Stereoselective Domino Reactions in the Synthesis of Spiro Compounds

Abstract

This review summarizes the latest developments in asymmetric domino reactions, with the emphasis on the preparation of spiro compounds. Discussions on the stereoselectivity of the transformations, the reaction mechanisms, the rationalization of the stereochemical outcome, and the applications of domino reactions to the synthesis of biologically active molecules and natural products are included when appropriate.

1 Introduction

2 Asymmetric Domino Reactions

2.1 Domino Reactions Initiated by Michael Reactions

2.2 Domino Reactions Initiated by Mannich Reactions

2.3 Domino Reactions Initiated by Knoevenagel Reactions

2.4 Domino Reactions Initiated by Cycloaddition Reactions

2.5 Domino Reactions Initiated by Metal Insertion

2.6 Other Mechanisms

3 Conclusion

Biographical Sketches

M.Sc. Regina Westphal was born in 1995 in Aimorés, MG, Brazil. She obtained her bachelor (2016) and M.Sc. degrees (2019) in chemistry, working on synthesis of triazine derivatives with anticorrosive activity, at Federal University of Espírito Santo (Espírito Santo, Brazil), under supervision of Prof. Sandro José Greco. Currently, she is a doctoral student at the same University under supervision of Prof. Sandro José Greco working on the synthesis of spiro compounds with potential anticancer and anti-Alzheimer activities through asymmetric multicomponent organocatalyzed reactions.

Dr. Eclair Venturini Filho was born in 1989 in São Paulo, Brazil. He graduated in Chemistry (2014) from the Federal University of Viçosa (Minas Gerais, Brazil) and obtained his M.Sc. degree (2016) at the Federal University of Espírito Santo (UFES, Espírito Santo, Brazil). He also received his Ph.D. in Chemistry (2021) under the supervision of Professor Sandro Greco from UFES. Recently he began postdoctoral research at UFES under the leadership of Professor Sandro Greco working on stereoselective organocatalyzed synthesis.

Dr. Fabrizio Medici obtained his master’s degree in organometallic chemistry at the University of Insubria in Como. He then moved to Paris and joined the group of Pr. Louis Fensterbank at Sorbonne University, where he obtained his Ph.D. in 2017 with a thesis on silicon complex based Lewis acids. After a postdoctoral fellowship at ICSN under the supervision of Dr. Voituriez and Dr. Marinetti working on photoswitchable bis Au(I) complexes, he returned to Italy, and he is currently working under the supervision of Prof. Benaglia on the development of stereoselective photochemical and electrochemical organic reactions.

Professor Maurizio Benaglia was born in Bergamo in 1966; after completing his doctoral studies at the University of Milano with Prof. M. Cinquini and F. Cozzi and two years as a postdoctoral fellow with Prof. Jay Siegel, at UCSD, University of California, San Diego, he was appointed in 2006 as Associate Professor and in 2015 as Full Professor of Organic Chemistry at the Department of Chemistry of the Università degli Studi di Milano. His research focuses on the development of novel sustainable synthetic methodologies and of new chiral organocatalysts, the study of stereoselective reactions in flow and with catalytic reactors, the synthesis of pharmaceutical products, taking advantage also of 3D-printing technologies, (organo)photoredox catalysis, organic electrochemistry, and alternative, biodegradable reaction media.

Professor Sandro J. Greco was born in 1974 in Rio de Janeiro, RJ, Brazil. He received his B.Sc. degree in chemistry in 1997 and his M.Sc. and Ph.D. degrees in 2001 and 2005 from the Federal University Fluminense (Rio de Janeiro, Brasil), working under the guidance of Professor Sergio Pinheiro on studies of the use of terpenes and terpenoids in the enantioselective synthesis of potential anticholinergic agents, and on the synthesis of amino alcohol based, new chiral phase-transfer catalysts. In 2006, he joined Professor Maria D. Vargas’s group at the Federal University Fluminense as a postdoctoral researcher to work on the synthesis and pharmacological evaluation of new anticancer drugs containing the ferrocenyl group. Currently he is associate professor of organic chemistry at the Federal University of Espírito Santo, with research interests in the design and synthesis of compounds with anticancer activities, asymmetric organocatalytic synthesis, asymmetric phase-transfer catalysis, and the development of new methodologies for multicomponent reactions.

Introduction

Organic synthesis, a fascinating and thought-provoking science, provides, among many other challenges, the preparation of highly complex three-dimensional chiral structures with complete control of stereochemistry. Also, in this context, the regio- and stereoselective synthesis of spiro compounds has a prominent role.[1]

Spiro compounds are bicyclic organic compounds with rings linked by a single atom (spiro atom) that present exceptional features, such as complexity and three-dimensional structure, besides the conformational rigidity of their scaffold. These compounds present many biological activities (Figure [1]).[2] Therefore, these molecules are excellent frameworks for medicinal chemistry.

Spiro compounds with their three-dimensional structures and conformational rigidity provide an efficient design of the pharmacophore and, consequently, a tool for rational optimization of H-bonding, hydrophobic, and π-stacking interactions. These properties can benefit the interaction drug/biological target and improve the solubility and lipophilicity of the drug.[3]

Moreover, in the preparation of spiro compounds there is the possibility to rapidly obtain a library of molecules, through structural modifications (functionalization), which comes from the different starting materials. This is an advantage when compared to common flat/aromatic scaffolds.[3] However, this advantage is still little explored, and the low diversity reflects the need for new methodologies for their efficient synthesis and derivatization.

It is worth mentioning the structure of spirooxindoles (Figure [1], compound 11), present in a large number of natural compounds, with relevant and different biological activities.[4] For several decades the synthesis of spirooxindoles has been a subject of interest for synthetic chemists, however, it is generally achieved by multiple-step synthesis in low yield and mostly with low stereoselectivity.[5] Although, recently, new spirooxindoles, analogous to natural products, have been efficiently synthesized through domino reactions as we will see throughout this review.

Another important use of spiro compounds is in organic optoelectronics and, these semiconductors as active offer several advantages over their inorganic counterparts.[6] Some examples of spiro compounds used as organic optoelectronics are shown in Figure [2].[6]

Spiro compounds are part of the structure of many natural products. One of the first isolated was β-vetivone (15), extracted from vetiver oil in 1939.[7a] Among natural products, alkaloids have a prominent place. To exemplify this class of compounds, marine alkaloid (+)-discorhabdin A (26) and the fused tetracyclic lycopodium alkaloid nankakurine A (30) are shown in Figure [3], along with other selected natural products.[7]

Finally, spirocyclic compounds have emerged as organocatalysts in asymmetric synthesis. The structural rigidity and 3D structure can assist in stereoselection in stereoselective reactions. Some organocatalysts, such as spirobiindane (spinol) 31, spirobis(oxazoline) 32, spinol-derived phosphoric acid 33, diphosphine spirOP 34, and the spiroketal diphosphine 35 are illustrated in Figure [4].[3] [8]

The chemistry of spiro compounds, however, still presents several challenges, such as difficulty in interconverting and introducing functional groups after formation of the 3D structure and, from a stereoselective perspective, the presence of the quaternary and generally stereogenic spiro atom.

Domino reactions have attracted great attention from the scientific community and this can be seen in the numerous reviews published.[9] However, as far as we know, no previous publication was dedicated specifically to the asymmetric synthesis of spiro compounds. Therefore, the present review aims to describe the recent advances in asymmetric domino reactions developed specifically for the synthesis of spiro compounds.

Domino reaction, according to Tietze, are reactions that involve the formation of two or more bonds using the same reaction conditions, without outside interference after the reaction begins, that is, after starting the reaction, reagents, including the catalyst, can no longer be added. Furthermore, the subsequent reactions are a consequence of the intermediates formed by bond formation or fragmentation in the previous step.[10]

It should be noted that this definition was used as a basis for bibliographic research and for the manuscript preparation. In addition, the domino reactions will be classified in this review based on the reaction types involved in the first synthetic step.

Asymmetric Domino Reactions

Domino Reactions Initiated by Michael Reactions

Michael-type reactions are one of the most powerful tools for the stereoselective formation of carbon–carbon and carbon–heteroatom bonds. Undoubtedly, domino reactions initiated by the Michael reaction have been highlighted in the synthesis of spiro compounds as shown in this section.

