Rhodium-catalyzed Synthesis Of Aryl Dictamnine Derivatives And The Cardiac Effects

Furo[2,3-b]pyridines are important heterocyclic scaffolds of natural products and pharmaceuticals（e.g.dictamnine,γ-fagarine,evolitrine,and skimmianine）.In this paper,the Rh₂（OAc）₄/IMes·HCl catalyzed chemoselective C–H arylation of furo[2,3-b]pyridine at the C2 position were reported for the first time.Fifteen 2-aryl furo[2,3-b]pyridine derivatives were synthesized in yields of 53-94%.Based on the experimental results and the relevant literature,we proposed a plausible mechanism.In the presence of NHC ligands,Rh₂（OAc）₄may react via either dimeric or monomeric species.Concerted metalation deprotonation was likely responsible for the C–H activation step,and the target product was obtained by oxidative addition and reductive elimination.The achievements of the rhodium-catalyzed C–H functionalization of furo[2,3-b]pyridines provided ideas for the structural modification of natural products and drugs containing furanpyridine skeletons.Dictamnine,a natural furoquinoline alkaloid isolated from the root of Dictamnus dasycarpus Turcz.,exhibits wide pharmacological properties.In addition to antimicrobial,antiviral,mutagenic,cytotoxic,and anticancer activities,it also exhibits cardiac effects at low doses.Aryl compounds play an important role in medicinal chemistry,material chemistry,and life sciences.Substituents in aryl compounds have a great impact on biological activity.Meanwhile,the structure-activity relationship of melatonin shows that arylation of the 2-position led to more potent than the parent compound melatonin.Based on these,the chemoselective C–H arylation of furo[2,3-b]pyridine was used to directly modify the natural product dictamnine.Twenty-three 2-aryl-dictamnine derivatives with different steric and electronic groups were synthesized in 74-95%yields,and were evaluated in vitro for their cardiac activity on isolated perfused frog hearts at different dose levels.The results showed that the force of contraction of the isolated frog hearts was enhanced after perfusing the most of 2-aryl-dictamnine derivatives,but the heart rate of the isolated frog hearts was not affected.The fluorinated analogues（17r-s and 17v）exhibited better cardiac effects than the parent compound dictamnine at a concentration of 160μg/m L,and the change rates of contractility were 49.38%,43.65%,and 62.15%,respectively.Preliminary mechanism of action studies pointed to the cardiac effects arising from inhibition of the epinephrineαreceptors,M-receptor,and calcium channel receptor.The results laid the foundation for the further modification and pharmacological studies of the natural product dictamnine.