Chiral Bifunctional Squaramide Research Articles

Organocatalytic Asymmetric Construction of Spirooxazines via Chemoselective Cascade Addition of N-Substituted Hydroxylamine with Keto-bis-enone.

Spirooxazines represent a privileged heterocyclic scaffold having pronounced biological importance. Herein, we introduce a chiral bifunctional squaramide catalyzed highly chemoselective cascade reaction involving aza-Michael/1,2-addition/oxa-Michael addition of N-substituted hydroxylamine with keto-bis-enones. This strategy enables the synthesis of highly enantioenriched oxa-spirooxazines with a broad substrate tolerance. Scalability and synthetic transformation have demonstrated the feasibility of the protocol. Furthermore, control experiments provided insights into the reaction mechanism.

Bifunctional Squaramide-Catalyzed Oxidative Kinetic Resolution: Simultaneous Access to Axially Chiral Thioether and Sulfoxide.

Axially chiral thioethers and sulfoxides emerge as two pivotal classes of ligands and organocatalysts, which have remarkable features in the stereoinduction of various asymmetric transformations. However, the lack of easy methods to access such molecules with diverse structures has hampered their broader utilization. Herein, an oxidative kinetic resolution for sulfides using a chiral bifunctional squaramide as the catalyst with cumene hydroperoxide as the terminal oxidant is established. This asymmetric approach provides a variety of axially chiral thioethers as well as sulfoxides bearing both axial and central chirality, with excellent diastereo- and enantioselectivities. This catalytic system also successfully extends to the kinetic resolution of benzothiophene-based sulfides. Preliminary mechanism investigation indicates that the multiple hydrogen bonding interactions between the bifunctional squaramide catalyst and substrates play a crucial role in determining the enantioselectivity and reactivity.

Synthesis of Chiral Diarylmethylamides via Catalytic Asymmetric Aza-Michael Addition of Amides to ortho-Quinomethanes.

Chiral diarylmethylamides are a privileged skeleton in many bioactive molecules. However, the enantioselective synthesis of such molecules remains a long-standing challenge in organic synthesis. Herein, we report a chiral bifunctional squaramide catalyzed asymmetric aza-Michael addition of amides to in situ generated ortho-quinomethanes, affording enantioenriched diarylmethylamides in good yields with excellent enantioselectivities. This work not only provides a new strategy for the construction of the diarylmethylamides but also represents the practicability of amides as nitrogen-nucleophiles in asymmetric organocatalysis.

Modular access to chiral cyclopentanes via formal [2+2+1] annulation enabled by palladium/chiral squaramide relay catalysis

An enantio- and diastereodivergent [2+2+1] annulation reaction of allyl ketones, acidic methylene compounds, and nitroalkenes to assemble highly functionalized cyclopentanes from readily available substances enabled by asymmetric relay catalysis of chiral bifunctional squaramide and palladium complex has been established. This method showcases that allyl ketones can serve as latent 1,2-dication synthons via a linear-selective allylic C–H functionalization and sequential 1,4-conjugated addition, enabling the rapid assembly of cyclopentane skeleton with a broad scope of methylene nucleophiles and nitroalkenes. Notably, chiral bifunctional squaramide catalyst engages in both the intermolecular and intramolecular Michael addition reactions accompanying with a kinetic resolution behavior to amplify the enantioselection. In addition, the stereodivergent synthesis of diastereomers from the resultant chiral cyclopentane derivatives is also accessible by a simple manipulation with base.

Organocatalytic Asymmetric Synthesis of Aza-Spirooxindoles via Michael/Friedel-Crafts Cascade Reaction of 1,3-Nitroenynes and 3-Pyrrolyloxindoles.

An asymmetric [3+3] cyclization of nitroenynes and 3-pyrrolyloxindoles has been realized with a chiral bifunctional squaramide catalyst. This Michael/Friedel-Crafts cascade strategy provides a facile and efficient access to enantioenriched polycyclic aza-spirooxindoles with 32-95% isolated yields and excellent stereocontrol under mild reaction conditions.

Organocatalytic Remote Asymmetric Inverse‐Electron‐Demand Oxa‐Diels‐Alder Reaction of Allyl Ketones with Isatin‐Derived Unsaturated Keto Esters

AbstractA remote cascade asymmetric inverse‐electron‐demand oxa‐Diels‐Alder reaction of allyl ketones with isatin‐derived β,γ‐unsaturated α‐keto esters has been developed in the presence of a chiral bifunctional squaramide catalyst. Taking advantage of the secondary amide activating group, a series of enantioenriched 3,4’‐pyranyl spirooxindole derivatives bearing three contiguous chiral centers were attained in high yields (84 to >99%) with excellent enantioselectivities (96–99% ee). Moreover, the gram‐scale synthesis and the construction of 1‐benzazepine scaffold by the product were also demonstrated.magnified image

Squaramide-Catalyzed Asymmetric Mannich Reactions of Azlactones with Isatin-Derived Ketimines: Access to α,β-Diamino Acid Derivatives Bearing Vicinal Quaternary Stereocenters.

