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1.
Beilstein J Org Chem ; 13: 384-392, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28382176

RESUMO

Dienoic acids and pentadienyl alcohols are coupled in a decarboxylative and dehydrative manner at ambient temperature using Pd(0) catalysis to generate 1,3,6,8-tetraenes. Contrary to related decarboxylative coupling reactions, an anion-stabilizing group is not required adjacent to the carboxyl group. Of mechanistic importance, it appears that both the diene of the acid and the diene of the alcohol are required for this reaction. To further understand this reaction, substitutions at every unique position of both coupling partners was examined and two potential mechanisms are presented.

2.
Bioorg Med Chem Lett ; 26(7): 1827-1830, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26916440

RESUMO

A series of 1,3,4-oxadiazol-2-ones was synthesized and tested for activity as antagonists at GPR55 in cellular beta-arrestin redistribution assays. The synthesis was designed to be modular in nature so that a sufficient number of analogues could be rapidly accessed to explore initial structure-activity relationships. The design of analogues was guided by the docking of potential compounds into a model of the inactive form of GPR55. The results of the assays were used to learn more about the binding pocket of GPR55. With this oxadiazolone scaffold, it was determined that modification of the aryl group adjacent to the oxadiazolone ring was often detrimental and that the distal cyclopropane was beneficial for activity. These results will guide further exploration of this receptor.


Assuntos
Desenho de Fármacos , Oxidiazóis/química , Oxidiazóis/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Arrestinas/metabolismo , Células CHO , Cricetulus , Humanos , Simulação de Acoplamento Molecular , Oxidiazóis/síntese química , Piperidinas/síntese química , Receptores de Canabinoides , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-Atividade , beta-Arrestinas
3.
Beilstein J Org Chem ; 12: 702-15, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27340462

RESUMO

Piperazine ranks within the top three most utilized N-heterocyclic moieties in FDA-approved small-molecule pharmaceuticals. Herein we summarize the current synthetic methods available to perform C-H functionalization on piperazines in order to lend structural diversity to this privileged drug scaffold. Multiple approaches such as those involving α-lithiation trapping, transition-metal-catalyzed α-C-H functionalizations, and photoredox catalysis are discussed. We also highlight the difficulties experienced when successful methods for α-C-H functionalization of acyclic amines and saturated mono-nitrogen heterocyclic compounds (such as piperidines and pyrrolidines) were applied to piperazine substrates.

4.
Org Lett ; 17(24): 6074-7, 2015 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-26635251

RESUMO

Novel and general copper-catalyzed cyclopropanol ring opening cross-coupling reactions with difluoroalkyl bromides, perfluoroalkyl iodides, monofluoroalkyl bromides, and 2-bromo-2-alkylesters to synthesize various ß-(fluoro)alkylated ketones are reported. The reactions feature mild conditions and excellent functional group compatibility and can be scaled up to gram scale. Preliminary mechanistic studies suggest the involvement of radical intermediates. The difluoroalkyl-alkyl cross-coupling products can also be readily converted to more valuable and diverse gem-difluoro-containing compounds by taking advantage of the carbonyl group resulting from cyclopropanol ring opening.


Assuntos
Cobre/química , Éteres Cíclicos/química , Hidrocarbonetos Bromados/química , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/síntese química , Iodetos/química , Catálise , Estrutura Molecular
5.
Org Lett ; 15(3): 586-9, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-23327495

RESUMO

A step-economical synthesis of clinprost is reported that concludes with 3 different transition metal-catalyzed reactions: Pd-catalyzed decarboxylation with allylic rearrangement, Rh-catalyzed diene-ene [2+2+1] reaction, and Ru-catalyzed cross-metathesis reaction. The complexity bestowed to the molecule from these reactions converts a readily accessible ester to clinprost without using protecting groups in only 9 total steps.

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