Organocatalytic Aza-Michael/Mannich Cascade Reaction: Synthesis of Enantioenriched 3,3'-Spirooxindole γ-Lactams.

Highly enantioselective synthesis of 3,3'-spirooxindole γ-lactams with three contiguous stereocenters (two quaternary) was achieved. The aza-Michael/Mannich cascade reaction of α-imine-ß-oxobutanamides and methyleneindolinones catalyzed by a bifunctional diaminocyclohexane-derived thiourea catalyst gave the desired products in moderate to good yields (up to 78%), moderate to good diastereoselectivities (up to 10:1 dr), and good to excellent enantioselectivities (up to >99% ee). A gram-scale synthesis and some transformations of 3,3'-spirooxindole γ-lactams were also carried out.

Asymmetric synthesis of chiral 1,2-oxazinane and hexahydropyridazin spirocyclic scaffolds by organocatalytic [4 + 2] cycloaddition.

A novel approach to synthesize chiral 1,2-oxazinane spirocyclic scaffolds by organocatalytic [4 + 2] cycloaddition reaction between methyleneindolinones and γ-aminooxy-α,ß-unsaturated ester has been disclosed. Furthermore, a hydrazide 1,4-synthon is designed and synthesized to construct chiral hexahydropyridazin spirocyclic scaffolds with methyleneindolinones via [4 + 2] cycloaddition reaction. Both reactions give corresponding products in good to excellent yield, excellent diastereoselectivity and good enantioselectivity.

Base-controlled dearomative [3 + 2] cycloadditions between 3-nitro-indoles and fumaric acid amide esters.

The base-controlled dearomative [3 + 2] cycloaddition reaction between 3-nitroindoles and fumaric acid amide esters has been disclosed by using the dearomatization and aromatization strategy. Three kinds of diverse functionalized pyrrolo[2,3-b]indole derivatives were obtained respectively with excellent chemoselectivities and good diastereoselectivities using different bases.

Porous dynamic covalent polymers as promising reversal agents for heparin anticoagulants.

Heparins are natural and partially degraded polyelectrolytes that consist of sulfated polysaccharide backbones. However, as clinically used anticoagulants, heparins are associated with clinical bleeding risks and thus require rapid neutralization. Protamine sulfate is the only clinically approved antidote for unfractionated heparin (UFH), which not only may cause severe adverse reactions in patients, but also is only partially effective against low molecular weight heparins (LMWHs). We here present the facile synthesis of four porous multicationic dynamic covalent polymers (DCPs) from the condensation of tritopic aldehyde and acylhydrazine precursors. We show that, as new water-soluble polymeric antidotes, the new DCPs can effectively include both UFH and LMWHs and thus reverse their anticoagulating activity, which is confirmed by the activated partial thromboplastin time and thromboelastographic assays as well as mouse tail transection assay (bleeding model). The neutralization activities of two of the DCPs were found to be overall superior to that of protamine and have wider concentration windows and good biocompatibility. This pore-inclusion neutralization strategy paves the way for the development of water-soluble polymers as universal heparin binding agents.

Unexpected Insertion of Nitrogen into a C-C Bond: Access to 2,3-Disubstituted Quinazolinone Scaffolds.

A novel, practical, highly efficient, and transition metal free nitrogen insertion reaction for the synthesis of 2,3-disubstituted quinazolinone derivatives was developed. Diverse functionalized 3-indolinone-2-carboxylates and nitrosoarenes with a wide range of substituted nitrosobenzenes, nitrosopyridines, dibenzofuranyl, or dibenzothienyl nitroso compounds worked smoothly to give 2,3-disubstituted quinazolinone derivatives in good to excellent yields (69-98%). A gram-scale reaction was achieved, and an afloqualone analogue was synthesized under the mild reaction conditions.

Organocatalytic Aza-Michael/Michael Cyclization Cascade Reaction: Enantioselective Synthesis of Spiro-oxindole Piperidin-2-one Derivatives.