Michael/Michael Domino Reactions

The Michael/Michael domino reaction is an important strategy in the synthesis of spiro compounds existing in the framework of many natural products. For example, in 2019 Zhou and co-workers reported the first use of an organocatalytic Michael/Michael domino reaction to prepare a pyrazolone-chromone synthon, which served to access hexahydroxanthone derivatives 36 with five continuous stereocenters, including two all-carbon quaternary spiro-stereocenters. These products were obtained in 55–87% yield, dr >20:1, and 90–99% ee under mild conditions (Scheme [1]).[11]

The stereoselection mechanism is shown in Scheme [2]. The tertiary amine of the catalyst activates pyrazolone 37 by deprotonation of the enol hydroxyl. At the same time, double hydrogen bonding interactions between the thiourea hydrogen atoms of the catalyst 38 and the carbonyl group activates 39. The Re-face of 39 is preferably attacked by the Si-face of enolized pyrazolone 37 to form the desired Michael adduct.

Spiropyrazolone-based cyclohexanes, cyclohexanones, and cyclohexenones have attracted interest due to their various biological activities as phosphodiesterase inhibitors[12a] and as antimicrobial, anticancer, and anti-inflammatory agents.[12]

An efficient diastereoselective Michael/Michael domino reaction of δ-nitro-α,β-unsaturated esters 40 with alkylidenepyrazolones 41 catalyzed by DABCO as the organocatalyst was made by Singh and co-workers to form carbocyclic spiropyrazolones 42 with three tertiary stereogenic centers and a quaternary stereocenter in high yields and excellent diastereoselectivities (Scheme [3]).[13]

This reaction was also performed in its enantioselective version using several cinchona alkaloids and their derivatives, but low enantiomeric excess was obtained (Scheme [3]).[13]

The synthesis of functionalized pyrazolones, like the previously described, has attracted considerable attention because of their potent bioactivities in medicinal chemistry.[14] Some structures are described in the Scheme [3].

The naturally occurring spirooxindoles as citrinalin B (27) and horsfiline (28) (Figure [3]) have diverse biological activities. Inspired by the natural spirooxindoles, new therapeutic agents have been prepared from a variety of reagents and substrates providing some clinical trials or preclinical studies.[15] In this sense, a series of spirocyclopentane-oxindoles 50 with four consecutive stereocenters including quaternary α-nitro esters were prepared in good yields (up to 73%) and excellent enantioselectivities (up to 97% ee), through enantioselective Michael/Michael domino reaction using nitroalkenes.[16] The reaction was realized and optimized with the aid of a chiral squaramide-amine catalyst 51 (Scheme [4]).

Five similar examples, were reported by the groups of Sasai, Wang, Quintavalla, Gong, and Melchiorre (Scheme [5]).[17]

In the work of the Sasai group the reaction of an α-substituted oxindole 54 with 1-phenylprop-2-yn-1-one (55), was promoted by the chiral multifunctional phosphine catalyst derived from (S)-valine 56, giving the respective spiro compound 57, in good yield and high enantioselectivity.[17a] In work by the Wang group, five-membered spirooxindoles 58 containing four consecutive stereocenters, including a spiro quaternary center, were constructed through reaction between 3-substituted bifunctional oxindoles 59 and α,β-unsaturated aldehydes 60, catalyzed by a chiral secondary amine 61. High diastereo- and enantioselectivities can be obtained via an organocatalytic iminium Michael/enamine Michael.[17b] A new domino Michael/Michael reaction between 2-(2-oxoindolin-3-ylidene)acetic esters 62 and nitroenoates 63 catalyzed by chiral bifunctional thiourea 64 that gave five- and six-membered spirooxindoles 65 was reported by the Quintavalla group.[17c] The Gong group carried out the asymmetric synthesis of spirocyclohexan-4-one-1,3′-oxindole derivatives 66 with excellent enantioselectivity, using a bifunctional organocatalytic Michael/Michael reaction (formal [4+2] cycloaddition) between the Nazarov reagents 67 and methyleneoxindoles 68.[17d] Finally, the Melchiorre group developed an organocatalytic enamine Michael/iminium Michael domino reaction between α,β-unsaturated ketones 70 and oxindole derivatives 71 for the synthesis of complex spirocyclohexane-oxindoles 72 with extraordinary levels of stereocontrol. In addition, they also developed an enamine-iminium-enamine/intramolecular aldol strategy, for the preparation of spirooxindoles using α,β-unsaturated aldehydes instead of ketones.[17e]

The construction of five-membered spirooxindoles was developed by Du and Zhao through a bifunctional squaramide-catalyzed Michael/Michael domino reaction. The corresponding products 74 with five contiguous stereocenters including a quaternary center were obtained in good to excellent yields with excellent stereoselectivities (Scheme [6]). Moreover, the potential of this methodology was confirmed by a gram-scale synthesis, of the resulting adduct by a one-pot four-component reaction.[18]

Dispirooxindole-cyclopentane-oxindoles 78 with two adjacent quaternary carbon centers and four consecutive cycles, were efficiently prepared by Wang and co-workers using a Michael/Michael domino cycloaddition reaction (Scheme [7]).[19a] The spiro compounds were obtained in excellent yields and diastereoselectivities under mild conditions and in a few minutes. Also in this case, a scale-up was performed with excellent results. A proposed mechanism for the Michael/Michael domino reaction is shown in Scheme [7]. Initially, the enolate 81, formed in the presence of the base, reacts with the isoindigo 79 via a Michael addition generating the adduct 82. This latter reacts with the double bond of the alkylidene-succinimide, via a second Michael addition, providing the final product 78.

The use of isoindigos bearing various R¹ and R² groups was examined. The reaction did not occur when R² was H or a methyl group, possibly due to the poor solubility of the isoindigos. Furthermore, by varying the substituents R³ and R⁴ on the α-alkylidenesuccinimide it was found that aryl substituents in the ortho position provided low yields, while substituents on the para position provided better yields. Notably, electron-withdrawing groups were more favorable.

Dispirooxindole-pyrrole-oxindoles 83 and spiroaziridine-oxindoles were also efficiently prepared by Wang and co-workers using a Michael/Michael domino reaction between methyleneoxindoles 84 and N-(tosyloxy)carbamates 85 (Scheme [7]).[19b] Similarly, Zhou and co-workers have prepared dispirooxindole-hexahydroxanthone-oxindoles 86 with five contiguous stereocenters (Scheme [7]). Antitumor activity evaluation of these compounds revealed that they exerted good cytotoxic effects on human K562, A549, and PC-3 cells.[19c]

A remarkably example of a Michael/Michael reaction between a naphthoquinone and nitroalkenes was recently presented by Hayashi and co-workers.[20] In this work functionalized spirocyclopentane-1,2′(1′H)-naphthalene derivatives with four continuous stereocenters were synthesized with excellent diastereo- and enantioselectivities (Scheme [8]). The reaction consists of the domino Michael/exo-Michael reaction of 2-(2-formylethyl)naphthalene-1,4-dione (89) and nitroalkenes 90 catalyzed by diphenylprolinol silyl ether 61a. To determine the absolute configuration, the obtained compound 91 was converted into diketone 92 through a 6-step synthesis.

A domino reaction, based on an organocatalyzed sulfa-Michael/Michael sequence, was applied in the asymmetric synthesis of spiropyrazolone-tetrahydrothiophenes 93 bearing three consecutive stereocenters in good yield and good diastereo- and enantioselectivity (Scheme [9]) by Meninno, Overgaard, and Lattanzi in 2017.[21] Tetrahydrothiophenes represent a fundamental class of heterocyclic compounds endowed with several biological activities,[22] illustrative structures are shown Scheme [9].

A catalytic cycle for the sulfa-Michael/Michael domino reaction catalyzed by 94 is given in Scheme [10]. The bifunctional organocatalyst deprotonates the pronucleophile 4-mercaptobut-2-enoate 95, whereas the pyrazolone 41 is steered by the thiourea group via hydrogen bonding. In this complex, the nucleophilic thiol attacks the Si-face of the Michael acceptor to give the (S)-configured adduct. Then, the enolate adduct attacks the Re-face of the enoate acceptor to give the (5R,6S,9R)-configured product.

