RESUMO
The one-pot sequential coupling of benzylamines, boronic esters, and aryl iodides has been investigated. In the presence of an N-activator, the boronate complex formed from an ortho-lithiated benzylamine and a boronic ester undergoes stereospecific 1,2-metalate rearrangement/anti-SN 2' elimination to form a dearomatized tertiary boronic ester. Treatment with an aryl iodide under palladium catalysis leads to rearomatizing γ-selective allylic Suzuki-Miyaura cross-coupling to generate 1,1-diarylalkanes. When enantioenriched α-substituted benzylamines are employed, the corresponding 1,1-diarylalkanes are formed with high stereospecificity.
RESUMO
Coupling reactions between benzylamines and boronic esters have been investigated. ortho-Lithiated benzylamines react with boronic esters and a N-activator to afford ortho-substituted benzylic boronic esters with formal 1,1'-benzylidene insertion into the C-B bond. The reaction occurs by a SN2' elimination and 1,2-metalate rearrangement of the N-activated boronate complex to afford a dearomatized intermediate, which undergoes a Lewis-acid catalyzed 1,3-borotropic shift to afford the boronic ester products in high yield and with excellent enantiospecificity. The use of enantioenriched α-substituted benzylamines gave the corresponding secondary boronic esters with high ee.
RESUMO
The chemical synthesis and biological activity of novel functionalized imidazoquinoline derivatives (ImQ) to generate Toll-like receptor (TLR) 7/8 specific prodrugs are presented. In vivo activity of ImQs to induce inflammation was confirmed in zebrafish larvae. After covalent ligation to fully biodegradable polyphosphazenes (ImQ-polymer), the macromolecular prodrugs were designed to undergo intracellular pH-sensitive release of ImQs to induce inflammation through binding to endosomal TLR7/8 (danger signal). We showed ImQ dissociation from prodrugs at a pHâ 5 pointing towards endosomal prodrug degradability. ImQ-polymers strongly activated ovalbumin-specific Tâ cells in murine splenocytes as shown by increased proliferation and expression of the IL-2 receptor (CD25) on CD8+ Tâ cells accompanied by strong IFN-γ release. ImQ prodrugs presented here are suggested to form the basis of novel nanovaccines, for example, for intravenous or intratumoral cancer immunotherapeutic applications to trigger physiological antitumor immune responses.
Assuntos
Pró-Fármacos/química , Receptor 7 Toll-Like/antagonistas & inibidores , Receptor 8 Toll-Like/antagonistas & inibidores , Animais , Animais Geneticamente Modificados/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Concentração de Íons de Hidrogênio , Inflamação/etiologia , Interferon gama/metabolismo , Larva/efeitos dos fármacos , Larva/metabolismo , Camundongos , Microscopia Confocal , NF-kappa B/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/toxicidade , Quinolinas/síntese química , Quinolinas/química , Quinolinas/toxicidade , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/metabolismo , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismo , Peixe-Zebra/crescimento & desenvolvimentoRESUMO
Pyrazino compounds such as quinoxalines are 1,4-diazines with widespread occurrence in nature. Quinolin-8-amines are isomerically related and valuable scaffolds in organic synthesis. Herein, we present intramolecular main group metal Lewis acid catalyzed formal hydroamination as well as hydroarylation methodology using mono-propargylated aromatic ortho-diamines. The annulations can be conducted utilizing equal aerobic conditions with either stannic chloride or indium(iii) chloride and represent primary examples for main group metal catalyzed 6-exo-dig and 6-endo-dig, respectively, cyclizations in such settings. Both types of reactions can also be utilized in a one-pot manner starting from ortho-nitro N-propargyl anilines using stoichiometric amounts SnCl2·2H2O or In powder. Mechanistic considerations are presented regarding the substituent-depending regioselectivity.