A simple, direct, and highly enantioselective synthesis of spiro-oxindole piperidin-2-one derivatives was achieved through an aza-Michael/Michael cyclization cascade sequence using a squaramide catalyst. The desired products were obtained in excellent yields (up to 99%) and good to high stereoselectivities (up to >20:1 dr and up to 99% ee) under mild conditions.

Porous Ru(bpy)32+-Linked Polymers for Recyclable Photocatalysis of Enantioselective Alkylation of Aldehydes.

Two metal porous organic polymers (POPs) that contain the [Ru(bpy)3]2+ cores are prepared via one-pot Suzuki-Miyaura coupling reactions. Both Ru-POPs are thermally stable at up to 340 °C in air and do not dissolve in all solvents tested. One of the POPs has been revealed to be highly effective and reusable as a heterogeneous photocatalyst for visible light-driven enantioselective alkylation of aldehydes. After 10 cycles, the catalyst still maintains the enantioselectivity, while the activity just decreases slightly.

Enantioselective aryl-aryl coupling facilitated by chiral binuclear gold complexes.

Herein, we report stoichiometric investigations embodying the first highly enantioselective aryl-aryl coupling facilitated by a gold complex. With up to 91% ee, this is the first demonstration of a transmetalation and C(sp2)-C(sp2) reductive elimination sequence with high enantioselectivity using a gold complex. The results offer a basis for development of enantioselective gold-catalyzed aryl-aryl coupling reactions.

Asymmetric Synthesis of Chiral Spiroketal Bisphosphine Ligands and Their Application in Enantioselective Olefin Hydrogenation.

A series of chiral spiroketal bisphosphine ligands containing 1,1'-spirobi(3 H,3' H)isobenzofuran backbones was accessed through asymmetric synthesis and subsequently tested in enantioselective Rh-catalyzed hydrogenation of α-dehydroamino acid esters. The ligand providing the highest enantioselectivity (up to 99.5%) was obtained in seven steps in an overall 38% yield. The synthesis could be performed on a gram scale, and no kinetic resolution of enantiomers is required. Overall, the developed ligand provides an easily accessible alternative to SDP ligands as well as other chiral bisphosphine ligands.

Asymmetric Organocatalytic [4 + 1] Annulations: Enantioselective Construction of Multifunctionalized Spirocyclopentane Oxindoles Bearing α,α-Disubstituted α-Amino-ß-keto Esters.

The highly enantioselective preparation of spirooxindoles bearing α,α-disubstituted α-amino-ß-keto esters was achieved through [4 + 1] annulation of oxindoles and α-imine-ß-oxo-γ,δ-unsaturated esters under mild conditions in good yields (up to 82%) and stereoselectivities (up to >20:1 dr, 96% ee). The reaction is amenable to gram scale synthesis using catalyst loading as low as 1 mol %. The corresponding chiral α,α-disubstituted α-amino-ß-keto esters could be easily transformed into cyclopenta[ b]indole derivatives without erosion of enantiopurity.

Asymmetric Total Syntheses of (-)-α-Lycorane, (-)-Zephyranthine, and Formal Synthesis of (+)-Clivonine.

An asymmetric route to (-)-α-lycorane and (-)-zephyranthine, and a formal total synthesis of (+)-clivonine were achieved. A pivotal intermediate, which serves as a potent precursor for the divergent syntheses of these natural products, was accessed by a diastereoselective Pd-catalyzed cinnamylation of an N-tert-butanesulfinyl imine.

Asymmetric cinnamylation of N-tert-butanesulfinyl imines with cinnamyl acetates: total syntheses of (+)-lycoricidine and (+)-7-deoxypancratistatin.

Highly diastereoselective palladium catalyzed cinnamylation of N-tert-butanesulfinyl imines with cinnamyl acetates has been established to provide enantioenriched ß-aryl homoallylic amines. The synthetic application of this stragety has been successfully demonstrated in the concise total syntheses of antitumor natural products (+)-lycoricidine and (+)-7-deoxypancratistatin.

Enantioselective synthesis of spirooxindole benzoquinolizines via organo-catalyzed cascade reactions.