In 2014, the Zhao group developed a domino sulfa-Michael/Michael reaction catalyzed by cinchona-derived thiourea 95 that gave spirooxindole-tetrahydrothiophenes 96 with high stereoselectivity (Scheme [9]).[23] Another enantioselective organocatalytic domino sulfa-Michael/Michael reaction, described by Li and co-workers in 2015, between 2-arylideneindane-1,3-diones 98 and 4-mercaptobut-2-enoate 99 in the presence of a tertiary amine-thiourea organocatalyst 100 gave chiral spiroindane-1,3-dione-tetrahydrothiophene skeletons 101 (Scheme [9]).[24]

Spirocyclic azlactones are usual precursors of cyclic quaternary amino acids. These compounds are of interest as building blocks for the synthesis of artificial peptide analogues with controlled geometry in the peptide backbone.[25] Peters and co-workers performed the catalytic asymmetric synthesis of spirocyclic azlactones 106 with moderate diastereoselectivities and high enantioselectivities using a Michael/Michael addition approach (Scheme [11]).[26]

This protocol involves a Pd^II-catalyzed double 1,4-addition of an in situ generated azlactone intermediate to the dienone (a formal [5+1] cycloaddition). The catalyst used, a planar chiral ferrocene bispalladacycle 107, suggests a monometallic reaction pathway.[26] Spectroscopic studies showed that the spirocycles prefer a twist to a chair conformation of the cyclohexanone moiety.

Chiral spirooxindole-δ-lactones 110 with three contiguous stereocenters including an all-carbon quaternary center was obtained by Xu and co-workers using a novel bifunctional thiourea 111 that catalyzed formal [5+1] cycloaddition of oxindoles 112 and ester-linked bisenones 113 (Scheme [12]).[27] This methodology involves a Michael/Michael addition and provided the desired compounds with high diastereoselectivities and enantioselectivities. Based on experimental results, a proposed mechanistic route for the control by the catalyst has oxindole and enone activated by the bifunctional thiourea group of the catalyst generating intermediate 114, which undergoes an intramolecular Michael addition to become intermediate 115. Then, another intramolecular Michael addition of the oxindole with the Si-face of the enone provides 110 and regenerates the catalyst (Scheme [12]).

Sheng and co-workers developed a Michael/Michael domino reaction for the preparation of spirooxindole-tetrahydrothiopyrans 116 from 3-(allylsulfanyl)oxindoles 117 and diverse enals 118. The reactions were catalyzed by diphenylprolinol silyl ether 61a in the presence of PhCO₂H as an additive (Scheme [13]).[28] The products were obtained in moderate to good yields and with excellent diastereo- and enantioselectivities. The spirooxindoles were validated as a new class of p53-MDM2 protein–protein interaction inhibitor with good antitumor activity. According to the proposed mechanism (Scheme [13]), first Michael addition occurs between the nucleophilic C3 of oxindole 117 and the conjugated double bond of the iminium ion, formed from the reaction of enal 118 and catalyst 61a. Then, the second Michael addition (intramolecular) provides the desired compound 116. This was the continuation of an earlier work developed by the Sheng group on anti-tumor spirooxindole-tetrahydrothiopyran derivatives.[29]

Lin and co-workers[30] realized the stereoselective synthesis of 2,6-trans-disubstituted spirocyclohexanone-1,2′-indanediones. Two chiral cinchona alkaloid derivatives catalyzed the synthesis of the thermodynamically less stable 2,6-trans-disubstituted spiroindanediones 119 and 120. Both of the enantiomeric forms of the trans isomer are obtained in excellent yields and enantioselectivities (Scheme [14]).

An important objective of Linn’s work[30] was to transform the kinetic trans-spiranes, into the thermodynamically stable cis congeners, thus demonstrating the generality of this method for the synthesis of all four stereoisomeric forms of the product. Mechanistic investigations revealed two competing pathways, a concerted Diels–Alder reaction and a stepwise Michael addition (Scheme [15]).

Another similar example of the synthesis of spirocyclohexane-indanediones was reported by Zhang and co-workers. An organocatalytic cascade Michael/Michael reaction between 2-arylideneindane-1,3-diones 123 and curcumins 125 was used to prepare multicyclic spiroindane-1,3-diones 126. Prolinol, chiral thiourea-tertiary amines, and cinchona alkaloids were evaluated as catalysts, and quinine 127 was identified as the best choice for the transformation (Scheme [14]).[31]

A quinine derivative 77 was also used as an organocatalyst by Grošelj and co-workers in the double spirocyclization of arylidene-2-pyrrolin-4-ones 128 with 3-isothiocyanatooxindoles 129 through a Michael/Michael domino reaction (1,4-/1,2-addition sequence). The goal was to construct dispirooxindole-pyrrolidinethione-2-pyrrolin-4-ones 130 (Scheme [16]).[32] The products containing three contiguous stereocenters were obtained with up to 98% ee and dr up to 99:1. The absolute configuration of the major diastereomer was determined by single crystal X-ray analysis. A plausible transition state to justify this configuration is shown in Scheme [16], where the protonated catalyst activates and coordinates the pyrrolone electrophile through the protonated quinuclidine moiety, while squaramide functionality orients and activates the nucleophile for the attack. The Si-face of the nucleophile attacks the Re-face of the electrophile, then spirocyclization occurs, yielding the desired compound.

In 2020, Sun and co-workers reported a simple, direct, and highly enantioselective synthesis of spirooxindole-piperidin-2-one derivatives 131 through a domino aza-Michael/Michael reaction using a squaramide catalyst. The desired products were obtained in excellent yields (up to 99%) and good to high stereoselectivities (up to >20:1 dr and up to 99% ee) under mild conditions (Scheme [17]).[33] A spirooxindole scaffold bearing a quaternary carbon stereocenter at C3, especially with a N-heterocycle, is a ubiquitous structural moiety in many bioactive natural products and synthetic compounds.[5] [15b] [34]

Under the optimized conditions, the reaction scope of various 3-methyleneoxindoles 75′ and N-protected acrylamides 133′ were also examined. Steric hindrance at both the α- and β-position of acylamides resulted in a decrease in the yield, albeit with excellent stereoselectivities. The transition state and mechanism are proposed to rationalize the outcome of stereoselectivities (Scheme [18]).

The squaramide moiety of the catalyst orients and activates 3-methyleneoxindole via hydrogen bonding. Simultaneously, the α,β-substituted acylamide were activated by the tertiary amine of the quinine component of the catalyst. Then, the Re-face of the activated 3-methyleneoxindole is attacked by α,β-substituted acylamide through an N-Michael addition. Subsequent intramolecular Michael addition to the Si-face of the α-carbonyl carbon of the acylamide furnishes the desired enantioenriched and less steric hindered product.

Other examples of diastereo- and enantioselective domino aza-Michael/Michael reaction have been reported by the Du group for the preparation of spiropyrrolidine-pyrazolones 134,[35a] spiropyrazolone-tetrahydroquinolines 135,[35b] spirooxindole-tetrahydroquinolines 136,[35c] and spirooxindole-3,3′-pyrrolidines 137 (Scheme [17]).[35d] It is important to highlight that in all these reactions, the best results were obtained when a chiral bifunctional tertiary amine squaramide was used as a catalyst.

Spirooxindole-tetrahydroquinolines 147 were synthesized by the Zhao group using an efficient amine acid-derived thiourea 148 catalyzed asymmetric aza-Michael/Michael domino reaction of various 3-methyleneoxindoles 75 with β-[o-(tosylamino)phenyl]-α,β-unsaturated ketones 149 (Scheme [19]).[36]

A chiral amine-catalyzed oxa- and aza-Michael/Michael domino strategy was used by Zhu and co-workers to synthesize enantiomerically enriched spirochromane-3,3′-oxindoles 150 or spirooxindole-3,3′-tetrahydroquinolines. The processes provided excellent stereocontrol (dr >20:1, >99% ee) in moderate conditions depending on the different Michael donors (Ar-OH/Ar-NHR) employed (Scheme [19]).[37]

In 2022, Li, Wang, Yan, and co-workers described an asymmetric domino sulfa-Michael/Michael reaction catalyzed by quinidine-derived ammonium salt 154 as a phase transfer catalyst employing 4-mercaptobut-2-enoates 155 with 3-(difluoromethylene)oxindoles 156. This method used only 5 mol% of phase transfer catalyst and gave CF₂H-containing spirooxindole-3,3′-thiophenes 157 under mild conditions in 75–98% yields and excellent diastereoselectivities and enantioselectivities at low reaction times (Scheme [20]).[38]

In addition, they highlighted the formation of three stereocenters including two vicinal quaternary centers in one step. A crystal structure of the product and experimental results aided in the proposed mechanism via a domino-reaction model involving ion pairing and H-bonding between the catalyst and substrate as factors that gave rise to high stereoselectivity (Scheme [21]).[38]

Michael/Aldol Domino Reactions

Another domino methodology initiated by a Michael reaction widely described in the literature is the Michael/aldol sequence; examples of this methodology are discussed in this section.

