ABSTRACT
The total synthesis of siladenoserinolâ A, an inhibitor of the p53-Hdm2 interaction, has been achieved. AuCl3 -catalyzed hydroalkoxylation of an alkynoate derivative smoothly and regioselectively proceeded to afford a bicycloketal in excellent yield. A glycerophosphocholine moiety was successfully introduced through the Horner-Wadsworth-Emmons reaction using an originally developed phosphonoacetate derivative. Finally, removal of the acid-labile protecting groups, followed by regioselective sulfamate formation of the serinol moiety afforded the desired siladenoserinolâ A, and benzoyl and desulfamated analogues were also successfully synthesized. Biological evaluation showed that the sulfamate is essential for biological activity, and modification of the acyl group on the bicycloketal can improve the inhibitory activity against the p53-Hdm2 interaction.
Subject(s)
Glycerylphosphorylcholine/pharmacology , Propanolamines/pharmacology , Propylene Glycols/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Tumor Suppressor Protein p53/antagonists & inhibitors , Catalysis , Dose-Response Relationship, Drug , Glycerylphosphorylcholine/chemical synthesis , Glycerylphosphorylcholine/chemistry , Gold Compounds/chemistry , Humans , Molecular Structure , Propanolamines/chemical synthesis , Propanolamines/chemistry , Propylene Glycols/chemical synthesis , Propylene Glycols/chemistry , Proto-Oncogene Proteins c-mdm2/chemistry , Proto-Oncogene Proteins c-mdm2/metabolism , Structure-Activity Relationship , Tumor Suppressor Protein p53/chemistry , Tumor Suppressor Protein p53/metabolismABSTRACT
The synthesis of pyrrolyl 4-quinolinone alkaloid, quinolactacide, and its analogues was successfully achieved using 9-azajulolidine (9-AJ)-catalyzed tandem acyl transfer-regioselective cyclization of N,N-diacyl-o-alkynoylaniline derivatives. In addition, this organocatalytic reaction was successfully utilized for the synthesis of a variety of 3-acyl-4-quinolinones in moderate-to-good yields. Mechanistic studies, including a time course nuclear magnetic resonance (NMR) experiment, indicated that the 1,4-addition of 9-AJ to an ynone system can be considered to be the rate-determining step in this quinolinone synthesis.
ABSTRACT
Lewis base-catalyzed tandem acyl transfer-cyclization of acylated o-alkynoylphenols leading to 3-aroylflavones was developed. 9-Azajulolidine smoothly promoted the reaction of the aroyl derivatives at ambient temperature, and the structure-diversed synthesis of 3-aroylflavones with distinct substituents was achieved in moderate to excellent yields.