A Michael-Mannich-hemiaminalization-dehydration cascade reaction was developed for the construction of spirooxindole benzoquinolizine derivatives. Additionally, spirooxindole benzoindolizidine was prepared conveniently through a ring-contracted rearrangement reaction from spirooxindole benzoquinolizine.

Practical Asymmetric Synthesis of Amathaspiramides B, D, and F.

The practical asymmetric synthesis of amathaspiramides B, D, and F has been accomplished by utilizing an aza-Barbier allylation as the key step to construct the common intermediate with two adjacent stereocenters. A kinetically controlled cyclization to build the challenging thermodynamically less stable 8R-hemiaminal moiety is also important in the synthesis of amathaspiramide D. The route is readily scalable, and gram quantity of the final product D has been prepared.

Squaramide-Catalyzed Synthesis of Enantioenriched Spirocyclic Oxindoles via Ketimine Intermediates with Multiple Active Sites.

A new method for the construction of five-membered spirocyclic oxindoles is based on a Michael-Mannich cascade reaction of a ketimine intermediated catalyzed by a bifunctional quinine-derived squaramide. The desired products were obtained in excellent yields (up to 94%) and stereoselectivities (up to >20:1 d.r., >99% ee). A scaled-up variant also proceeded smoothly showing that the one-pot reaction might find application in the synthesis of bioactive-compound libraries.

A highly efficient asymmetric synthesis of quaternary stereocenter-containing indolizidine and quinolizidine alkaloids using aldehydes, nitroalkenes, and unactivated cyclic ketimines.

A highly efficient approach for the construction of indolizidines and quinolizidines bearing a bridged quaternary stereocenter has been established in a one-pot fashion using aldehydes, nitroalkenes, and cyclic ketimines with excellent enantioselectivities and in high yields. Moreover, this method could be applied to the synthesis of indolizidines in the gram scale.

One-pot enantioselective construction of indoloquinolizidine derivatives bearing five contiguous stereocenters using aliphatic aldehydes, nitroethylenes, and tryptamine.

An organocatalytic cascade reaction was established for the construction of indoloquinolizidine derivatives bearing five contiguous stereocenters from readily available aliphatic aldehydes, nitroethylenes, and tryptamine. This one-pot process gave 30-55% overall yields with excellent d.r. (>20 : 1 in all cases) and ee (91-98%). Additionally, quaternary stereogenic carbon center-containing indoloquinolizidines were prepared through NBS-mediated cyclization of one of the intermediates.

Dual-organocatalyst-promoted asymmetric cascade reaction: highly efficient construction of enantiopure fully substituted tetrahydro-1,2-oxazines.

A four-component asymmetric α-aminoxylation/aza-Michael/Mannich cascade reaction for the construction of fully substituted chiral tetrahydro-1,2-oxazine derivatives was accomplished in high yields with excellent enantio- and diastereoselectivities under mild conditions. The 1,2-oxazine derivative could be transformed to the corresponding multifunctional chiral amino alcohol by N-O cleavage and fused-tricyclic 4-amino-substituted tetrahydroquinolines in good yields with excellent stereoselectivities followed by a Friedel-Crafts reaction. Also a 4-alkoxy-substituted tetrahydroquinoline was achieved by C-4 inversion of a 4-amino-substituted tetrahydroquinoline.

Highly efficient asymmetric construction of quaternary carbon-containing homoallylic and homopropargylic amines.

A highly efficient method for the asymmetric synthesis of chiral quaternary carbon-containing homoallylic and homopropargylic amines under mild conditions was achieved with good yields and high diastereoselectivities.

A highly efficient access to enantiopure tetrahydropyridines: dual-organocatalyst-promoted asymmetric cascade reaction.

A highly efficient cascade process of Michael-aza-Henry-hemiaminalization-dehydration was established for the construction of enantiopure tetrahydropyridines using the combination of prolinol trimethylsilyl ether and cinchona alkaloid catalysts. This new approach allowed for the application of aliphatic imines, generated in situ from aldehydes and amines. Good yields (up to 90%), high enantio- (up to >99% ee) and diastereoselectivities (>99 : 1 d.r. in all cases) were achieved for a broad spectrum of substrates under mild conditions.