Synthesis And Structure Activity Relationship Of Novel β-carboline Alkaloid Based On Perlolyrine

Theβ-carboline skeleton exists extensively in numerous drugs and natural products,with biological activities such as anti-cancer and anti-plasmodium.Inspired by the previous work on the research of aryl oxazoline pharmacophore and isoquinoline-3-oxazoline,novelβ-carboline-oxazoline andβ-Carboline amide compounds were designed and synthesized to explore their application as new antifungal leads and chiral ligands in asymmetric synthesis.The main results obtained are as follows:（1）29β-carboline-oxazoline and their analogs were synthesized based on tryptophan and tryptamine through the pictet-spengler reaction,Steglich esterification and other reaction with natural product perlolyrine as the leader.Then 36β-carboline amide synthesized as isosteres ofβ-carboline-oxazoline.Two highly selectivity methods of asymmetric addition was established based onβ-carboline-oxazoline compounds.The structures were confirmed by nuclear magnetic resonance spectrum of hydrogen spectrum（¹H-NMR）,nuclear magnetic resonance spectrum of carbon(¹³C-NMR),Electrospray ionization high-resolution mass spectrometry（ESI-HRMS）.（2）The target compounds were tested against Rhizoctonia solani,Sclerotinia sclerotiorum,Fusarium graminearum,Phytophthora capsici,Botrytis cinerea and Magnaporthe grisea at the concentration of 50μg/m L.The biological activity of alangiobussinine and analogues were revealed for the first time;The antifungal activity assay showed thatβ-carboline amides2ba and 2bn have a good inhibitory effect against on Botrytis cinerea..On this basis of perlolyrine,β-carboline-oxazolines were further optimized in antifungal activity;Structure-antifungal activity showed that the antifungal activity of these compounds were higher thanβ-carboline amide.The EC₅₀ of compounds L2,L3,L4,L6,L7 and L9were all less than positive control Boscalid.The EC₅₀ of compounds L2-L7 and L9 against S.sclerotiorum were between 3.82-6.88μg/m L.When theβ¹-carboline-oxazoline substituent is S-tert-butyl（L6）,the EC₅₀ for R.solani and P.capsici was 10.45μg/m L and 7.87μg/m L,so using L6 as the derivatization core point,some heterocyclic-oxazoline and analogs were prepared.The results show that the antifungal activity of other heterocyclic oxazoline were generally lower than that ofβ-carboline-oxazoline.At the same time,comparing the configuration of chiral groups on oxazoline,antifungal activity showed that the L9 is much higher than that of L8.Among them,the EC₅₀ for R.solani,S.sclerotiorum,and P.capsici.is5.36μg/m L,3.94μg/m L and 5.64μg/m L,respectively,which demonstrating its potential as fungicides lead.（3）Using chiralβ-carboline-oxazoline compounds as ligands for metal catalysts,aiming the asymmetric synthesis ofβ-arylamine in amides fungicides and related drugs,a highly selectivity method for asymmetric addition of nitrostyrene and phenylboric acid was established.Compared with the isoquinoline-3-oxazoline,the reaction system has higher stereoselectivity to electron-withdrawing nitroolefin.Using this catalytic system can realize the asymmetric addition ofβ-cyclohexenone and obtain cyclohexanone containing quaternary carbon center with higher ee value.Based on tryptophan and its analogs,2 types of 65 newβ-carboline alkaloids were designed and synthesized.The study on the structure-activity relationship protruded four antifungal candidates.Two highly selectivity method of asymmetric addition of nitrostyrene andβ-cyclohexenone with phenylboric acid were established,Which can provide technical support for the discovery and asymmetric synthesis of new amides agrochemical.