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1.
Org Lett ; 21(7): 2060-2063, 2019 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-30855967

RESUMEN

The facile synthesis of functionalized azetidines has been an ongoing challenge. Here, we report a general method to directly alkylate 1-azabicyclo[1.1.0]butane (ABB) with organometal reagents in the presence of Cu(OTf)2 to rapidly prepare bis-functionalized azetidines. This method allows for the preparation of azetidines bearing alkyl, allyl, vinyl, and benzyl groups. This catalyst system was extended to aziridines and spirocycles. Several building blocks and drug-like compounds were prepared in rapid fashion and in good yield.

2.
J Am Chem Soc ; 139(8): 3209-3226, 2017 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-28140573

RESUMEN

Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their lead compounds. Too often, however, the difficulty of installing these fragments surpasses the challenges posed even by the construction of the parent drug scaffold. This full account describes the development and application of a general strategy where spring-loaded, strained C-C and C-N bonds react with amines to allow for the "any-stage" installation of small, strained ring systems. In addition to the functionalization of small building blocks and late-stage intermediates, the methodology has been applied to bioconjugation and peptide labeling. For the first time, the stereospecific strain-release "cyclopentylation" of amines, alcohols, thiols, carboxylic acids, and other heteroatoms is introduced. This report describes the development, synthesis, scope of reaction, bioconjugation, and synthetic comparisons of four new chiral "cyclopentylation" reagents.


Asunto(s)
Alcoholes/química , Aminas/química , Ácidos Carboxílicos/química , Compuestos de Sulfhidrilo/química , Alcoholes/síntesis química , Aminas/síntesis química , Ácidos Carboxílicos/síntesis química , Estructura Molecular , Estereoisomerismo , Compuestos de Sulfhidrilo/síntesis química
3.
J Am Chem Soc ; 138(7): 2174-7, 2016 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-26835704

RESUMEN

A new transformation is presented that enables chemists to couple simple alkyl carboxylic acids with aryl zinc reagents under Ni-catalysis. The success of this reaction hinges on the unique use of redox-active esters that allow one to employ such derivatives as alkyl halides surrogates. The chemistry exhibits broad substrate scope and features a high degree of practicality. The simple procedure and extremely inexpensive nature of both the substrates and pre-catalyst (NiCl2·6H2O, ca. $9.5/mol) bode well for the immediate widespread adoption of this method.


Asunto(s)
Ácidos Carboxílicos/química , Ésteres/química , Níquel/química , Compuestos Organometálicos/química , Catálisis , Ésteres/síntesis química , Estructura Molecular , Oxidación-Reducción
4.
Science ; 351(6270): 241-6, 2016 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-26816372

RESUMEN

To optimize drug candidates, modern medicinal chemists are increasingly turning to an unconventional structural motif: small, strained ring systems. However, the difficulty of introducing substituents such as bicyclo[1.1.1]pentanes, azetidines, or cyclobutanes often outweighs the challenge of synthesizing the parent scaffold itself. Thus, there is an urgent need for general methods to rapidly and directly append such groups onto core scaffolds. Here we report a general strategy to harness the embedded potential energy of effectively spring-loaded C-C and C-N bonds with the most oft-encountered nucleophiles in pharmaceutical chemistry, amines. Strain-release amination can diversify a range of substrates with a multitude of desirable bioisosteres at both the early and late stages of a synthesis. The technique has also been applied to peptide labeling and bioconjugation.


Asunto(s)
Técnicas de Química Sintética , Péptidos/síntesis química , Preparaciones Farmacéuticas/síntesis química , Aminación , Química Farmacéutica
5.
Angew Chem Int Ed Engl ; 53(37): 9851-5, 2014 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-25088979

RESUMEN

A simple method to convert readily available carboxylic acids into sulfinate salts by employing an interrupted Barton decarboxylation reaction is reported. A medicinally oriented panel of ten new sulfinate reagents was created using this method, including a key trifluoromethylcyclopropanation reagent, TFCS-Na. The reactivity of six of these salts towards C-H functionalization was field-tested using several different classes of heterocycles.


Asunto(s)
Ácidos Sulfínicos/química , Ácidos Sulfínicos/síntesis química , Ácidos Heterocíclicos , Catálisis , Modelos Moleculares , Estructura Molecular
8.
J Am Chem Soc ; 133(10): 3292-5, 2011 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-21341741

RESUMEN

A direct functionalization of a variety of quinones with several boronic acids has been developed. This scalable reaction proceeds readily at room temperature in an open flask using inexpensive reagents: catalytic silver(I) nitrate in the presence of a persulfate co-oxidant. The scope with respect to quinones is broad, with a variety of alkyl- and arylboronic acids undergoing efficient cross-coupling. The mechanism is presumed to proceed through a nucleophilic radical addition to the quinone with in situ reoxidation of the resulting dihydroquinone. This method has been applied to complex substrates, including a steroid derivative and a farnesyl natural product.


Asunto(s)
Ácidos Borónicos/química , Quinonas/química , Productos Biológicos/síntesis química , Catálisis
9.
J Am Chem Soc ; 132(38): 13194-6, 2010 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-20812741

RESUMEN

A direct arylation of a variety of electron-deficient heterocycles with arylboronic acids has been developed. This new reaction proceeds readily at room temperature using inexpensive reagents: catalytic silver(I) nitrate in the presence of persulfate co-oxidant. The scope with respect to heterocycle and boronic acid coupling partner is broad, and sensitive functional groups are tolerated. This method allows for rapid access to a variety of arylated heterocycles that would be more difficult to access with traditional methods.


Asunto(s)
Ácidos Borónicos/química , Carbono/química , Compuestos Heterocíclicos/química , Hidrógeno/química
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