Chiral Brønsted Acid Catalyzed Enantioselective Synthesis of Spiro-Isoindolinone-Indolines via Formal [3 + 2] Cycloaddition.

A novel organocatalytic asymmetric formal [3 + 2] cycloaddition of 3-substituted 1H-indoles with in situ generated 3-hydroxy-isoindolinone-derived ß,γ-alkynyl-α-ketimines has been developed. A variety of biologically relevant chiral spiro-isoindolinone-indolines were achieved with excellent yields (up to 99%) and enantioselectivity (up to 99% ee) under mild conditions. The gram-scale reaction of this methodology and several interesting transformations of the products have been demonstrated.

Brønsted acid-catalyzed enantioselective addition of 1,3-diones to in situ generated N-acyl ketimines.

A Brønsted acid-catalyzed asymmetric Mannich-type addition of 1,3-diones to cyclic N-acyl ketimines is reported for the synthesis of enantioenriched isoindolinones. Various dicarbonyl-substituted isoindolinones bearing a quaternary carbon stereocenter were synthesized with excellent yields (up to 98%) and moderate to high enantioselectivities (up to 95% ee), and most of them possess a fluorine atom at the reactive center. Furthermore, the synthetic utility of the protocol has been demonstrated by the debenzoylation of the product.

Organocatalytic Asymmetric Cascade Michael-acyl Transfer Reaction between 2-Fluoro-1,3-diketones and Unsaturated Thiazolones: Access to Fluorinated 4-Acyloxy Thiazoles.

Quinine derived bifunctional urea catalyzed cascade Michael-acyl transfer reaction of 5-alkenyl thiazolones and monofluorinated ß-diketones has been developed. The fluorine containing 4-acyloxy thiazoles were synthesized in high yields and good diastereo-and excellent enantioselectivities. Synthetic transformations, including synthesis of 4-hydroxy thiazoles, have been demonstrated.

Cu(I)-Catalyzed asymmetric exo-selective synthesis of substituted pyrrolidines via a 1,3-dipolar cycloaddition reaction.

An (R)-DM-BINAP/Cu(CH3CN)4BF4 complex catalyzed exo-selective asymmetric 1,3-dipolar cycloaddition (1,3-DCA) reaction of imino esters with α,ß-unsaturated pyrazoleamides has been developed. A series of highly functionalized pyrrolidines with multiple stereogenic centers were obtained with good yields and diastereoselectivities and excellent enantioselectivities (up to 99% ee).

A General Catalytic Route to Enantioenriched Isoindolinones and Phthalides: Application in the Synthesis of ( S)-PD 172938.

Chiral Brønsted acid catalyzed enantioselective syntheses of isoindolinones and phthalides have been accomplished via tandem Mannich-lactamization and aldol-lactonization reactions, respectively. A variety of enantioenriched isoindolinones (up to 99% ee) and phthalides (up to 85% ee) containing α-diazoesters were afforded in excellent yields. Furthermore, a concise synthesis of ( S)-PD 172938 has been demonstrated by using this protocol.

A chiral Brønsted acid-catalyzed highly enantioselective Mannich-type reaction of α-diazo esters with in situ generated N-acyl ketimines.

A chiral phosphoric acid-catalyzed asymmetric Mannich-type reaction of α-diazo esters with in situ generated N-acyl ketimines, derived from 3-hydroxyisoindolinones has been demonstrated in this communication. A variety of isoindolinone-based α-amino diazo esters bearing a quaternary stereogenic center were afforded in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee). Furthermore, the synthetic utility of the products has been depicted by the hydrogenation of the diazo moiety of adducts.

Enantioselective Hydrophosphonylation of in Situ Generated N-Acyl Ketimines Catalyzed by BINOL-Derived Phosphoric Acid.

An efficient route to pharmacologically interesting isoindolinone-based α-amino phosphonates is described via asymmetric hydrophosphonylation of in situ generated ketimines catalyzed by BINOL-derived phosphoric acid. The reaction proceeds smoothly at ambient temperature affording a variety of α-amino phosphonates with a quaternary stereogenic center embedded in isoindolinone motif in high yields with excellent enantiomeric ratios (up to 98.5:1.5 er). Several interesting transformations of the products into valuable synthetic intermediates are also depicted.

An Efficient Entry to syn- and anti-Selective Isoindolinones via an Organocatalytic Direct Mannich/Lactamization Sequence.

An organocatalytic direct Mannich-lactamization sequence for the syntheses of pharmacologically important enantioenriched isoindolinones is reported. The method utilizes simple α-amino acids to deliver syn- and anti- selective isoindolinones with remarkably high enantioselectivity (up to >99% ee) in good to excellent yields and diastereomeric ratios. The overall sequence involves one C-C and two C-N bond forming events in one pot starting from inexpensive starting material.

A general catalytic route to isoindolinones and tetrahydroisoquinolines: application in the synthesis of (±)-crispine A.

An unprecedented highly efficient Lewis acid catalyzed one-pot cascade has been demonstrated as a general catalytic system for the synthesis of diversely substituted isoindolinones and tetrahydroisoquinolines. The cascade effects one C-C and two C-N bond-forming events in one pot. Several interesting transformations of the products into valuable synthetic intermediates are featured with the successful total synthesis of (±)-crispine A.

Asymmetric direct vinylogous Michael addition to 2-enoylpyridine N-oxides catalyzed by bifunctional thio-urea.

Catalytic enantioselective direct vinylogous Michael addition of α,α-dicyanoalkenes to 2-enoylpyridine N-oxides with a bifunctional organocatalyst is described. The methodology offers an efficient way to install an asymmetric carbon-carbon bond at the γ-position of α,α-dicyanoalkenes in excellent regio-, diastereo-, and enantioselectivity. Further, application in desymmetrization of achiral α,α-dicyanoalkene to access highly functionalized enantioenriched cyclohexylidenemalononitrile derivatives has been demonstrated.