In 2019, Ričko and co-workers developed a new methodology for organocatalyzed sulfa-Michael/aldol domino spirocyclizations with mercaptoacetaldehyde dimer 158 using 2-pyrrolin-4-ones 159 as substrates.[39] The unsaturated 2-pyrrolin-4-ones are easily transformed into the corresponding spiropyrroline-tetrahydrothiophenes with high stereocontrol (up to >99% ee, up to 95:5 dr) in good yields under organocatalyzed conditions (Scheme [22]).

The absolute configuration of the product is dependent on the configuration of the exocyclic double bond in the starting material. These results point to the possibility of a widespread use of these building blocks in various domino transformations for accessing libraries of 3D-rich pyrrolone-based spiro heterocycles.

The 2-pyrrolin-4-one core is an interesting motif prominent in several natural products like brevianamide A (161),[40a] bioactive molecules as modulators of opioid receptors,[40b] antimalarials,[40c] HIV-1 protease inhibitors[40d] and herbicides[40e] (see Scheme [22]).

Tetrahydrothiophene spirocycles have attracted a great attention due to their presence as building blocks in natural products, bioactive compounds, and materials. The groups of Perumal, Enders, Xie, Kong, Wang, and Xiao used diastereo- and enantioselective sulfa-Michael/aldol domino reactions to synthesize tetrahydrothiophene spirocycles (Scheme [23]).[41]

The Barbas group developed a highly efficient organocatalytic domino Michael/aldol approach for the construction of dispirooxindole-cyclopentane-oxindoles 180 containing four chiral centers, including three quaternary carbons chiral centers. The methodology was carried out under mild conditions and catalyzed by a cinchona alkaloid 181 to give the products with excellent stereocontrol (up to >99:1 dr and 98:2 er) (Scheme [24]). In addition, catalyst reconfiguration provided access to the opposite enantiomer.[42]

The Wang group realized the synthesis of enantiopure spirocyclohexane-oxindoles 184 through domino Michael/aldol reactions between 2-(2-oxoindolin-3-ylidene)acetic esters 62 and pentane-1,5-dial (185) in the presence of diphenylprolinol silyl ether 186 as aminocatalyst. A series of multistereogenic and functionalized spirocyclohexane-oxindoles were obtained in good yields with moderate diastereoselectivities but excellent enantioselectivities (Scheme [25]). The proposed mechanism is shown in Scheme [25]. Initially, the catalyst 186 activates aldehyde 185 giving the enamine intermediate 187, which reacts with 2-(2-oxoindolin-3-ylidene)acetic ester 62 via Michael addition to form 188. Then, cyclization of 188 via intramolecular aldol reaction provides intermediate 189, which after hydrolysis, yields the desired six-membered spirocycle 184.[43]

Notably, the Michael/aldol reactions with substrates bearing electron-donating groups generally required longer reaction times (7–15 h) and provide the desired products in 71–88% yields with moderate diastereoselectivities and excellent enantioselectivities. In contrast, substrates bearing halogen substituents on the oxindole backbones, performed very well in the corresponding domino reactions in less than two hours, resulting in the desired products in 74–83% yields with 5.2:1 to 8.7:1 dr and >97% ee.[43]

The spirocyclohexane-oxindoles structure was determined by single crystal X-ray diffraction analysis, which showed that the formyl and hydroxy groups are in trans configuration (Scheme [25]). In addition, electronic circular dichroism (ECD) spectroscopy and time-dependent density functional theory (TD-DFT) were used to investigate the rational structures of spirocyclohexane-oxindoles.[43]

Similar studies were performed independently by the Chen and Ghosh groups (Scheme [26]).[44]

An efficient asymmetric vinylogous Michael/aldol domino reaction between α-arylidenepyrazolinones 193 and β,γ-unsaturated α-keto esters 194 catalyzed by a chiral N,N′-dioxide–Sc^III complex 195 in aqueous media has been established by the Feng group.[45] Various spirocyclohexene-pyrazolones were obtained in excellent yields with good diastereoselectivities and enantioselectivities (Scheme [27]). Pyrazole and pyrazolone derivatives represent a class of valuable five-membered nitrogen heterocyclic compounds, which contain unique structures found in some bioactive natural products and pharmaceuticals.[46]

After optimization of the reaction conditions, the substrate scope of this domino reaction was examined. Keto esters containing isopropyl, cyclopentyl, or methyl ester substituents delivered the related products with high enantioselectivities. Both electron-withdrawing and electron-donating groups on the β-aryl moiety of the keto ester were tolerated yielding the products in excellent yields (95–99%) with good diastereoselectivities (81:19–85:15) and high enantioselectivities (87–90% ee). In addition, various α-arylidenepyrazolinones were evaluated. When 194 bears an R¹ aryl group with electron-donating substituents then slightly higher enantioselectivities are obtained than when an R¹ aryl group with electron-withdrawing substituents is present. The proposed mechanism is shown in Scheme [28].

First, two carbonyl oxygens of β,γ-unsaturated α-keto ester 194 coordinate with the 195/Sc^III complex to form an octahedral transition state. Because of the steric hindrance between the adamantyl group, of the ligand, and the active dienoate species of α-arylidenepyrazolinones 193, the vinylogous Michael addition occurs preferentially from the β-Si face, followed by an intramolecular aldol addition to afford the corresponding spiropyrazolone.

The same ligand 195, but now coordinate to Ni^II, was used by the Feng group to catalyze the domino thia-Michael/aldol reaction of 1,4-dithiane-2,5-diol (158) with 3-methyleneoxindoles 197 to give various spirooxindole-tetrahydrothiophenes 198 in good yields of up to 97%, with excellent enantioselectivities (98% ee) and diastereoselectivities (dr >19:1) (Scheme [27]).[47]

Spiro-pyrazolone scaffolds 199 with five contiguous stereogenic centers, two quaternary and three tertiary, were also synthesized by Zhou and co-workers using 4-substituted 5-nitropentan-2-ones 200 as chiral building blocks in the presence of DBU. The Michael/aldol domino methodology employed, provided spirocyclohexane-pyrazolone 199 with high levels of diastereo- and enantioselectivity. Moreover, the reaction could be scaled up without any loss in terms of yield and stereoselectivity (Scheme [29]).[48]

Wang and co-workers developed an efficient Michael/aldol/dehydration domino reaction for the construction of spirocyclic benzofuranones[49a] and six-membered spirocyclic oxindoles.[49b] Both reactions used cinchona-based primary amines 122 and 204 as catalysts. Examples of these reactions are shown in Scheme [29]. In the first example, chiral spirocyclohexane-benzofuranones 205 were obtained in excellent stereoselectivities (dr >20:1 and up to 96% ee) and moderate to excellent yields (up to 98%). In second example, spirocyclohex-2-enone-oxindole motifs 206 were obtained with high yields and excellent stereoselective.

Enantioenriched spirocyclopentane-indane-1,3-diones 210 with three stereocenters were prepared by asymmetric Michael/aldol domino reaction between 2-arylideneindane-1,3-diones 98 and nitroaldehydes 211 in the presence of a squaramide-tertiary amine catalyst 167 (Scheme [30]). Chiral spirocyclopentane-indane-1,3-diones 210 were obtained in good yields with high enantioselectivities and diastereoselectivities.[50]

An asymmetric Michael-aldol domino reaction of methyleneoxindoles 212 and thiosalicylaldehydes 213 catalyzed by bis(imidazolidine)pyridine (PyBidine, 215) and Ni(OAc)₂ was employed by Arai and co-workers to produce spirooxindole-thiochromanes 214 (Scheme [31]) containing three contiguous stereogenic centers in good yields and diastereo- and enantioselectivities.[51]

In the proposed catalytic cycle (Scheme [32]), the reaction starts with formation of the nickel-thiolate 216 of thiosalicylaldehyde (213). Then, nickel-thiolate 216 attacks methyleneoxindole 212 through a Michael addition to give oxindole enolate 217, which undergoes intramolecular aldol reaction to give 214 and regenerating the catalyst.[51]

The complex [PyBidine–Ni–S(C₆H₄)CHO]⁺ 216 was identified through HRMS analysis, which showed a peak at m/z = 898.3075. In addition to generating the nickel enolate, the PyBidine–Ni(OAc)₂ catalyst also activated methyleneoxindole by hydrogen bonding with the NH of the imidazolidine ring, as shown in Scheme [31]. Therefore, hydrogen bonding controls the direction of methyleneoxindole for acceptance of nucleophilic addition of thiolate and guided the subsequent aldol reaction.

