Aloperine

苦豆碱Chemical Name: (1R,2S,9R,10R)-3,15-Diazatetracyclo[7.7.1.0(2,7).0(10,15)]heptadec-7-ene; (6aR,7R,13R,13aS)-2,3,4,6,6a,7,8,9,10,12,13,13a-dodecahydro-1H-6,13-methanodipyrido[1,2-a:3,2-e]azocine
CAS No. 56293-29-9
项目整合开发状态: Biological Testing
项目研究机构: Acad. Tradit. Chin. Med. Mat. Med. (Originator)
合成路线:The acylation of 3-hydroxypiperidine with tosyl chloride followed by oxidation of the OH group with CrO3 and H2SO4 gives 1-tosylpiperidine-3-one (II),which is converted into the enol triflate (III) by reaction with LHMDS and PhN(SO2CF3)2 in THF.The condensation of (III) with 1-(tert-butoxycarbonyl)-2-vinylpiperidine (IV) by means of Pd(OAc)2 affords the diene (V),which is selectively deprotected with NaOH in methanol to afford the piperidine (VI).The condensation of (VI) with silylated methyl propenoate (VII) by means of triethylamine in dichloromethane gives the nonisolated intermediate (VIII) that cyclizes to the tetracyclic compound (IX) (as major isomer).The reaction of (IX) with HF and pyridine in refluxing dichloromethane affords the silylated tetracyclic ketone (X) (as major isomer),which is desilylated with KF,KHCO3 and H2O2 in refluxing methanol/THF providing the tetracyclic hydroxyketone (XI) (as major isomer),separated by column chromatography.Elimination of the OH group of (XI) with C6F5OC(S)-Cl,Bu3SnH and AIBN in refluxing benzdene yields the tetracyclic ketone (XII),which is finally reduced with LiAlH4 in THF.

合成路线:Vinylpiperidine (IV): The reduction of (R)-piperidine-2-carboxylic acid (XIII) with BH3-THF gives the carbinol (XIV),which is protected at the NH group with tert-butoxycarbonyl anhydride yielding the N-protected carbinol (XV).The Swern oxidation of (XV) affords the corresponding aldehyde (XVI),which is finally condensed with trimethylphenylphosphonium bromide and potassium hexamethyldisylazane (KHMDS) in THF to provide the target intermediate (IV).

合成路线:Silylated propenoate (VII): The reaction of 3-iodopropenoic acid methyl ester (XVII) with phenyldimethylsilyllithium and CuCN in THF gives the corresponding silylated compound (XVIII),which is then treated with trifluoromethanesulfonic acid in dichloromethane to afford the target intermediate (VII).