title: Solid-Phase Synthesis of 1,3,7,8-Tetrasubstituted Xanthine Derivatives on Traceless Solid Support.
abstract: Traceless solid-phase synthesis of 1,3,7,8-tetrasubstituted xanthine (1,3,7,8-tetrasubstituted 1H-purine-2,6(3H,7H)-dione) derivatives has been developed. The solid-phase synthetic route began on a solid supported N'-cyano-N-substituted carbamimidothioate, which was prepared from cyanamide, isothiocyanate, and Merrifield resin. After N-alkylation of carbamimidothioate resin with ethyl 2-bromoacetate, an imidazole ring is introduced by Thorpe-Ziegler-type cyclization. The resulting imidazole resin is converted to 1,3,7-trisubstituted xanthine resin using sequential reactions, such as Lewis acid-catalyzed urea formation, pyrimidine ring cyclization, and N-alkylation. After oxidation of sulfides to sulfones, traceless cleavage with amine or thiol nucleophiles afforded the desired 1,3,7,8-tetrasubstituted xanthines in good purities and overall yields (eight-steps; 36 examples). This efficient solid-phase synthesis enables the incorporation of four diversity points into the preparation of the 1,3,7,8-tetrasubstituted xanthines.
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University , 80 Daehak-ro, Buk-gu, Daegu 702-701, Korea.
authors.forename: Doohyun
authors.initials: D
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University , 80 Daehak-ro, Buk-gu, Daegu 702-701, Korea.
authors.forename: Seungyeon
authors.initials: S
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University , 80 Daehak-ro, Buk-gu, Daegu 702-701, Korea.
authors.forename: Kwang-Hyeon
authors.initials: KH
authors.lastname: Liu
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University , 80 Daehak-ro, Buk-gu, Daegu 702-701, Korea.
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
authors.affiliation: College of Pharmacy, Natural Medicine Research Institute, Mokpo National University , 1666 Youngsan-ro, Muan-gun, Jeonnam 534-729, Korea.
authors.forename: Dong Jae
authors.initials: DJ
authors.lastname: Baek
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University , 80 Daehak-ro, Buk-gu, Daegu 702-701, Korea.
authors.forename: Taeho
authors.initials: T
authors.lastname: Lee
mesh_terms: D000478:Alkylation; D002384:Catalysis; D003500:Cyclization; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry; D058116:Lewis Acids / Q000737:chemistry; D060327:Solid-Phase Synthesis Techniques / Q000379:methods*; D013890:Thiourea / Q000031:analogs & derivatives; D014970:Xanthines / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D007093:Imidazoles; D058116:Lewis Acids; D014970:Xanthines; D013890:Thiourea
keywords: 1,3,7,8-tetrasubstituted xanthines; Thorpe−Ziegler-type cyclization; carbamimidothioate; traceless solid-phase synthesis