The Sheng group developed a Michael/aldol domino process catalyzed by proline (218) between 3-substituted oxindoles 219 and α,β-unsaturated aldehydes 220 for the construction of spirooxindole-tetrahydrothiopyrans 221 containing diverse functional groups in moderate to good yields and excellent diastereoselectivities (Scheme [33]).[52] In addition, the products 221 were found to be potent p53-MDM2 inhibitors with good antitumor activity. A plausible reaction mechanism is depicted in Scheme [33]. Initially, the formation of the iminium ion 222 occurs from the reaction between proline (218) and α,β-unsaturated aldehyde 220. This is followed by the Michael addition of the nucleophilic C3 of 219′ to the conjugated double bond of 222 generating intermediate 223, which after enamine-iminium tautomerism, gives intermediate 224. This in turn undergoes hydrolysis generating 225 and regenerating catalyst 218, then, 225 undergoes an intramolecular aldol reaction providing spiro compound 221.

Michael/Michael/Aldol and Michael/Michael/Michael/Aldol Domino Reactions

In 2010, Rios and co-workers developed an organocatalytic methodology for the synthesis of spiro compounds via a Michael/Michael/aldol reaction. The reaction provided spirocyclohexene-oxindoles 226 in good yields in almost diastereo- and enantiomerically pure forms (Scheme [34]). In addition to oxindoles, the methodology can also be applied to other heterocycles, such as benzofuranones, pyrazolones, and azlactones, giving the corresponding spirocycles in good yields and with excellent stereoselectivities.[53] The proposed mechanism is shown in Scheme [34], where oxindole 227 initially reacts with α,β-unsaturated aldehyde 220 leading to 228 and then 229. However, the quaternary carbon formed in 229 is non-stereogenic; this compound is desymmetrized in an irreversible dehydration after the aldolic reaction. The relative configuration of the compounds was determined by NOE and NOESY NMR experiments, and the absolute configuration was assigned by TD-DFT calculations of the electronic circular dichroism (ECD) spectra.

In 2013, Enders and co-workers developed a ‘branched domino reaction’ where, contrary to the traditional domino reaction, the starting material is used in two parallel reactions at the same time under identical conditions to generate two intermediates, which then act as reactants in the next reaction step to form the desired product. In this work a two-component four-step branched domino reaction of oxindole-derived spirocyclic compounds was developed through an asymmetric organocatalytic cascade of a Michael/Michael addition with parallel oxidation, using 2-iodoxybenzoic acid (IBX) as an oxidant, and a final aldol condensation. Both the enamine nucleophile and the iminium electrophile are derived from the same aldehyde (Scheme [35]).[54]

The reaction of aldehyde 230 with 2-(2-oxoindolin-3-ylidene)acetates 196 afforded spirocyclohexene-oxindoles 231 in good yields and with excellent diastereo- and enantioselectivities. The absolute configuration of the spiro compound 231 with R¹ = Me, R² = H, and R³ = CO₂Et was confirmed by crystallography.

The mechanism suggests that aldehyde 230 first reacts with the amine catalyst, diphenylprolinol silyl ether 61a, to form enamine 233 as an intermediate, which undergoes Michael addition with 2-(2-oxoindolin-3-ylidene)acetate 196 leading to adduct 234. Simultaneously, enamine 233 is oxidized to the iminium ion 235, which reacts as a Michael acceptor with 234 to form intermediate 236 through aldol condensation. Finally, hydrolysis leads to product 231 and release of the catalyst (Scheme [36]).

Also in 2013, Veselý and co-workers described a Michael/Michael/aldol domino reaction to afford the spirocyclohexene-benzothiophenones 237 in good yields (up to 68%) and with excellent selectivities (dr 20:1, up to 99% ee) through reaction between benzothiophen-2(3H)-one (238) and enals 239 in the presence of a secondary amine catalyst, diphenylprolinol silyl ether 61a (Scheme [37]).[55]

In almost all cases, the stereoselectivity of the reaction were excellent, only unsubstituted acrylaldehyde (R = H) exhibited a lower selectivity with 60% ee. Aliphatic enals reacted quickly with moderate-to-good yields with benzoic acid as the acidic additive, but, with electron-withdrawing group substituted enals (R = CO₂Et), benzoic acid appeared to be inefficient, and the use of a stronger acid additive (2,4-dinitrobenzoic acid, DNBA) was required.

An efficient Michael/Michael/aldol reaction was developed for the synthesis of dispirocyclohexanes 240 from 2-arylideneindane-1,3-diones 241 and aldehydes 242. The spirocycles were obtained in reasonable-to-good chemical yields and with high stereoselectivities (>95:5 dr and up to 99% ee) using α,α-l-diphenylprolinol trimethylsilyl ether (61a) as the catalyst and DABCO in DMF at –20 °C (Scheme [38]).[56] According to the proposed mechanism (Scheme [38]), initially reaction of catalyst 61a and aldehyde 242 gives nucleophilic enamine 243. Then, the enamine 243 undergoes Michael addition with the 2-arylideneindane-1,3-dione 241 from the Si-face to give intermediate 244, which in the presence of DABCO is converted into the nucleophilic enolic species 245 that reacts with the second 2-arylideneindane-1,3-dione 241 to provide bis(indane-1,3-dione)-substituted aldehyde 246. Finally, intramolecular aldol reaction in 246 gives 240.

Still using catalyst diphenylprolinol silyl ether 61a the Chen group developed Michael/Michael/Michael/aldol aminocatalytic domino sequences to give fused carbocycles (Scheme [39]).[57] The efficient assembly of hydroindane derivatives incorporating a spirooxindole motif was realized under the optimized conditions via domino reaction between (E)-4-(1-methyl-2-oxoindolin-3-ylidene)-3-oxobutanoates 247 and two molecules of an α,β-unsaturated aldehyde 220. The complex products 248 bearing six contiguous stereogenic centers were obtained in excellent stereoselectivities (96 to >99% ee, >99% dr).

The mechanism, a quadruple iminium-enamine-iminium-enamine catalysis of chiral secondary amine is shown in Scheme [40]. The authors further highlighted that intermediate B could be utilized in a highly diastereoselective Michael addition/Henry reaction with nitroalkenes.

The Wang group also developed an asymmetric organocatalytic quadruple domino reaction of (E)-3-(2-hydroxybenzylidene)oxindole derivatives 249 and two molecules of α,β-unsaturated aldehyde 220 under quadruple iminium-enamine-iminium-enamine catalysis for the synthesis of highly functionalized polycyclic spiro-fused carbocyclic oxindoles 250 (Scheme [41]).[58]

The products bearing a spiro quaternary center and five contiguous stereocenters were obtained in moderate to high yields (up to 90%) with good diastereoselectivities (up to 8:1) and excellent ee values (up to 99% ee). In addition, by expanding the substrate scope it was possible to obtain spiro derivatives 251 from 2-(2-hydroxybenzylidene)indane-1,3-dione (252) (Scheme [41]). These derivatives showed moderate antitumor activities in the micromolar range.[58]

The structure and absolute configuration of the products were confirmed by NMR spectroscopy and single crystal X-ray analysis; the proposed mechanism is shown in Scheme [42]. In the first oxo-Michael addition step of the domino reaction, the activated iminium 254 is attacked on its Re-face by the hydroxyl group of 249′ (TS-1) generating intermediate enamine 255, which, through an intramolecular Michael addition, provide the intermediate 256. This intermediate, act as nucleophile in a third Michael addition, attacking the Re-face of another molecule of 254 (TS-2). The third Michael addition step leads to intermediate 256′, which reacts through an intramolecular aldol condensation providing product 251′ and regenerating the catalyst.