A highly stereoselective Mannich reaction of α-amino acid derived azlactones with isatin-derived ketimines enabled by a chiral bifunctional squaramide organocatalyst is reported, affording α,β-diamino acid derivatives bearing vicinal quaternary stereocenters in moderate to good yields (40-95%), moderate to excellent diastereoselectivities (3:1 → 20:1), and good to excellent enantioselectivities (66-97%). This reaction can be readily performed on gram scale, and the Mannich adduct could be easily converted to the corresponding α,β-diamino ester via simple operations.

Catalytic Asymmetric Hydrophosphination of ortho-Quinone Methides.

An efficient catalytic asymmetric hydrophosphination of ortho-quinone methides with H-phosphine oxides is established. A chiral bifunctional squaramide is superior to catalyze this enantioselective carbon-phosphorus bond formation, delivering optically active α-arylmethyl phosphine oxides in high yields with high enantioselectivities (up to 94% yield, 99:1 er). Additionally, employing in situ-generated o-QMs for this hydrophosphination step economically provides the corresponding phosphine oxides with comparable yield and enantioselectivity.

Organocatalytic Enantioselective Michael Addition of 3‐Indolinone‐2‐Carboxylates to Maleimides

An organocatalyzed asymmetric conjugate addition of 2‐substituted 3‐indolinones to maleimides has been developed by using a chiral bifunctional squaramide derived from quinidine to promote the reaction. This method provides easy access to 3‐indolinone‐2‐carboxylate‐succinimide adducts in high yields with excellent diastero and entantioselectivities and is a useful approach for the construction of vicinal quaternary‐tertiary chiral centers. In addition, product 4l was successfully converted into a chiral indoline‐pyrrolidine adduct.

Enantioselective access to tetrahydropyrano[2,3- c ]pyrazoles via an organocatalytic domino Michael-hydroalkoxylation reaction

Abstract An asymmetric domino Michael-hydroalkoxylation reaction of trans-α-alkynyl-nitroolefins with N-arylpyrazolinones has been accomplished using a chiral bifunctional squaramide catalyst. Under the organocatalytic method, a broad range of tetrahydropyrano[2,3-c]pyrazoles with an exocyclic alkene at the C-6 position were prepared in high yields and excellent stereoselectivities. The presence of an exocyclic double bond and nitro group in the pyranopyrazoles provide a wide scope for further structural transformations.

Organocatalyzed Asymmetric Michael Addition of 1-Acetylindolin-3-ones to β,γ-Unsaturated α-Ketoesters: An Access to Chiral Indolin-3-ones with Two Adjacent Tertiary Stereogenic Centers.

Asymmetric Michael addition of 1-acetylindolin-3-ones to β,γ-unsaturated α-ketoesters was investigated for the synthesis of chiral indolin-3-ones with two adjacent tertiary stereogenic centers. Under the catalysis of a chiral bifunctional squaramide derived from l-tert-leucine, a wide range of 1-acetylindolin-3-ones and β,γ-unsaturated α-ketoesters were well-tolerated in this transformation to provide the corresponding novel densely functionalized chiral indolin-3-one derivatives in high yield with excellent diastereo- and enantioselectivity under mild reaction conditions.

Organocatalytic, Enantioselective Synthesis of Cyclohexadienone Containing Hindered Spirocyclic Ethers through an Oxidative Dearomatization/Oxa‐Michael Addition Sequence

AbstractAn unprecedented enantioselective oxa‐Michael reaction of α‐tertiary alcohols using cinchona‐alkaloid‐based chiral bifunctional squaramide catalysts is reported. An oxidative dearomatization of phenol followed by an enantioselective oxa‐Michael addition sequence provided a broad array of chiral sterically hindered tetrahydrofurans and tetrahydropyrans attached to a cyclohexadienone moiety in spiro fashion. In general, good yields and excellent enantioselectivities (up to 99 %) were observed. The chiral oxo‐cycles obtained have easily been transformed into chromans without disturbing the enantioselectivity.

Organocatalytic, Enantioselective Synthesis of Cyclohexadienone Containing Hindered Spirocyclic Ethers through an Oxidative Dearomatization/Oxa-Michael Addition Sequence.

An unprecedented enantioselective oxa-Michael reaction of α-tertiary alcohols using cinchona-alkaloid-based chiral bifunctional squaramide catalysts is reported. An oxidative dearomatization of phenol followed by an enantioselective oxa-Michael addition sequence provided a broad array of chiral sterically hindered tetrahydrofurans and tetrahydropyrans attached to a cyclohexadienone moiety in spiro fashion. In general, good yields and excellent enantioselectivities (up to 99 %) were observed. The chiral oxo-cycles obtained have easily been transformed into chromans without disturbing the enantioselectivity.

ChemInform Abstract: Chiral Bifunctional Squaramide Catalyzed Asymmetric Michael Addition of Ethyl α‐Nitroacetate to β,γ‐Unsaturated α‐Ketoesters.

