Organocatalytic Tandem Reaction to Construct Six‐Membered Spirocyclic Oxindoles with Multiple Chiral Centres through a Formal [2+2+2] Annulation

An efficient tandem reaction for the asymmetric synthesis of six‐membered spirocyclic oxindoles has been successfully developed through a formal [2+2+2] annulation strategy. The amine‐catalysed stereoselective Michael addition of aliphatic aldehydes to electron‐deficient olefinic oxindole motifs gave chiral C3 components, which were further combined with diverse electrophiles (activated olefins or imines) to afford spirocyclic oxindoles with versatile molecular complexity (up to six contiguous stereogenic centres, high diastereo‐ and enantioselectivities).     

Stereoselective synthesis of spirocyclic oxindoles based on a one-pot Ullmann coupling/Claisen rearrangement and its application to the synthesis of a hexahydropyrrolo[2,3-b]indole alkaloid

An efficient and convenient approach to the synthesis of spirocyclic oxindoles from iodoindoles has been developed. The most striking feature of this approach is that the sequential intramolecular Ullmann coupling and Claisen rearrangement proceeds in a one-pot manner to afford 3-spiro-2-oxindoles in good yield with excellent diastereoselectivity. Application of this one-pot reaction to chiral non-racemic tertiary alcohol substrates resulted in complete chirality transfer to the spirocyclic quaternary carbon. Using this method, asymmetric total synthesis of (−)-debromoflustramine B was accomplished.     

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.     

Extending Pummerer reaction chemistry. Asymmetric synthesis of spirocyclic oxindoles via chiral indole-2-sulfoxides

The conversion of (Ss)-3-(omega-allylsilane and silyl enol ether)indole-2-sulfoxides to spirocyclic indolenines and then to oxindoles proceeds, in favorable cases, with moderate levels of chirality transfer from sulfur to C3 of the indole core. A mechanistic model, which features either an Sn2'-like additive Pummerer sequence or a tight ion pair generated by an Sn1-like vinylogous Pummerer transform, is proposed to rationalize the sense of asymmetric induction.     

A novel method for the synthesis of functionalized spirocyclic oxindoles by one-pot tandem reaction of vinyl malononitriles with isatylidene malononitriles

One-pot synthesis of novel spirocyclic oxindoles was achieved via vinylogous Michael addition of vinyl malononitriles on isatin-malononitrile adducts as the key step followed by a sequential tandem reaction.     

Application of copper(II)-mediated radical cross-dehydrogenative coupling to prepare spirocyclic oxindoles and to a formal total synthesis of Satavaptan

Application of radical cross-dehydrogenative coupling (CDC) procedures to prepare a range of novel spirocyclic oxindoles and to a formal total synthesis of the vasopressin V₂ receptor antagonist Satavaptan is reported. The key step involves a copper-mediated oxidative cyclisation of a simple linear anilide precursor to give the spirocyclic oxindole core. This synthetic approach was also used to prepare novel Satavaptan scaffolds and analogues.     

Asymmetric pericyclic cascade approach to spirocyclic oxindoles

The reaction of chiral N-arylnitrones with carbocyclic alkylarylketenes generates spirocyclic oxindoles in good yields and with excellent levels of enantioselectivity (90-99% ee) via a pericyclic cascade process.     

Highly diastereoselective Claisen rearrangement leading to vicinal quaternary carbons construction of oxindoles

An efficient approach to spirocyclic oxindole architecture with vicinal quaternary carbon centers is described. The reaction of 2-allyloxyindolin-3-ones with cyanomethylphosphonate at low reaction temperature proceeds smoothly with consecutive olefination, isomerization, deacylation, and anion-accelerated Claisen rearrangement to give the 3,3-disubstituted oxindoles with vicinal quaternary all-carbon centers in high yield and diastereoselectivity. The oxindoles are readily converted into more synthetically advanced spiro-products.     

Asymmetric Double Michael Reaction Catalyzed by Simple Primary Amine Catalysts: A Straightforward Approach to Construct Spirocyclic Oxindoles

The enantioselective double Michael reaction of N‐Boc‐3‐nonsubstitued oxindoles with dienones catalyzed by chiral monoimide protected cyclohexane‐1,2‐diamines was developed. A wide range of optically active spirocyclic oxindoles were obtained up to 98% yield and up to 89% ee.     

A highly organocatalytic stereoselective double Michael reaction: efficient construction of optically enriched spirocyclic oxindoles

An effective double Michael reaction has been disclosed to access spirocyclic oxindoles in high yields (up to 98%) and excellent enantioselectivities (up to 98% ee).     

Efficient entry to diversely functionalized spirocyclic oxindoles from isatins through carbonyl-addition/cyclization reaction sequences

A novel approach to diversely functionalized spirocyclic oxindoles has been developed by using different metal-mediated carbonyl-addition/cyclization reaction sequences. Spirocyclization precursors, 2-indolinone-tethered homoallylic alcohols, (buta-1,3-dien-2-yl)methanols, and alpha-allenols have been obtained by regioselective addition of stabilized organoindium reagents to isatins in aqueous environment. Ruthenium-, silver-, and palladium-catalyzed reactions of the above unsaturated alcohol derivatives provided oxaspiro oxindoles.     