In a similar work, Hong and co-workers demonstrated an organocatalyzed enantioselective Michael/Michael/Michael/aldol domino reaction for the construction of spirocyclopentane-oxindoles with six contiguous stereocenters including a quaternary center in good yields with excellent enantioselectivities (Scheme [43]).[59]

Under the optimized conditions, the scope of domino reactions between enals 257 and 3-(3-nitroallyl)oxindoles 258 was examined. The reaction of 3-(halophenyl)propenals 257 (R³ = hal) and 1-methyl-3-(3-nitroallyl)oxindole 258 (R¹ = Me) required a slightly longer time to go to completion. This four-step cascade reaction would potentially generates six new chiral centers, but only two diastereomers 259 and 260 were obtained in ca. 7:3 ratio with excellent enantiomeric excesses (96–99% ee).[59]

The proposed mechanism begins with conjugate addition of oxindole 258 to 3-phenylpropenal (257′) through the iminium activation process (TS-1) to generate intermediate 262 (Scheme [44]). Then, conjugate addition of enamine-activated aldehyde 262 to nitroalkene (TS-2) affords the trans-substituted cyclopentane 263. A later intermolecular conjugate addition of nitroalkane 263 to 257′ and subsequent intramolecular aldol condensation provides 259. The concurrent path initiated by Michael addition of oxindole 258 to 3-phenylpropenal (257′) via transition state TS-3, which is less favorable than TS-1 due to steric hindrance, gives intermediate 264. Subsequent Michael/Michael/aldol reactions provides 260 as the minor product.[59]

Domino Michael/Cyclization Processes

In 2019, the Chen group reported a reaction between 3-isothiocyanatooxindoles 266 and 4-(het)aryl-2-oxobut-3-enoates 267 catalyzed by a chiral thiourea organocatalyst 268 via a domino Michael/cyclization. The process provided spirooxindole-3,2′-pyrrolidine-5′ thiones 269 with anti-inflammatory activities in high yields and good stereoselectivities (Scheme [45]).[60] Under the optimized conditions, the reactions showed excellent reactivity and were complete within 4 h, however, the reactivity and stereoselectivity were affected by various substituents on the aryl group of 267. Specifically, meta-substituted 4-aryl-2-oxobut-3-enoates 267 had decreased enantioselectivity.

A possible dual activation model to explain the stereochemistry of the domino Michael/cyclization reaction was proposed (Scheme [46]).

Another example of a domino Michael/cyclization reaction was described by Wang and co-workers where the first organocatalytic enantioselective Michael/cyclization domino reaction between 3-amidooxindoles 270 and α,β-unsaturated aldehydes was realized. After sequential oxidation with pyridinium chlorochromate the products, highly sterically hindered spirooxindole-pyrrolidinones 271, were obtained in 51–81% yields with 75–97% ee and ≤ 80:20 dr (Scheme [47]).[61] The acidity of the additive had an effect on the yield and stereoselectivity with the best results obtained with TFA. Lower temperatures improved the stereoselectivity but the yields dropped significantly. Evaluation of the effect of substituents in the phenyl ring of the 3-phenylpropenal 220 showed that the electronic characteristics and substituted position were well tolerated. The substituents R² and R³ affected the yields and stereoselectivities of the reactions.

A plausible mechanism, based on experimental results, is shown in Scheme [48]. 2-Phenylpropenal 220 is first activated by catalyst 61a in the presence of acid additives to form iminium ion 272 that reacts with 3-amidooxindole 270 via transition state 1 to afford major product 271. However, it should be noted that in transition state 1 aromatic ring A experiences considerable steric hindrance with aromatic ring B, while in transition state 2 aromatic ring A has some steric repulsion with the OTMS and the hindrance with aromatic ring B is released effectively. The comparable two transition states account for the low diastereoselectivity.[61]

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 by Yuan and co-workers.[62] The reaction of 3-isothiocyanatooxindoles 266 with unsaturated pyrazolones 277 and unsaturated isoxazolones 278 catalyzed by commercially available quinine (279) gave spirooxindoles 280 and 281, respectively (Scheme [49]). A plausible dual activation working model was proposed to rationalize the stereochemistry of the domino Michael/cyclization process (Scheme [49]).

An efficient organocatalyzed asymmetric Michael/cyclization reaction sequence of α-isothiocyanatoacetamides 282 with various 2-(2-oxoindolin-3-ylidene)acetates 283 using 284 as the catalyst and mild reaction conditions was developed by the Wang group for the synthesis of 2-thioxospirooxindole-3,3′-oxindoles 285 (Scheme [50]).[63] Generally, the products were obtained in excellent yields (up to 99%) and with excellent diastereomeric ratio (>20:1) and enantiomeric excess (>99% ee). However, the use of a 2-(2-oxoindolin-3-ylidene)acetate 283 with a bulkier ester group increased steric hindrance and resulted in a decrease in the diastereomeric ratio of the products (16:1 and 7:1) and also these reactions required longer reaction times. The absolute and relative configurations of the spirooxindoles were determined by X-ray crystallography. A model was proposed to explain the stereochemistry of the reaction (Scheme [50]). The 2-(2-oxoindolin-3-ylidene)acetate 283 is activated by hydrogen bonds between the carbonyl group in the oxindole and the thiourea hydrogen atoms of the catalyst; the α-isothiocyanatoacetamide is enolized by deprotonation at its α-carbon atom by the tertiary amine. Thus, the Re-face of the enolate nucleophilically attacks the Si-face of the C=C bond of the 2-(2-oxoindolin-3-ylidene)acetate. Subsequently, the enolate generated in the 2-(2-oxoindolin-3-ylidene)acetate makes a C-nucleophilic attack on the electron-deficient carbon of the enolate of the α-isothiocyanatoacetamide leading to the spiro compound with the 3R,4′R,5′R configuration obtained experimentally.

In addition, 2-thioxospiropyrrole-3,3′-oxindole-5-carboxamides 285 were converted into 2-thioxospiropyrrole-3,3′-oxindole-5-carboxylates 287, in near quantitative yield without loss of diastereo- and enantioselectivity, and spiropyrrole-3,3′-oxindole-5-carboxylates 288 in moderate yield without change in dr and ee values, as shown in Scheme [51].

Wang and co-workers also disclosed the synthesis of highly optically active spiropyrazolone-pyrrolidinethione 289 through an organocatalyzed asymmetric Michael/cyclization sequence of α-isothiocyanatoacetamides 290a–c with various unsaturated pyrazolones 291 using 292 as the catalyst (Scheme [52]).[64] The resulting spiro compounds 289 were obtained with high levels of enantio- and diastereoselectivity (up to 20:1 dr and 99% ee), except when a bulky 1-naphthyl group was introduced as R² (in this case only 4:1 dr, 72% yield, and 81% ee were obtained). When 2-furyl-substituted pyrazolone 291 (R² = 2-furyl) was used, lower 71% yield, 73% ee, and 4:1 dr were also obtained. In addition, the results suggested that the rigid skeleton of the isoxazolidinone functional group in R³ is necessary for stereocontrol in this reaction, because when methyl isothiocyanatoacetate was employed, the product was obtained with only 71% ee and 3:1 dr. A model for the asymmetric construction of spiropyrazolones is shown in Scheme [52]. The absolute and relative configurations of this kind of spiropyrazolones were determined by X-ray crystallography of one of the synthesized compounds.

The transformation of the spiropyrazolone skeletons to several valuable compounds was performed as shown in Scheme [53]. Preliminary studies on the cytotoxicity of some of the synthesized compounds toward the human T-cell leukemia cell line (jurkat), human cervical cancer cell line (Hela), and human bladder cancer cell line (5637) proved to be promising.

Dispirooxindole-pyrrolidine-oxindoles 296 were synthesized by Lu and co-workers from an efficient asymmetric Michael/cyclization domino reaction of 3-isothiocyanatooxindoles 266 with 3-(trifluoroethylidene)oxindoles 297 (Scheme [54]). The products were conveniently constructed in a highly stereoselective manner (up to 96% yield, >20:1 dr, and >99% ee), under bifunctional organocatalysis with a cinchona alkaloid derived squaramide catalyst 132.[65] An additional scaled-up experiment showed that this reaction could be performed on the gram scale, and although the yield decreased slightly, the diastereoselectivity and the enantioselectivity (86% yield, >20:1 dr, and >99% ee) were maintained.

