Highly Enantioselective CuAAC of Functional Tertiary Alcohols Featuring an Ethynyl Group and Their Kinetic Resolution.

The first highly enantioselective CuI -catalyzed azide-alkyne cycloaddition (CuAAC) of tertiary alcohols and their kinetic resolution is reported. This approach allows facile access to multifunctional tertiary alcohols featuring an α-ethynyl or α-triazole moiety, and represents the first successful kinetic resolution of racemates with a tetrasubstituted carbon stereocenter via CuAAC. Newly developed pyridinebisoxazoline (PYBOX) ligands with a C4 phosphonate group play a key role.

Enantioselective Construction of Spiro[indoline-3,2'-pyrrole] Framework via Catalytic Asymmetric 1,3-Dipolar Cycloadditions Using Allenes as Equivalents of Alkynes.

The first catalytic asymmetric 1,3-dipolar cycloadditions (1,3-DCs) of isatin-derived azomethine ylide with allenes have been established, which efficiently assembly isatins, amino-esters and 2,3-allenoate into enantioenriched spiro[indoline-3,2'-pyrrole] derivatives with a quaternary stereogenic center in generally high enantioselectivities (80-98% ee). In this allene-involved 1,3-DC, an unexpected spirooxindole framework bearing an intra-annular C═C double bond was generated, which is quite different from previously reported 1,3-DCs of allenes. This approach not only confronted the great challenge in using allenes as dipolarophiles of 1,3-DCs, but also provided a unique strategy of using allenes as equivalents of alkynes to construct spiro[indoline-3,2'-pyrrole] structure. Besides, this reaction also represents the first catalytic asymmetric ketone-involved 1,3-DCs of allenes, which will also greatly enrich the research contents of 1,3-DCs, the chemistry of allenes as well as the synthetic methods of spirooxindoles.

Catalytic asymmetric formal [3+3] cycloaddition of an azomethine ylide with 3-indolylmethanol: enantioselective construction of a six-membered piperidine framework.

A catalytic asymmetric formal [3+3] cycloaddition of 3-indolylmethanol and an in situ-generated azomethine ylide has been established to construct a chiral six-membered piperidine framework with two stereogenic centers. This approach not only represents the first enantioselective cycloaddition of isatin-derived 3-indolylmethanol, but also has realized an unusual enantioselective formal [3+3] cycloaddition of azomethine ylide rather than its common [3+2] cycloadditions. Besides, this protocol combines the merits of a multicomponent reaction and organocatalysis, which efficiently assembles a variety of isatin-derived 3-indolylmethanols, aldehydes, and amino esters into structurally diverse spiro[indoline-3,4'-pyridoindoles] with one all-carbon quaternary stereogenic center in high yields and excellent enantioselectivities (up to 93 % yield, >99 % enantiomeric excess (ee)). Although the diastereoselectivity of the reaction is generally moderate, most of the diastereomers can be separated by using column chromatography followed by preparative TLC.

Organocatalytic asymmetric inverse-electron-demand 1,3-dipolar cycloaddition of N,N'-cyclic azomethine imines.

The first organocatalytic asymmetric inverse-electron-demand 1,3-dipolar cycloaddition (IED 1,3-DC) of N,N'-cyclic azomethine imines has been established in the presence of chiral phosphoric acid. This approach assembles N,N'-cyclic azomethine imines and o-hydroxystyrenes into chiral N,N-bicyclic pyrazolidin-3-one derivatives with the creation of two stereogenic centers, one of which is quaternary, in excellent diastereoselectivities and good enantioselectivities (up to >95:5 dr, 88:12 er). The investigation of the activation mode of the reaction revealed that the dual hydrogen-bonding interaction between the two substrates and the catalyst together with the conjugative effect initiated by the o-hydroxyl group played a crucial role in the designed IED 1,3-DC. This study will not only greatly enrich the underdeveloped research potential of catalytic asymmetric IED 1,3-DCs but will also facilitate the design of other enantioselective IED 1,3-DCs based on different activation modes.

Enantioselective construction of 2,5-dihydropyrrole skeleton with quaternary stereogenic center via catalytic asymmetric 1,3-dipolar cycloaddition involving α-arylglycine esters.

A catalytic asymmetric construction of synthetically and biologically important 2,5-dihydropyrrole scaffolds with concomitant creation of multiple chiral carbon centers including one quaternary stereogenic center in high yields (up to 99%) and excellent enantioselectivities (up to 99% ee) has been established via an organocatalytic 1,3-dipolar cycloaddition using α-arylglycine esters as azomethine precursors. Moreover, a detailed investigation has been performed on the catalytic asymmetric 1,3-dipolar cycloadditions of α-arylglycine ester-generated azomethine ylides with alkynes, providing an efficient way to simultaneously access both 2,5-dihydropyrrole diastereomers in good enantioselectivities.

Enantioselective synthesis of P-chiral tertiary phosphine oxides with an ethynyl group via Cu(i)-catalyzed azide-alkyne cycloaddition.

We report the highly enantioselective synthesis of P-chiral tertiary phosphine oxides featuring an ethynyl group via Cu(i)-catalyzed azide-alkyne cycloaddition. Newly developed chiral pyridinebisoxazolines (PYBOX) bearing a bulky C4 shielding group play an important role in achieving excellent enantioselectivity while suppressing side bis-triazoles formation in desymmetrizing prochiral diethynylphosphine oxides. Notably, by tuning the size of the C4 shielding group, it is possible to achieve excellent remote enantiofacial control in desymmetrizing phosphole oxide-diynes with the prochiral P-center farther from the ethynyl group by four covalent bonds. Time-dependent enantioselectivity is observed for these desymmetric CuAAC reactions, suggesting a synergic combination of a desymmetrization and a kinetic resolution, and our ligands prove to be better than unmodified PYBOX in both steps. This finding contributes to a highly enantioselective kinetic resolution of racemic ethynylphosphine oxides. The resulting chiral ethynylphosphine oxides are versatile P-chiral synthons, which can undergo a number of diversifying reactions to enrich structural diversity.

Enantioselective Cu(I)-Catalyzed Cycloaddition of Prochiral Diazides with Terminal or 1-Iodoalkynes.

We report an unprecedented highly enantioselective desymmetric Cu(I)-catalyzed 1,3-dipolar cycloaddition of diazides with terminal alkynes and 1-iodoalkynes, affording tertiary alcohols bearing a 1,2,3-triazole moiety in high yield and excellent ee value. PYBOX ligands with a C4 shielding group once again show the promising ability to achieve higher enantioselectivity.

Catalytic chemoselective [3+3] cycloadditions of azomethine ylides with quinone monoimides leading to the construction of a dihydrobenzoxazine scaffold.

A chemoselective [3+3] cycloaddition of in situ generated azomethine ylides with quinone monoimides has been established, which efficiently led to the construction of dihydrobenzoxazine frameworks with biological relevance, with excellent chemoselectivities and high yields (up to >95 : 5 cr and 98% yield).

A catalytic asymmetric isatin-involved Povarov reaction: diastereo- and enantioselective construction of spiro[indolin-3,2'-quinoline] scaffold.

The first catalytic asymmetric isatin-involved Povarov reaction has been established. This method provides an unprecedented approach to access the enantioenriched spiro[indolin-3,2'-quinoline] scaffold with concomitant creation of two quaternary stereogenic centers in high yields and excellent stereoselectivities (all >99:1 dr's, up to 97% ee).