RESUMO
A strategy to prepare compounds with multiple chirality axes, which has led to a concise total synthesis of compound 1A with complete stereocontrol, is reported.
RESUMO
The development of a short and efficient synthesis of a complex 6-azaindole, BMS-663068, is described. Construction of the 6-azaindole core is quickly accomplished starting from a simple pyrrole, via a regioselective Friedel-Crafts acylation, Pictet-Spengler cyclization, and a radical-mediated aromatization. The synthesis leverages an unusual heterocyclic N-oxide α-bromination to functionalize a critical C-H bond, enabling a highly regioselective copper-mediated Ullmann-Goldberg-Buchwald coupling to install a challenging triazole substituent. This strategy resulted in an efficient 11 step linear synthesis of this complex clinical candidate.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Compostos Aza/síntese química , Compostos Aza/farmacologia , Indóis/síntese química , Indóis/farmacologia , Organofosfatos/síntese química , Organofosfatos/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Ligação Viral/efeitos dos fármacos , Compostos Aza/química , Óxidos N-Cíclicos/química , HIV-1/efeitos dos fármacos , Halogenação , Humanos , Indóis/química , Estrutura Molecular , Organofosfatos/química , Piperazinas/química , Pró-Fármacos , Pirróis/química , EstereoisomerismoRESUMO
Kinetic and computational studies on the amidation of esters with mixtures of formamide and sodium methoxide are described. Rate studies are consistent with a fast deprotonation of formamide followed by two reversible acyl transfers affected by solvent participation. MP2 calculations suggest that the first acyl transfer between the ester and sodium formamide is rate-determining. The transition structures leading to the formation and collapse of the first tetrahedral intermediate are calculated to be isoenergetic.