The synthetic utility of this domino reaction was illustrated by converting one of the products into other functionalized 3′-trifluoromethyl-substituted dispirooxindole-pyrrolidine-oxindoles (Scheme [54]). The absolute configurations of the products were determined by analogy to X-ray crystallographic analysis of one of the compounds.

Based on the experimental results and the literature, a bifunctional transition state was proposed (Scheme [55]). The squaramide moiety of the catalyst forms two hydrogen bonds with the carbonyl group of the 3-(trifluoroethylidene)oxindole. Meanwhile, the tertiary amine moiety deprotonates and activates the 3-isothiocyanatooxindole through a double hydrogen bond. Thus, in the Michael addition step, the activated 3-isothiocyanatooxindole (Si-face) attacks the β-position (Re-face) of the 3-trifluoroethylidene group. Subsequently, in the cyclization step, the α-position of the 3-trifluoroethylidene group approaches the NCS group of the 3-isothiocyanatooxindole resulting in dispirooxindole-pyrrolidine-oxindoles with fixed stereochemistry.[65]

Highly functionalized dispirooxindole-pyrrolidine-oxindoles 300 bearing three contiguous stereogenic centers with two quaternary stereocenters were also synthesized by Xiao and co-workers in almost quantitative yields (up to 99%) and with extremely high enantio- and diastereoselectivities (>99% ee, >95:5 dr) through an organocatalytic asymmetric Michael addition/cyclization domino reaction (formal [3+2] cycloaddition) of 2-(2-oxoindolin-3-ylidene)acetates 283 with 3-isothiocyanatooxindoles 266′ (Scheme [56]).[66]

A series of chiral multifunctionalized tetracyclic spirochromeno[3,4-c]pyrrole-1,3′-indolines 302 with four vicinal chiral carbon centers, including two quaternary stereocenters, were successfully prepared by Xie and co-workers through an asymmetric Michael addition/cyclization sequence between 3-isothiocyanatooxindole 266′′ and various 3-nitro-2H-chromene derivatives 303 with moderate to good enantioselectivities (up to 84% ee) by employing a bifunctional thiourea 304 as an organocatalyst (Scheme [56]).[67]

(2-Oxoindolin-3-ylidene)malononitriles have been widely used as starting material in the construction of spirooxindole derivatives through domino Michael/cyclization sequences. Wu and co-workers, for example, developed a highly enantioselective Michael/cyclization domino reaction between dimedone (305) and (2-oxoindolin-3-ylidene)malononitriles 306 organocatalyzed by a chiral tertiary amine-squaramide 307 for the synthesis of chiral 2-aminospiro-4H-pyran-oxindoles 308 (Scheme [57]).[68] The products were obtained in excellent yields (97–99%) with excellent enantioselectivities (up to 99.7% ee). A study of the substrate scope revealed that the substituents on the nitrogen atom of (2-oxoindolin-3-ylidene)malononitriles significantly influenced the enantioselectivity (6–98% ee) and the N-trityl substrate yielded the best result (98% ee). Various (N-trityl-2-oxoindolin-3-ylidene)malononitriles 306 (R¹ = CPh₃) were used and gave the corresponding products with 94–99.7% ee. This reaction was performed on a gram scale under the optimized conditions.

Treatment of the chiral product 308 with triethyl orthoformate in the presence of acetic acid at 90 °C afforded imine 309 in 90% yield with 99% ee (Scheme [57]).

In addition, the one-pot, three-component reaction of dimedone, malononitrile, and N-tritylisatin was carried out under the same reaction conditions, but using 10 mol% of the catalyst and increasing the temperature to 0 °C. In this case, the reaction occurred through a Knoevenagel/Michael/cyclization domino sequence, providing the desired product in 96% yield and 95% ee.

The Wu group reported three other works also using (2-oxoindolin-3-ylidene)malononitriles 310 in the construction of spirooxindole derivatives 311, 315, and 317 through organocatalyzed domino Michael/cyclization reactions with acyclic β,γ-unsaturated amides 312,[69a] pyrazolones 313,[69b] and α-cyano ketones 314, respectively (Scheme [58]).[69c] Good yields and stereoselectivities were achieved in all cases.[69]

Similarly, Wang and co-workers reported the organocatalytic asymmetric domino Michael/cyclization of 2-hydroxynaphthalene-1,4-diones 320 to (2-oxoindolin-3-ylidene)malononitriles 306 to give spiro-4H-benzo[g]chromene-indolines 321 in up to 99% yield with up to 99% ee (Scheme [58]). To illustrate the utility of these products, a further transformation was performed to generate a spiropolyheterocyclic compound in moderate yield without loss of enantioselectivity (>99% ee). The evaluation of the biological activity of the spirobenzo[g]chromene-indoline derivatives showed excellent antiproliferative activity against cancer cell lines, with an inhibition rate ranging from 93% to 99% at a concentration of 50 μM.[70]

Chiral spirooxindole-pyrans 323 were synthesized by Wang and co-workers through an asymmetric strategy via organocatalyzed Michael/cyclization reaction from (2-oxoindolin-3-ylidene)malononitriles 306 and α-keto esters (Scheme [58]). The spirooxindole-pyrans 323 were subsequently converted into spirooxindole-pyranopyrimidines, several which showed significant antiproliferative activity of various cancer cells, which suggested that such compounds can serve as a potential chemotherapeutic agent.[71]

Xie and co-workers developed a facile and mild synthesis of dispirooxindole-dihydrofuran- and -cyclopentene-oxindoles 326 and 327, respectively, via Michael addition/cyclization and an unexpected redox-oxidative coupling-cyclization to afford 328 (Scheme [59]).[72] Both domino reactions used simple and available starting materials, in addition they presented good tolerance to a range of functional groups for the production of substituted dispirooxindole frameworks in moderate to good yields with excellent diastereoselectivities.

A possible mechanism for the Michael addition/cyclization reaction and for the unexpected oxidative coupling-cyclization is shown in Scheme [60]. The deprotonation of 329′ by cinchonine followed by a domino Michael intramolecular cyclization-proton transfer, formed the dispirooxindole-dihydrofuran-oxindole 326 by steps a–c. On the other hand, for the formation of compound 327, initially compound 329′ is deprotonated by cinchonine and then a hydride is transferred to compound 306, generating intermediate 332 (step d), which in turn is protonated to give 333 (step e). The deprotonation of 334 under basic conditions followed by domino Michael intramolecular cyclization proton transfer gives compound 327 (steps f and g). Simultaneously, an unexpected oxidative coupling (through oxidative dimerization or a radical process) gives intermediate 335 (steps h–j), which after an intramolecular cyclization proton transfer (steps k and l) gives compound 328 under basic conditions.

A hybrid-type squaramide-fused amino alcohol 338 containing both a Brønsted basic site and hydrogen-bonding sites in the molecule was used by Nakano and co-workers as an organocatalyst in the enantioselective domino Michael addition/cyclization reaction of oxindoles 339 with cyclic 1,3-diketones 340 to afford the chiral 2-aminospiro-4H-pyran-oxindoles 341 in excellent yields (up to 98%) and enantioselectivities (up to 95% ee) (Scheme [61]).[73]

The reaction of N-methyloxindole with acyclic 1,3-diketones provided the products as racemates in good chemical yields (72–81%). The products of the reactions between dimedone and 2-(5-bromo-1-methyl-2-oxoindolin-3-ylidene)malononitrile or ethyl (E)-2-cyano-2-(1-methyl-2-oxoindolin-3-ylidene)acetate were also obtained as racemates in 92% and 81% yield, respectively. The reasons for these results were not clear, however a plausible mechanism is shown in Scheme [61]. The active methylene proton of dimedone is abstracted by basic tertiary nitrogen in the pyrrolidine ring of 338, and the generated enolate species forms a hydrogen bond with ammonium site of 338. In turn, the oxindole is fixed to catalyst through two hydrogen-bonding interactions of the cyano groups with two amino hydrogen atoms of the squaramide part of the catalyst. Among the two possible transition states (TS-I and TS-II), the Michael addition can occur through TS-II, which has fewer steric interactions between the substrate and the enolate. Therefore, the enolate attacks the electrophilic C=C bond of the oxindole on the Si-face, providing the chiral Michael adduct 342. Then, intramolecular cyclization of 342 gives intermediate 343, whose tautomerization might afford the formation of (3S)-341 as the major enantiomer.[73]

Spirocyclopentene-oxindoles 344 containing three contiguous stereocenters including a quaternary stereogenic center joining the two rings were synthesized by Miao and co-workers through a phosphine-catalyzed [3+2] annulation of 2-(2-oxoindolin-3-ylidene)acetates 345 with alkynoates 283 (Scheme [62]).[74] This reaction afforded the products 344 in high to excellent yields (up to 99%) with high regioselectivity and from moderate to high diastereoselectivities (up to 20:1).

