Organocatalytic Direct Asymmetric Aldol Reactions of 3-Isothiocyanato Oxindoles to Ketones: Stereocontrolled Synthesis of Spirooxindoles Bearing Highly Congested Contiguous Tetrasubstituted Stereocenters

Abstract

The first example of a direct catalytic asymmetric intermolecular aldol reaction of 3-isothiocyanato oxindoles to simple ketones with bifunctional thiourea-tertiary amine as catalyst is reported. This strategy provides a promising approach for the asymmetric synthesis of a range of enantioenriched spirocyclic oxindoles bearing two highly congested contiguous tetrasubstituted carbon stereocenters. Versatile transformations of the spirocyclic oxindole products into other structurally diverse spirocyclic oxindoles have also been demonstrated.The catalytic asymmetric aldol reaction is one of the most important methods for the asymmetric formation of CÀC bonds and has found widespread application in organic synthesis.1 In this respect, in contrast to the remarkable advances that have been made with aldehydes as electrophiles, 1,2 the development of aldol additions to ketones was quite slow.3 This state is attributable, at least in part, to the lower reactivity of ketones and the decreased steric discrimination compared to aldehydes. 4 Therefore, the direct asymmetric ketoneÀaldol reactions to date mainly focus on the activated ketone electrophiles 5 or intramolecular aldol additions based on enamine catalysis.

Efficient synthesis of functionalized spiro[imidazolidine-2-thione-oxindoles] via catalyst-free domino Mannich cyclization

“…The spirocyclic oxindole derivatives are recognized as attractive synthetic targets because of their prevalence in numerous natural products and pharmaceutical agents as well as useful intermediates for the easy access of a variety of heterocyclic compounds by rearrangement reaction due to their steric strain associated with the quaternary carbon. [1][2][3][4] Recently, 3-isothiocyanato oxindoles have been used as the most attractive substrates in catalytic cascade Michael/cyclization reactions, [5][6][7][8][9] Mannich/cyclization reactions [10][11] Aldol/cyclization reactions [12][13] and [3+2] cyclization [14][15][16][17][18] for the synthesis of the highly functionalized spirocyclic oxindole derivatives.…”

Construction of Spirocyclic Oxindoles through Regio‐ and Stereoselective [3+2] or [3+2]/[4+2] Cascade Reaction of α,β‐Unsaturated Imines with 3‐Isothiocyanato Oxindole

“…[2] Recently,akind of highly reactive oxindole derivative, 3-isothiocyanato oxindole, was used for the synthesis of spirooxindoles with an itrogen atom at the C3-position of the oxindole unit. [3,4] On the basis of cycloaddition of 3-isothiocyanato oxindole with electron-deficient unsaturated bonds,s uch as C=O, C=N, C=C, N=N, and C C, av ariety of novel spirooxindoles have been synthesized.[4] For example, Yuan and coworkers discloseda no rganocatalyst-directeda symmetrica ldol reactiono f3 -isothiocyanato oxindoles with simplek etones; [4a] Kanai and Matsunaga's group reported aS r-catalyzed asymmetric Mannich-type reactiono fi sothiocyanato oxindoles with electron-deficient imines;[3c] Wang and co-workerse xplored ah ighly efficient bi-or multifunctional cinchonaa lkaloid-catalyzed asymmetric Michael addition/cyclizationr eaction of isothiocyanato oxindoles with electron-deficient olefins. Encouraged by these elegant studies as well as our recent successes in preparing diverses pirocyclico xindoles, [5] we reasoned that 3-isothiocyanato oxindoles could undergo diversified regio-and stereoselective [6] cycloadditions with imines [7] containing two or three electron-deficient unsaturated bonds to achieves tereocontrolledd ivergent synthesis of spirocyclic oxindoles (Scheme 1).…”

Asymmetric Michael/Cyclization Cascade Reaction of 3-Isothiocyanato Oxindoles and 3-Nitroindoles with Amino-Thiocarbamate Catalysts: Enantioselective Synthesis of Polycyclic Spirooxindoles

“…13 Product 3a could be readily transformed into compound 4 with iodomethane and K 2 CO 3 according to the reported procedure. 5 Similarly, reacting 3a with benzyl bromide gave compound 5 bearing a benzylated thiolactam ring. Notably, 4 and 5 could be obtained in nearly quantitative yields and no changes happened in dr and ee values during the conversions.…”