ABSTRACT
Ecofriendly N-heterocyclic carbene (NHC) organocatalysis can control the N1-functionalization (aza-Michael addition) and C3-functionalization (Morita-Baylis-Hillman reaction, MBH) of isatins in the absence of (1) a protecting group, (2) a stoichiometric reagent, and (3) heat energy. The challengeable N1-functionalization of N-unsubstituted isatins into N-substituted (NS) isatins was realized through 10 mol % NHC and 10 mol % 1,8-diazabicyclo[5.4.0]undec-7-ene catalysts within 10 min with up to 98% isolation yield. The subsequent MBH adducts of as-synthesized NS-isatins (N1/C3-functionalization) was perfectly acquired in 10 mol % NHC and 10 mol % 1,4-diazabicyclo[2.2.2]octane catalysis within 30 min with superiority to C3/N1-functionalization (MBH/aza-Michael). For guiding the application to a versatile druggable isatin library, the NHC catalysis was compared with reported functionalization of isatins in view of green chemistry principles including solvent scoring of ACS GCI pharmaceutical roundtable, E-factor, atom economy, and so on.
ABSTRACT
A facile synthesis of piperidine alkene-alkaloids including natural (+)-Caulophyllumine B in high yields has been developed by Heck cross-coupling reaction catalyzed by simple in situ formed palladium-N-heterocyclic carbenes (Pd-NHCs). Formation of Pd(0) nanoparticles has been noticed during the reaction course. The synthesized piperidine alkene-alkaloids were evaluated for in vitro anti-cancer activity against a panel of human tumor cell lines of lung, breast and ovarian. Several of these piperidine alkene-alkaloids were found to possess highest growth inhibition activity than the standard drug cisplatin and support the concept to modulate drug receptor interaction.
Subject(s)
Alkaloids/chemistry , Alkenes/chemistry , Antineoplastic Agents/pharmacology , Organometallic Compounds/chemistry , Piperidines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Catalysis , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Heterocyclic Compounds/chemistry , Humans , MCF-7 Cells , Methane/analogs & derivatives , Methane/chemistry , Molecular Conformation , Organometallic Compounds/chemical synthesis , Palladium/chemistry , Structure-Activity RelationshipABSTRACT
Regioselective synthesis of isoxazole-mercaptobenzimidazole hybrids and their efficiency in in vivo analgesic and anti-inflammatory activity was described. A comparison of structure-activity relationship for there compounds was also emphasized.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Structure-Activity RelationshipABSTRACT
A first example of organo-N-heterocyclic carbene (NHC) catalyzed click-type fast 1,3-dipolar cycloaddition of nitrile oxides with alkynes was developed for the regioselective synthesis of 3,5-di- and 3,4,5-trisubstituted isoxazoles. Triethylamine (Et(3)N) was employed as an effective base to generate both nitrile oxide and the organo-NHC catalyst in situ. This catalytic approach was used to attach a variety of substituents, including other biologically active fragments, onto the isoxazole ring to selectively design multinucleus structures. Further, we have also optimized the conditions for Cu(I)-free Sonogashira cross-coupling to obtain internal alkynes in high yields, which were subsequently used in cycloaddition. A catalytic cycle is proposed and the remarkable regiocontrol in the formation of isoxazoles was ascribed to a beneficial zwitterion intermediate developed by the interaction of the strongly nucleophilic organo-NHC catalyst with alkyne followed by nitrile oxide.
