RESUMO
In this Letter, we describe the first total synthesis of cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata, with anticholinergic activity as well as an unnatural analogue. The streamlined synthesis proceeds in 9 steps, 7 steps longest linear sequence, in 25.2% overall yield, and features novel methodology to construct the pyrrolizidine core. Biological evaluation of cremastrine and the unnatural analogue indicated that both are pan-mAChR functional antagonists.
RESUMO
Closing in on azacines: We have developed a new six step approach for the rapid and enantioselective synthesis of indolizidine, pyrrolo[1,2-a]azepine, and pyrrolo[1,2-a]azocine azabicyclic systems and their respective lactam congeners, which are found in a host of natural products as well as pharmaceutical preparations. This protocol enables a concise enantioselective total synthesis of (+)-grandisineâ D in 16.4 % overall yield from commercial materials (see scheme).
Assuntos
Alcaloides/síntese química , Compostos Azabicíclicos/síntese química , Produtos Biológicos/síntese química , Indolizinas/síntese química , Alcaloides/química , Compostos Azabicíclicos/química , Produtos Biológicos/química , Ciclização , Indolizinas/química , Lactamas Macrocíclicas/síntese química , Lactamas Macrocíclicas/química , Estrutura Molecular , EstereoisomerismoRESUMO
The marine invertebrate-derived meridianin A, the originally proposed structure for psammopemmin A, and several related 3-pyrimidylindole analogs were synthesized and subsequently investigated for central nervous system, antimalarial, and cytotoxic activity. A Suzuki coupling of an indoleborate ester to the pyrimidine electrophile was utilized to form the natural product and derivatives thereof. The 3-pyrimidineindoles were found to prevent radioligand binding to several CNS receptors and transporters, most notably, serotonin receptors (<0.2 µM K(i) for 5HT(2B)). Two compounds also inhibited the human malaria parasite Plasmodium falciparum (IC(50) <50 µM). Only the natural product was cytotoxic toward A549 cells (IC(50)=15 µM).