Studies Of Enantioselective Copper-Catalyzed Azide-Alkyne Cycloaddition Reactions

As one of the most important click reactions,the copper-catalyzed azide-alkyne cycloaddition(CuAAC)has found widespread applications in many areas of researches.Nevertheless,enantioselective CuAAC remains remains largely undeveloped,despite they might provide efficient access to structurally diverse enantioenriched compounds featuring an azide,terminal alkyne or 1,2,3-triazoles,which are valuable structural units in organic synthesis or medicinal chemistry.Therefore,the development of asymmetric CuAAC reactions is important and with potential applications.This dissertation has developed two kinds of asymmetric CuAAC reactions for the facile access of chiral azides and triazoles,namely the the kinetic resolution of racemic ?-tertiary azides and desymmetrization of 1,3-bisazides tertiary alcohols.They are briefly introduced as follows:1)A new type of pyridine-2,6-bis(oxazolines)(Pybox)ligands featuring a sulfonyl group at the C4 position of the pyridine moiety is developed,and successfully applied to the asymmetric CuAAC reaction of racemic 3-substituted 3-azidooxindoles and their kinetic resolution.Compared with known Pybox ligands,newly developed sulfonyl-Pybox ligands could achieve better enantiofacial control,allowing chiral3-azidooxindole to be recovered in 40-49% yield with 40%-99% ee.By adjusting the amount of alkyne,C3 triazole-bearing quaternary oxindoles were obtained in 87-99%yield with 83-93% ee.This method is also suitable for the kinetic resolution of??-azide-?-keto esters and their CuAAC reactions.Initial study on the kinetic resolution of secondary azides has been carried out.For example,under the standard condition,the kinetic resolution of racemic azido-indane could afford the recovered starting material and chiral triazole in up to 84% ee and 83% ee,respectively.2)By using Pybox ligand bearing a bulky benzyloxy shielding group at the C4 position of the pyridine moiety,a highly enantioselective desymmetric CuAAC of diazido alcohols with terminal alkynes was achieved.A series of chiral tertiary alcohols bearing a triazole moiety could be obtained in up to 73% yield and 94% ee.In addition,we further realized the first enantioselective CuAAC using alkynyl iodides,affording products with iodine-substituted triazole groups in moderate yields and excellent enantioselectivity.Mechanism studies revealed that the obtained high enantioselectivity was related to the synergic combination of a desymmetrization and a kinetic resolution.Meanwhile,it was found that the hydroxyl group on the substrate plays a crucial role in the control of stereoselectivity and the ratio of mono-to bis-triazole.