Organocatalytic double arylation of 3-isothiocyanato oxindoles: Stereocontrolled synthesis of complex spirooxindoles

Quinones, precursors of aromatic structures, were firstly employed as the electrophiles for the organocatalytic Michael addition/cyclization cascade reaction with versatile 3-isothiocyanato oxindoles. Chiral bifunctional organocatalyst was appropriate for this enantioselective transformation to afford a variety of novel spirooxindoles, possessing a spirocyclic stereocenter adjacent to the aromatic ring, via asymmetric double arylation. These synthesized spirooxindoles are very difficult to access by the reported methods and were obtained in excellent chemical yields with excellent enantioselectivities.     

Recent Progress on Routes to Spirooxindole Systems Derived from Isatin

Because of their definite or potential biological and pharmaceutical activities, spirooxindole heterocycles have been widely studied, and there has occurred a research boom on routes to these significant compounds in recent years. This review surveys the last 5‐year progress on the construction of spirooxindole systems derived from isatin with typical examples.     

Mg-catalyzed one-pot preparation of benzimidazoles and spirooxindoles by an immobilized chlorophyll b on magnetic nanoparticles

Chlorophyll b was extracted from Heliotropium europaeum plant, then immobilized on magnetic nanoparticles (Fe₃O₄@SiO₂@Chl-Mg) and found as an efficient and green catalyst for the preparation of a variety of benzimidazoles and spirooxindoles in mild conditions. The catalyst was fully characterized by Fourier-transform infrared (FTIR), ultraviolet–visible (UV–vis) spectroscopy, X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDX), thermogravimetric (TGA), vibrating sample magnetometer (VSM), transmission electron microscopy (TEM), and dynamic light scattering (DLS) analyses. To prove the catalytic influence of Mg over the reactions, the catalytic activity of the demetalated chlorophyll b as well as some other control experiments was investigated. High to excellent yields were achieved for all entries, whether benzimidazole or spirooxindole derivatives at short reaction times. The catalyst could be recovered and reused for several consecutive runs by a simple external magnetic field without any considerable reactivity loss. The properties of the recovered catalyst were investigated by various analyses. Finally, the reasonable mechanisms were proposed for the reactions based on the literature.     

Phosphine‐mediated Highly Enantioselective Spirocyclization with Ketimines as Substrates

Phosphine‐catalyzed enantioselective annulation reactions involving ketimines are a daunting synthetic challenge owing to the intrinsic low reactivity of ketimine substrates. A highly enantioselective [3+2] cycloaddition reaction that makes use of isatin‐derived ketimines as reaction partners was developed. Notably, both simple and γ‐substituted allenoates could be utilized, and various 3,2′‐pyrrolidinyl spirooxindoles with a tetrasubstituted stereocenter were obtained in excellent yields and with nearly perfect enantioselectivity (>98 % ee in all cases).     

Engaging Allene‐Derived Zwitterions in an Unprecedented Mode of Asymmetric [3+2]‐Annulation Reaction

Catalytic addition of chiral phosphine, that is, (R)‐ or (S)‐SITCP, to an α‐substituted allene ester generated a zwitterionic dipole. Under optimized reaction conditions, this dipole could engage isatine‐derived N‐Boc‐ketimines in a novel mode of [3+2] annulation reaction. Pyrrolinyl spirooxindoles are thus afforded in high yields and with excellent enantioselectivities. The unprecedented annulation reaction successfully facilitated the construction of sp³‐rich and highly substituted 3,2′‐pyrrolidinyl spirooxindoles supporting many chiral centers.     

An expedient synthesis of spirooxindoles incorporating 2-amino pyran-3-carbonitrile unit employing dialkyl acetone-1,3-dicarboxylates

Spirooxindoles are a class of molecules possessing significant biological effects such as antiviral, antifungal, antibacterial and anticancer properties. Herein we report a series of spirooxindole molecules having 2-amino pyran-3-carbonitrile and with two ester groups. These molecules were prepared by the reaction of dialkyl acetone-1,3-dicarboxylate and isatilidenes in the presence of triethyl amine.     

Refactoring the Concise Biosynthetic Pathway of Cyanogramide Unveils Spirooxindole Formation Catalyzed by a P450 Enzyme

Cyanogramide ( 1 ) from the marine actinomycete Actinoalloteichus cyanogriseus WH1‐2216‐6 features a unique spirooxindole skeleton and exhibits significant bioactivity to efficiently reverse drug resistance in tumor cells. The biosynthetic gene cluster of 1 in A. cyanogriseus WH1‐2216‐6 was identified and refactored by promoter engineering for heterologous expression in Streptomyces coelicolor YF11, thereby enabling the production of 1 and five new derivatives. Interesting, four of them, including 1 , were identified as enantiomeric mixtures in different ratios. The functions of tailoring enzymes, including two methyltransferases (CyaEF), and three cytochrome P450 monooxygenases (CyaGHI) were confirmed by gene inactivation and feeding experiments, leading to the elucidation of a concise biosynthetic pathway for 1 . Notably, CyaH was biochemically verified to catalyze the formation of the spirooxindole skeleton in 1 through an unusual carbocation‐mediated semipinacol‐type rearrangement reaction.     

Enantioselective Cascade Michael Addition/Cyclization Reactions of 3‐Nitro‐2H‐Chromenes with 3‐Isothiocyanato Oxindoles: Efficient Synthesis of Functionalized Polycyclic Spirooxindoles

An unprecedented Zn(OTf)₂‐catalyzed asymmetric Michael addition/cyclization cascade of 3‐nitro‐2H‐chromenes with 3‐isothiocyanato oxindoles has been disclosed. This transformation provides an efficient access to various synthetically important polycyclic spirooxindoles in a highly stereoselective manner under mild conditions (72–99 % yields, up to >95:5 d.r. and >99 % ee). The reaction leads to the formation of three consecutive stereocenters, including 1,3‐nonadjacent tetrasubstituted carbon stereocenters, in a single operation. A bifunctional activation model of the chiral Zn(OTf)₂/bis(oxazoline) complex was proposed based on control experiments, wherein the Zn^II moiety serves as a Lewis acid and the N atom of the free NH group acts as a Lewis base by a hydrogen‐bonding interaction.