4-Methyldicamphanoylkhellactone, PA-344, 4-Methyl-DCK
Chemical Name: Bis[(1S,1'S,4R,4'R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylic acid] (9R,10R)-4,8,8-trimethyl-2-oxo-9,10-dihydro-2H,8H-benzo[1,2-b:3,4-b']dipyran-9,10-diyl ester; (9R,10R)-4,8,8-Trimethyl-9,10-bis[4(R),7,7-trimethyl-3-oxo-2-oxabicyclo[2,2,1]heptan-1(S)-ylcarbonyloxy]-9,10-dihydro-2H,8H-benzo[1,2-b:3,4-b']dipyran-2-one; 3',4'-Di-O-[(-)-(S)-camphanoyl]-4-methyl-(3'R,4'R)-cis-khellactone
CAS No. 214330-43-5
项目整合开发状态: Preclinical
项目研究机构: Biotech Research Laboratories (Originator), University of North Carolina (Originator), Panacos (Licensee)
合成路线:4-Methyl-7-hydroxycoumarin (I) was alkylated with 3-chloro-3-methyl-1-butyne (II) in the presence of K2CO3 and KI to afford the corresponding aryl propargyl ether (III).Claisen rearrangement of (III) in refluxing diethylaniline furnished the tricyclic system (IV).The target 3'R,4'R-dihydroxylated derivative (V) was obtained by Sharpless asymmetric dihydroxylation of (IV) with hydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)2-PYR) as the chiral catalyst.Diol (V) was finally esterified with (-)-S-camphanoyl chloride (VI) to afford the title diester.
合成路线:Vilsmeier formylation of orcinol (I) by means of POCl3 and DMF afforded 2,4-dihydroxy-6-methylbenzaldehyde (II).Coumarin (V) was then prepared by Wittig condensation of (II) with carbethoxymethylene triphenylphosphorane (III) followed by intramolecular cyclization in refluxing xylene.Alkylation of (V) with 3-chloro-3-methyl-1-butyne (VI) in the presence of K2CO3 and KI produced the corresponding alpha,alpha-dimethylpropargyl ether (VII),and subsequent thermal cyclization in refluxing N,N-diethylaniline gave rise to the tricyclic system (VIII).Osmium-catalyzed asymmetric dihydroxylation of (VIII) in the presence of the enantioselective ligand hydroquinone 2,5-diphenyl-4,6-pyrimidinediyl diether [(DHQ)2-PYR] produced the required (R,R)-(+)-cis-diol (IX).This was finally acylated with (S)-(-)-camphanic chloride (X) in the presence of pyridine to produce the target dicamphanoyl ester.
📌 参考资料/链接：
参考文献标题:Anti-AIDS agent 33.Synthesis and anti-HIV activity of mono-methyl substituted 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) analogues
文献作者:Xie,L.; Takeuchi,Y.; Cosentino,L.M.; Lee,K.-H.
参考来源:Bioorg Med Chem Lett 1998,8(16),2151
📄 详细内容
合成路线:4-Methyl-7-hydroxycoumarin (I) was alkylated with 3-chloro-3-methyl-1-butyne (II) in the presence of K2CO3 and KI to afford the corresponding aryl propargyl ether (III).Claisen rearrangement of (III) in refluxing diethylaniline furnished the tricyclic system (IV).The target 3'R,4'R-dihydroxylated derivative (V) was obtained by Sharpless asymmetric dihydroxylation of (IV) with hydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)2-PYR) as the chiral catalyst.Diol (V) was finally esterified with (-)-S-camphanoyl chloride (VI) to afford the title diester.
合成路线:Vilsmeier formylation of orcinol (I) by means of POCl3 and DMF afforded 2,4-dihydroxy-6-methylbenzaldehyde (II).Coumarin (V) was then prepared by Wittig condensation of (II) with carbethoxymethylene triphenylphosphorane (III) followed by intramolecular cyclization in refluxing xylene.Alkylation of (V) with 3-chloro-3-methyl-1-butyne (VI) in the presence of K2CO3 and KI produced the corresponding alpha,alpha-dimethylpropargyl ether (VII),and subsequent thermal cyclization in refluxing N,N-diethylaniline gave rise to the tricyclic system (VIII).Osmium-catalyzed asymmetric dihydroxylation of (VIII) in the presence of the enantioselective ligand hydroquinone 2,5-diphenyl-4,6-pyrimidinediyl diether [(DHQ)2-PYR] produced the required (R,R)-(+)-cis-diol (IX).This was finally acylated with (S)-(-)-camphanic chloride (X) in the presence of pyridine to produce the target dicamphanoyl ester.
参考文献标题:Anti-AIDS agents.37.(1) synthesis and structure-activity relationships of (3'R,4'R)-(+)-cis-khellactone derivatives as novel potent anti-HIV agents
文献作者:Xie,L.; Takeuchi,Y.; Cosentino,L.M.; Lee,K.H.
参考来源:J Med Chem 1999,42(14),2662