靛红Morita-Baylis-Hillman碳酸酯与环状N-磺酰亚胺的不对称烯丙基烷基化反应研究

本课题组近年来发展的通过路易斯碱催化靛红Morita-Baylis-Hillman(MBH)碳酸酯的烯丙基烷基化反应是合成光学纯3,3-二取代2-氧化吲哚化合物的一种有效方法. 在此基础上, 本文研究了手性叔胺催化靛红MBH碳酸酯与环状N-磺酰亚胺的不对称烯丙基烷基化反应, 通过亲电反应途径以较高的立体选择性(达86% ee, dr＞95∶5)和高收率(达96%)合成C-3位含季碳手性中心的多官能团氧化吲哚产物. 通过简单的转化可以得到含多个手性中心的2-吲哚酮-3,4'-哌啶环类骨架, 这为进一步合成生理活性物质研究奠定了基础.     

Access to spirocyclic oxindoles via N-heterocyclic carbene-catalyzed reactions of enals and oxindole-derived α,β-unsaturated imines

A diastereoselective access to β-lactam fused spirocyclic oxindoles and related compounds bearing all carbon spiro centers is described. This N-heterocyclic carbene-catalyzed process employed challenging β,β-disubstituted α,β-unsaturated imines to react with enals.     

Quinine-catalyzed asymmetric domino Michael-cyclization reaction for the synthesis of spirocyclic oxindoles bearing two spiro quaternary centers and three consecutive stereocenters

An efficient organocatalytic diastereo- and enantioselective method for the construction of spirocyclic oxindole derivatives bearing two spiro quaternary centers and three consecutive stereocenters via a domino Michael/cyclization process has been developed. Using commercially available quinine as catalyst, the reactions of 3-isothiocyanato oxindoles with unsaturated pyrazolones and unsaturated isoxazolones proceeded smoothly under mild reaction conditions for giving two classes of spirocyclic oxindole compounds in high to excellent yields with moderate to good diastereoselectivities and enantioselectivities. A plausible dual activation working model was tentatively proposed to account for the stereochemistry of the domino Michael/cyclization process.     

Palladium-catalyzed asymmetric benzylation of 3-aryl oxindoles

Herein we report palladium-catalyzed asymmetric benzylic alkylation with 3-aryl oxindoles as prochiral nucleophiles. Proceeding analogously to asymmetric allylic alkylation, asymmetric benzylation occurs in high yield and enantioselectivity for a variety of unprotected 3-aryl oxindoles and benzylic methyl carbonates using chiral bisphosphine ligands. This methodology represents a novel asymmetric carbon-carbon bond formation between a benzyl group and a prochiral nucleophile to generate a quaternary center.     

A convenient method for synthesis of polyfunctional dihydropyrrole spiro-fused oxindole-2-ones via an organocatalytic tandem Michael/cyclization sequence

A new methodology was developed for the synthesis of spirocyclic oxindoles bearing polyfunctional dihydropyrrole units via an organocatalytic tandem Michael/cyclization sequence. Products bearing adjacent quaternary–tertiary stereocenters were smoothly obtained in high yields (up to 97% yield) with excellent diastereoselectivities up to >20/1.     

Asymmetric Allylic Alkylation with Deconjugated Carbonyl Compounds: Direct Vinylogous Umpolung Strategy

An atom‐economic and highly efficient vinylogous umpolung strategy is developed for deconjugated carbonyl compounds, which generate electron‐deficient π‐allylpalladium complexes with Pd(OAc)₂ under ligand‐free conditions. In cooperation with a chiral‐phosphonium‐based phase‐transfer catalyst, the asymmetric direct oxidative allylic alkylations of 3‐substituted oxindoles are furnished under O₂ atmosphere. The γ‐ or even remote ?‐regioselective alkylation products, with substantial substituents, are delivered with excellent enantioselectivity, and can be further used to access diverse chiral spirocyclic architectures effectively. The Mukaiyama dienol silyl ether can be utilized similarly, indicating that the current active π‐allylpalladium species results from tautomerization of the Pd^II‐dienolate intermediate.     

Asymmetric synthesis of chiral oxindoles using isatin as starting material

Asymmetric synthesis plays an important role in the synthesis of therapeutics and natural products. Asymmetric oxindoles with a stereogenic quaternary carbon center are extensively present in various natural products and biologically active compounds. Several methods such as employing chiral auxiliaries or chiral catalysts were developed for asymmetric synthesis of spirooxindoles or 3,3-disubtituted oxindoles. In this review, we make a detailed overview of the latest developments in the use of isatin as starting material for the asymmetric synthesis of spirooxindoles and 3,3-disubstituted oxindoles during the period from 2015 to 2017.     

N-heterocyclic carbene-catalyzed homoenolate additions with N-aryl ketimines as electrophiles: efficient synthesis of spirocyclic γ-lactam oxindoles

In pole position: A simple and efficient approach to spirocyclic γ-lactam oxindoles by the N-heterocyclic carbene catalyzed addition of homoenloate equivalents to N-aryl isatinimines has been developed (see scheme). The use of N-aryl isatinimines as electrophiles in the NHC-catalyzed umpolung reaction of α,β-unsaturated aldehydes is demonstrated for the first time.     

Copper-catalysed approach to spirocyclic oxindoles via a direct C–H,Ar-H functionalisation

A practical and efficient entry to spirocyclic oxindoles from readily accessible anilide precursors, using only catalytic amounts of an inexpensive copper salt together with air as the sole re-oxidant, is described. In addition to providing access to a broad range of spiro-oxindole products, the utility of this method is demonstrated in a formal synthesis of the natural product, horsfiline.