Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros

Base de dados
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Bioorg Med Chem Lett ; 24(3): 963-8, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24412067

RESUMO

As part of an effort to identify agonists of TRPV1, a peripheral sensory nerve ion channel, high throughput screening of the NIH Small Molecule Repository (SMR) collection identified MLS002174161, a pentacyclic benzodiazepine. A synthesis effort was initiated that ultimately afforded racemic seco analogs 12 of the SMR compound via a silver mediated intramolecular [3+2] cycloaddition of an azo-methine ylide generated from α-iminoamides 11. The cycloaddition set four contiguous stereocenters and, in some cases, also spontaneously afforded imides 13 from 12. The synthesis of compounds 12, the features that facilitated the conversion of 12-13, and their partial agonist activity against TRPV1 are discussed.


Assuntos
Amidas/química , Compostos Azo/química , Benzodiazepinonas/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Iminas/química , Prata/química , Canais de Cátion TRPV/agonistas , Capsaicina/química , Ciclização , Reação de Cicloadição
2.
J Org Chem ; 78(8): 3720-30, 2013 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-23510238

RESUMO

The discovery and application of a new branching pathway synthesis strategy that rapidly produces skeletally diverse scaffolds is described. Two different scaffold types, one a bicyclic iodo-vinylidene tertiary amine/tertiary alcohol and the other, a spirocyclic 3-furanone, are each obtained using a two-step sequence featuring a common first step. Both scaffold types lead to intermediates that can be orthogonally diversified using the same final components. One of the scaffold types was obtained in sufficiently high yield that it was immediately used to produce a 97-compound library.


Assuntos
Alcinos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Propanóis/química , Compostos de Espiro/química , Estrutura Molecular , Estereoisomerismo
3.
J Org Chem ; 78(13): 6529-39, 2013 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-23758452

RESUMO

This report describes the preparation of a series of 17 novel racemic spirocyclic scaffolds that are intended for the creation of compound libraries by parallel synthesis for biological screening. Each scaffold features two points of orthogonal diversification. The scaffolds are related to each other in four ways: (1) through stepwise changes in the size of the nitrogen-bearing ring; (2) through the oxidation state of the carbon-centered point of diversification; (3) through the relative stereochemical orientation of the two diversification sites in those members that are stereogenic; and (4) through the provision of both saturated and unsaturated versions of the furan ring in the scaffold series derived from 3-piperidone. The scaffolds provide incremental changes in the relative orientation of the diversity components that would be introduced onto them. The scaffolds feature high sp(3) carbon content which is essential for the three-dimensional exploration of chemical space. This characteristic is particularly evident in those members of this family that bear two stereocenters, i.e., the two series derived from 3-piperidone and 3-pyrrolidinone. In the series derived from 3-piperidone we were able to "split the difference" between the two diastereomers by preparation of their corresponding unsaturated version.


Assuntos
Compostos Heterocíclicos/síntese química , Compostos de Espiro/síntese química , Compostos Heterocíclicos/química , Estrutura Molecular , Compostos de Espiro/química
4.
Org Lett ; 9(2): 347-9, 2007 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-17217301

RESUMO

This letter extends the scope of the rhodium(I)-catalyzed allenic Alder-ene carbocyclization reaction to the preparation of delta- and epsilon-lactams from amides. A variety of allenic propiolamides were cycloisomerized to give a number of unsaturated delta-lactams. In addition, allenic propargylamides give good yields of the corresponding epsilon-lactams. Formation of lactams possessing these ring sizes has rarely been accomplished via transition-metal-catalyzed carbon-carbon bond forming strategies. Thus, this approach provides an alternative strategy for synthesizing these substructures. [reaction: see text].


Assuntos
Alcadienos/química , Alcadienos/síntese química , Alcenos/química , Alcinos/química , Lactamas/síntese química , Ródio/química , Catálise , Ciclização , Lactamas/química , Estrutura Molecular , Estereoisomerismo
6.
ACS Comb Sci ; 13(2): 166-74, 2011 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-21332123