Abstract We have developed an efficient bifunctional squaramide catalyst for the asymmetric Michael addition of ethyl α-nitroacetate to β,γ-unsaturated α-ketoesters. This organocatalytic asymmetric reaction provides convenient and valuable access to highly functionalized 2-nitro-5-oxo-3-arylhexanedioates in excellent yields with uniformly high levels of enantioselectivity (up to >99% ee) albeit with no diastereoselectivity. The resulting products could be conveniently transformed into 5-nitro-2-oxo-4-arylpentanoic acids without loss of enantiomeric excess via basic hydrolysis and the subsequent decarboxylation. This represents an example of in-direct, but efficient asymmetric conjugate addition of pyruvic acid to nitroolefins.

Chiral bifunctional squaramide catalyzed asymmetric Michael addition of ethyl α-nitroacetate to β,γ-unsaturated α-ketoesters

We have developed an efficient bifunctional squaramide catalyst for the asymmetric Michael addition of ethyl α-nitroacetate to β,γ-unsaturated α-ketoesters. This organocatalytic asymmetric reaction provides convenient and valuable access to highly functionalized 2-nitro-5-oxo-3-arylhexanedioates in excellent yields with uniformly high levels of enantioselectivity (up to >99% ee) albeit with no diastereoselectivity. The resulting products could be conveniently transformed into 5-nitro-2-oxo-4-arylpentanoic acids without loss of enantiomeric excess via basic hydrolysis and the subsequent decarboxylation. This represents an example of in-direct, but efficient asymmetric conjugate addition of pyruvic acid to nitroolefins.

ChemInform Abstract: Chiral Bifunctional Squaramide Catalyzed Asymmetric Tandem Michael‐Cyclization Reaction: Efficient Synthesis of Optically Active 2‐Amino‐4H‐chromene‐3‐carbonitrile Derivatives.

AbstractAn enantioselective cascade Michael addition/cyclization of ortho‐hydroxy‐nitrostyrenes (I) with malononitrile is developed using a chiral bifunctional squaramide derivative as catalyst.

Bifunctional Squaramide‐Catalyzed One‐Pot Sequential Michael Addition/Dearomative Bromination: Convenient Access to Optically Active Brominated Pyrazol‐5(4H)‐ones with Adjacent Quaternary and Tertiary Stereocenters

AbstractThe organocatalytic asymmetric, one‐pot, sequential Michael addition/dearomative bromination reaction of pyrazol‐5‐ones to nitro olefins and N‐bromosuccinimide (NBS) has been developed. Under the catalysis of a chiral bifunctional squaramide, a wide variety of chiral brominated pyrazol‐5‐one derivatives with contiguous quaternary and tertiary stereocenters was obtained in high yields (up to >99 %) with good to excellent diastereoselectivities (62:38–99:1 dr) and uniformly high levels of enantioselectivity (92 to >99 % ee). This experimentally simple process facilitates access to various enantioenriched, multiply substituted pyrazolin‐5‐one derivatives, potential biologically active molecules, starting from readily available starting materials.

ChemInform Abstract: Chiral Squaramide as Multiple H‐Bond Donor Organocatalysts for the Asymmetric Michael Addition of 1,3‐Dicarbonyl Compounds to Nitroolefins.

Abstract A series of chiral bifunctional squaramide multiple H-bond donor organocatalysts have been designed and synthesized by the rational assembly of chiral privileged scaffolds of indanol and cinchona alkaloids. In the presence of 1 mol % 1a , the asymmetric Michael addition reaction of 1,3-dicarbonyl compounds to nitroolefins proceeded to provide the product in high yields (up to 92%) and with good to high ee values (up to 96%). The additional H-bond in this squaramide system plays a crucial role in enhancing the enantioselectivity.

Squaramide–Tertiary Amine Catalyzed Asymmetric Cascade Sulfa-Michael/Michael Addition via Dynamic Kinetic Resolution: Access to Highly Functionalized Chromans with Three Contiguous Stereocenters

An efficient asymmetric cascade sulfa-Michael/Michael addition reaction catalyzed by a chiral bifunctional squaramide-tertiary amine catalyst has been developed. This organocatalytic cascade reaction provides easy access to highly functionalized chromans with three contiguous stereocenters, including one quaternary center. In addition, a novel cascade sulfa Michael/retro-sulfa-Michael/sulfa-Michael/Michael reaction process, involving dynamic kinetic resolution, is described.

Chiral squaramide as multiple H-bond donor organocatalysts for the asymmetric Michael addition of 1,3-dicarbonyl compounds to nitroolefins

A series of chiral bifunctional squaramide multiple H-bond donor organocatalysts have been designed and synthesized by the rational assembly of chiral privileged scaffolds of indanol and cinchona alkaloids. In the presence of 1mol% 1a, the asymmetric Michael addition reaction of 1,3-dicarbonyl compounds to nitroolefins proceeded to provide the product in high yields (up to 92%) and with good to high ee values (up to 96%). The additional H-bond in this squaramide system plays a crucial role in enhancing the enantioselectivity.