitor grazoprevir is reported. Intramolecular SN2 displacement-ring closure, followed by a Baeyer-Villiger oxidation, yields the desired trans-cyclopropanol with full control of diastereoselectivity. A terminal alkyne is then effectively installed using LiNH(CH2)2NEt2. Starting from (S)-epichlorohydrin, the cyclopropoxy building block is prepared in 51% overall yield with >99.8% optical purity without isolation of any intermediates.

9.
Top Curr Chem (Cham) ; 374(6): 77, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27807768

RESUMO

This article reviews antiviral therapies that have been approved for human use during the last decade, with a focus on the process chemistry that enabled access to these important drugs. In particular, process chemistry highlights from the practical syntheses of the HCV drugs sofosbuvir (Gilead), grazoprevir (Merck), and elbasvir (Merck), the HIV therapy darunavir (Tibotec) and the influenza treatment peramivir (BioCryst) are presented.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Infecções por HIV/tratamento farmacológico , Hepatite C/tratamento farmacológico , Influenza Humana/tratamento farmacológico , Animais , Antivirais/química , Descoberta de Drogas , HIV/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Humanos
10.
Org Lett ; 18(22): 5888-5891, 2016 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-27802043

RESUMO

A scalable and efficient synthesis of the GPR40 agonist MK-8666 was developed from a simple pyridine building block. The key step to set the stereochemistry at two centers relied on an enzymatic dynamic kinetic reduction of an unactivated ketone. Directed evolution was leveraged to generate an optimized ketoreductase that provided the desired trans alcohol in >30:1 dr and >99% ee. Further, it was demonstrated that all four diastereomers of this hydroxy-ester could be prepared in high yield and selectivity. Subsequently, a challenging intramolecular displacement was carried out to form the cyclopropane ring system with perfect control of endo/exo selectivity. The endgame coupling strategy relied on a Pd-catalyzed C-O coupling to join the headpiece chloropyridine with the benzylic alcohol tailpiece.

11.
Org Lett ; 17(14): 3616-9, 2015 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-26125106

RESUMO

A concise and atom-economical Suzuki-Miyaura coupling of trialkyl- and triarylboranes with aryl halides is described. This new protocol represents the first general, practical method that efficiently utilizes peralkyl and peraryl groups of the unactivated trialkyl- and triarylboranes for the Suzuki-Miyaura coupling reaction.


Assuntos
Boranos/química , Halogênios/química , Hidrocarbonetos Halogenados/química , Catálise , Estrutura Molecular
12.
Org Lett ; 5(22): 4175-7, 2003 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-14572278

RESUMO

[reaction: see text]. A practical synthesis of sultams was developed via intramolecular sulfonamide dianion alkylation. This method has been applied toward the synthesis of chiral sultams, which are synthetically valuable as chiral auxiliaries.

13.
Org Lett ; 6(6): 929-31, 2004 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-15012067

RESUMO

[reaction: see text] A new general method for the synthesis of medicinally important diversely functionalized imidazoles from N-acylated alpha-aminonitriles has been developed. N-Acylated alpha-aminonitriles were reacted with triphenylphosphine and carbon tetrahalide to afford 2,4-disubstituted 5-halo-1H-imidazoles in good yield. This new methodology was applied for the synthesis of 2-butyl-4-chloro-5-hydroxymethylimidazole. These halo-imidazoles can be directly converted to 2,4,5-trisubstituted imidazoles through palladium-catalyzed coupling reactions.

14.
Angew Chem Int Ed Engl ; 40(11): 2145-2149, 2001 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29712189

RESUMO

A multitude of natural product like molecules such as 2 and 3 can be readily obtained from hydroxyketoamide 1. The versatile 1 is derived, via the intermediate o-azaquinone 4, from the Dess-Martin periodinane oxidation of the corresponding anilide.

15.
Angew Chem Int Ed Engl ; 38(4): 549-552, 1999 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-29711784

RESUMO

A seven-step cascade reaction-in which selective mesylation, epoxide formation, epoxide lysis, cyclization, reiterative oxidation, and nitrogen-oxygen exchange occur sequentially-facilitates the construction of the maleic anhydride moiety of CP molecules 1 and 2 (>93% yield per step). Unstable intermediates of this reaction sequence were detected, providing evidence for the proposed mechanism and resulting in the discovery of a new chemical entity.

17.
Org Lett ; 16(22): 5890-3, 2014 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-25365229

RESUMO

An asymmetric synthesis of dual orexin receptor antagonist MK-6096 (1) is described. Key steps for the trans-2,5-disubstituted piperidinyl ether fragment include a biocatalytic transamination, a trans-selective Mukaiyama aldol, and a regioselective pyridyl SNAr process. The pyrimidyl benzoic acid was synthesized via a Negishi coupling and a nitrile hydrolysis. Coupling of the two fragments via a catalytic T3P-mediated amidation completed the synthesis. Unusual behaviors in the hydrolysis of pyrimidyl benzonitrile and the amide coupling of the pyrimidyl benzoic acid are also described.


Assuntos
Antagonistas dos Receptores de Orexina , Piperidinas/síntese química , Piperidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Pirimidinas/farmacologia , Catálise , Estrutura Molecular , Piperidinas/química
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