RESUMO

A diverging diversity-oriented synthesis (DOS) strategy using an allene-containing tryptophan as a key starting material was investigated. An allene-yne substituted derivative of tryptophan 12 gave indolylmethylazabicyclooctadiene 17 when subjected to a microwave-assisted allenic [2 + 2] cycloaddition reaction. This same tryptophan-derived precursor afforded an indolylmethyldihydrocyclopentapyridinone 14 when subjected to a rhodium(I)-catalyzed cyclocarbonylation reaction and an indolylmethylpyrrolidinocyclopentenones 16 when reacted with molybdenum hexacarbonyl. Construction of allenic tetrahydro-ß-carboline scaffolds via a Pictet-Spengler reaction and subsequent silver(I)-catalyzed cycloisomerization afforded tetrahydroindolizinoindoles (21). Attachment of allene and alkyne groups to the tetrahydro-ß-carboline, followed by a microwave-assisted allenic [2 + 2] cycloaddition reaction, provided tetrahydrocyclobutaindoloquinolizinones 24 and the tetrahydrocyclopentenone indolizinoindolone 26 when reacted with molybdenum hexacarbonyl. These six scaffolds were used as templates for the construction of a virtual library of 11 748 compounds employing 44 indoles, 12 aldehydes, and 51 alkynes. Diversity analyses using a combination of cell-based chemistry space computations using BCUT (Burden (B) CAS (C) Pearlman at the University of Texas (UT)) metrics and Tanimoto coefficient (Tc) similarity calculations using two-dimensional (2D) fingerprints showed that the compounds in the virtual library occupied new chemical space when compared to the 327,000 compounds in the molecular libraries small molecule repository (MLSMR). A subset of fifty-three compounds was identified from the virtual library using the DVS package of Sybyl 8.0; this subset represents the most diverse compounds within the chemical space defined by these compounds and will be synthesized and screened for biological activity.


Assuntos
Alcadienos/química , Desenho de Fármacos , Triptofano/química , Técnicas de Química Combinatória/métodos , Ciclização , Estrutura Molecular , Bibliotecas de Moléculas Pequenas
7.
ACS Comb Sci ; 13(5): 466-77, 2011 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-21528920

RESUMO

Parallel solution-phase synthesis of combinatorial libraries of dihydroindenoisoquinolines employing a sequential Cu(I)/Pd(0)-catalyzed multicomponent coupling and annulation protocol was realized. The scope and limitations of the protocol with respect to the substitution pattern in the aryl ring of the indene core, as well as the N-substituent have been defined, revealing that the methodology is compatible with a wide-range of aliphatic linear, branched, and ester functionalized N-substituents. Unexpectedly, the formation of regioisomers featuring a 1,2,3-contiguous substitution pattern in the aromatic ring of the indene core was observed. Three distinct combinatorial libraries with a total of 111 of members were synthesized, and 80 highly substituted dihydroindenoisoquinolines structurally related to known medicinal agents including some consisting of mixtures of two regioisomers were made available for biological activity testing.


Assuntos
Técnicas de Química Sintética , Cobre/química , Indenos/síntese química , Isoquinolinas/síntese química , Paládio/química , Bibliotecas de Moléculas Pequenas/síntese química , Catálise , Indenos/química , Isoquinolinas/química , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , Soluções , Estereoisomerismo
8.
ACS Comb Sci ; 13(5): 511-7, 2011 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-21866904

RESUMO

The construction of two libraries of triazole-containing isothiazolidine 1,1-dioxides is reported utilizing either a one-pot click/aza-Michael or click/OACC esterification protocol. One core dihydroisothiazole 1,1-dioxide scaffold was prepared rapidly on multigram scale via ring-closing metathesis (RCM) and was subjected to a one-pot multicomponent click/aza-Michael protocol with an array of amines and azides for the generation of a 180-member triazole-containing isothiazolidine 1,1-dioxide library. Alternatively, three daughter scaffolds were generated via the aza-Michael of three amino alcohols, followed by a one-pot, multicomponent click/esterification protocol utilizing a ring-opening metathesis polymerization (ROMP)-derived coupling reagent, oligomeric alkyl carbodiimide (OACC) to generate a 41-member library of triazole-containing isothiazole 1,1-dioxides.


Assuntos
Técnicas de Química Sintética , Óxidos S-Cíclicos/síntese química , Isoxazóis/síntese química , Sondas Moleculares/análise , Sondas Moleculares/síntese química , Bibliotecas de Moléculas Pequenas/síntese química , Triazóis/química , Óxidos S-Cíclicos/química , Isoxazóis/química , Sondas Moleculares/química , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , Estereoisomerismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA