RESUMO
Herein, we describe a rhodium-catalyzed enantio- and diastereoselective Suzuki-Miyaura cross-coupling between racemic fused bicyclic allylic chlorides and boronic acids. The highly stereoselective transformation allows for the coupling of aryl, heteroaryl, and alkenyl boronic acids and gives access to functionalized bicyclic cyclopentenes, which can be converted into other five-membered-ring scaffolds with up to five contiguous stereocenters. Preliminary mechanistic studies suggest that these reactions occur with overall retention of the relative stereochemistry and are enantioconvergent for pseudo-symmetric allylic chloride starting materials. In addition, a bicyclic allylic chloride starting material without pseudo-symmetry undergoes a highly enantioselective regiodivergent reaction.
RESUMO
A new asymmetric conjugate addition method was developed for ß-substituted cyclopentenones to form quaternary centres using alkylzirconocene nucleophiles giving up to 97% yield and 92% ee. Key to the reaction's success was the design of suitable phosphoramidite ligands which was aided by a linear quantitative structure-selectivity relationship (QSSR). QSSR models were created from the ligand screening data (a total of 36 ligands) which revealed important electronic and steric requirements and led to the synthesis of more enantioselective ligands. DFT calculations of competing transition structures enable the interpretation of the electronic and steric terms present in the QSSR models.
RESUMO
A Hit-to-Lead optimisation programme was carried out on the high throughput screening hit, the triazolethiol 1, resulting in the discovery of the potent, orally bioavailable triazolethiol CXCR2 receptor antagonist 45.
Assuntos
Receptores de Interleucina-8B/antagonistas & inibidores , Triazóis/farmacologia , Administração Oral , Animais , Quimiocinas/antagonistas & inibidores , Quimiocinas/metabolismo , Quimiocinas/farmacologia , Técnicas de Química Combinatória , Bases de Dados Factuais , Humanos , Estrutura Molecular , Ratos , Receptores de Interleucina-8B/química , Receptores de Interleucina-8B/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/metabolismoRESUMO
A Hit-to-Lead optimisation programme was carried out on the adamantane high throughput screening hit 1 resulting in the discovery of a number of potent P2X(7) antagonists.