Dragocins A-C are structurally unique marine natural products featuring an uncommon tri-oxa-tricyclic[6.2.1]undecane moiety.However,their extremely low natural abundance has hindered extensive screening of their bioac...Dragocins A-C are structurally unique marine natural products featuring an uncommon tri-oxa-tricyclic[6.2.1]undecane moiety.However,their extremely low natural abundance has hindered extensive screening of their bioactivities.We hereby describe an efficient and modular approach to synthesizing dragocins A-C and their analogues using commercially available and inexpensive anisomycin and D-ribosyl thioglycoside derivative as the starting materials.A key feature of our synthesis is the construction of the uncommon tri-oxa-tricyclic[6.2.1]undecane skeleton.This challenging architecture is achieved by the stereocontrolled formation of theβ-ribofuranosidic bond and the DDQ(2,3-dichloro-5,6-dicyano-1,4-benzoquinone)-promoted intramolecular cross-dehydrogenative etherification at the benzylic position.Our synthesis is also characterized by the successful installation of a chlorine atom and a methoxy group at the tertiary C-4'position via a late-stage silver-catalyzed decarboxylative chlorination reaction and an electrophilic etherification reaction of the enol intermediate.Cytotoxicity evaluations of the synthesized compounds revealed demethyl dragocin A,the N-demethylated derivative of dragocin A,as a potential anticancer candidate due to its strong cytotoxicity against A549 lung,HCT116 colorectal and MCF7 breast cancer cell lines.This work also demonstrated the preliminary structure-activity relationship of this compound,setting a solid foundation for developing novel anticancer candidates.展开更多
基金the Marine S&T Fund of Shandong Province for Qingdao Marine Science and Technology Center(Qingdao)(No.2022QNLM030003-2)the National Natural Science Foundation of China(No 22377114).
文摘Dragocins A-C are structurally unique marine natural products featuring an uncommon tri-oxa-tricyclic[6.2.1]undecane moiety.However,their extremely low natural abundance has hindered extensive screening of their bioactivities.We hereby describe an efficient and modular approach to synthesizing dragocins A-C and their analogues using commercially available and inexpensive anisomycin and D-ribosyl thioglycoside derivative as the starting materials.A key feature of our synthesis is the construction of the uncommon tri-oxa-tricyclic[6.2.1]undecane skeleton.This challenging architecture is achieved by the stereocontrolled formation of theβ-ribofuranosidic bond and the DDQ(2,3-dichloro-5,6-dicyano-1,4-benzoquinone)-promoted intramolecular cross-dehydrogenative etherification at the benzylic position.Our synthesis is also characterized by the successful installation of a chlorine atom and a methoxy group at the tertiary C-4'position via a late-stage silver-catalyzed decarboxylative chlorination reaction and an electrophilic etherification reaction of the enol intermediate.Cytotoxicity evaluations of the synthesized compounds revealed demethyl dragocin A,the N-demethylated derivative of dragocin A,as a potential anticancer candidate due to its strong cytotoxicity against A549 lung,HCT116 colorectal and MCF7 breast cancer cell lines.This work also demonstrated the preliminary structure-activity relationship of this compound,setting a solid foundation for developing novel anticancer candidates.