Mechanistically, the phosphine catalyst reacts with the alkynoate to produce zwitterionic intermediate 346, which can isomerize to intermediate 346′. In turn, intermediate 346′ undergoes Michael addition to generate intermediate 347, which further undergoes intramolecular cyclization to furnish the phosphine ylide 348. Then, 348 is converted into intermediate 349 via H-shift; elimination of phosphine gives the product 344.

An asymmetric Michael annulation process was employed by Zhou and co-workers in 2020 for the synthesis of structurally diverse polysubstituted spirooxindole-hexahydroxanthones 350 with five contiguous stereogenic centers including one spiro quaternary center in acceptable yields and diastereo- and enantioselectivities (up to 76% yield, >20:1 dr, and >99% ee). The reaction, catalyzed by the thiourea 351, was carried out between bifunctional oxindole-chromones 352 as C₄ synthons and β,γ-unsaturated α-keto esters 353 as C₂ synthons under mild conditions (Scheme [63]).[75] The absolute configurations of the products were assigned by analogy to the configuration determined for one of the compounds by single-crystal X-ray analysis. The proposed mechanism based on experimental results is shown in Scheme [63]. The substrate 352 is activated by protonation from the chiral tertiary amine moiety of the catalyst. Meanwhile, the carbonyl bond of substrate 353 is activated by hydrogen bonding interaction with the thiourea group of the catalyst. Then, the γ-position of the electrophilic substrate 353 is attacked at the Re-face by the activated enolized substrate 352 from the Si-face. Finally, the Si-face of the electron-deficient chromone moiety is attacked by the Si-face of the carbon anion intermediate, to afford the expected product. In addition, scale-up demonstrated the applicability of this protocol.

In 2021, Wang and co-workers designed a new synthesis of spirooxindole-dihydropyrroles using 3-aminooxindole Schiff bases 354. The enantioselective Michael/cyclization reaction of 354 with terminal vinyl ketone 355 catalyzed by a cinchona base 356 produced a wide variety of chiral spirooxindole-3,2′-dihydropyrroles 357 in excellent yields and enantioselectivities (Scheme [64]). The proposed transition state is shown in Scheme [64].[76]

Domino Michael/Mannich Reactions

In the first example, a domino α′-regioselective Michael addition γ-regioselective Mannich reaction to give fused or bridged architectures with a spirocyclic skeleton was provided by the Chen group.[77] The use of various cyclopent-2-enones 358 and 3-vinyl-1,2-benzoisothiazole 1,1-dioxides 359 was examined under the optimal conditions with 9-amino-9-deoxyepiquinine (363) or 9-amino-9-deoxyepiquinidine (364) as the catalyst with 5-nitrosalicylic acid as additive to give spiro compounds 360 in good yields, excellent enantiomeric excess (Scheme [65]). Spiro compounds 360 exhibited promising anticancer activity in A549 lung adenocarcinoma epithelial, DU145 prostate cancer, Eca109 esophageal squamous carcinoma, MDA-MB-231 breast cancer, and U937 leukemic monocyte lymphoma.

The Chen group also developed a domino Michael addition/Mannich reaction between diversely structured aliphatic ketones 361 and electron-deficient cyclic 1-azadienes, 1,2-benzoisothiazoles 1,1-dioxide 359, catalyzed by cinchona-based amine 363 with salicylic acid as the additive to afford spirocyclic architectures 362 with excellent diastereo- and enantioselectivities (Scheme [65]).[78] 1,2,3-Benzoxathiazine 2,2-dioxide was also used as the electron-deficient cyclic 1-azadiene in one example.

A strategy for the asymmetric synthesis of trifluoromethylated dispirooxindole-pyrrolidine-oxindoles 365 with four contiguous stereogenic centers, including two vicinal spiro-stereocenters, was described by the Enders group.[79] 3-Iminooxindoles 366 and 2-(2-oxoindolin-3-ylidene)acetates 283 were employed in the domino Michael/Mannich/[3+2] cycloaddition catalyzed by a bifunctional thiourea 367 to provide the products 365 in good yields and very high stereoselectivities (Scheme [66]). The gram-scale reaction between 366 (R¹ = Bn, R² = H) and 283 (R³ = Et, R⁴ = H, R⁵ = H) gave the corresponding product in 91% yield with >20:1 dr and 89% ee thus demonstrating the practical utility and robustness of the methodology. The absolute configuration of this gram-scale product was determined by X-ray crystallography and the configuration of other products was assigned by analogy.

A highly diastereo- and enantioselective domino Michael/Mannich/[3+2] cycloaddition reaction of 3-(2,2,2-trifluoroethylimino)oxindoles 368 with rhodanine derivatives 369 in the presence of a squaramide tertiary amine catalyst 370 was developed by the Du group for the synthesis of a wide range of CF₃-containing dispirooxindole-pyrrolidine-rhodanines 371, as promising drug candidates for chemical biology and drug discovery (Scheme [67]).[80] The applicability of the methodology was demonstrated by a large-scale experiment and subsequent product transformation. In mechanistic terms, initially catalyst 370 promotes the formation of transition state A, through deprotonation of the 3-(2,2,2-trifluoroethylimino)oxindole 368. Then, both 368 and 369 are simultaneously activated via hydrogen-bonding with 370. Rhodamine 369 then undergoes Michael addition on the Si-face by deprotonated 3-(2,2,2-trifluoroethylimino)oxindole by transition state B. The resulting nucleophilic rhodanine anion attacks C=N of the imine in a Mannich/cyclization reaction through intermediate C, providing the desired product and regenerating the catalyst.

The Du group also developed a similar methodology for the enantioselective synthesis of biologically important CF₃-containing spirooxindole-pyrrolidines 372 via a organocatalytic asymmetric domino Michael/Mannich/[3+2] cycloaddition of 3-(2,2,2-trifluoroethylimino)oxindoles 368 and arylidene azlactones 373 using a hydroquinine-derived thiourea 374 as the catalyst. The products 372 were obtained in high yields (up to 93% yield) with excellent diastereo­selectivities (>20:1 dr, in all cases) and enantioselectivities (up to >99% ee) (Scheme [68]).[81] A bifunctional squaramide-catalyzed one-pot three-component Michael­/ Mannich/Michael/cyclization sequential cascade reaction was another interesting methodology reported in 2019 by the Du group for the enantioselective construction of dispirooxindole-pyrrolidine-oxindole spirooxindole-pyrrolidine ketones 375 with seven stereocenters in good yields with excellent stereoselectivities (up to >20:1 dr, 99% ee) (Scheme [68]).[82]

Miscellaneous Reactions Initiated by Michael Additions

In this section examples of domino reactions that start with a Michael reaction followed by various transformations, such as Povarov, Mannich, alkylation, acylation etc., not covered in previous sections will be presented.

An asymmetric organocatalytic one-pot procedure for the construction of spirooctahydroacridine-3,3′-oxindole scaffolds was successfully developed through domino Michael/Povarov reaction.[83] Chiral octahydroacridines can act as gastric acid secretion inhibitors.[84] In this reaction some challenges had to be overcome such as the creation of four new chemical bonds and five stereocenters including a spiro quaternary center, the use of styrene-type substrates as the dienophile component in the Povarov reaction, and the control of diastereo- and enantioselectivity of the products. The optimized conditions utilized a chiral secondary amine diphenylprolinol triethylsilyl ether 381 in combination with 10 mol% of additive 382. Various 3-substituted oxindoles 379, α,β-unsaturated aldehydes 220, and aniline derivatives 380 reacted under the optimized conditions to give spirooctahydroacridine-3,3′-oxindoles 383 in 30–89% yield with 5:1 to 20:1 dr and 84–99% ee (Scheme [69]).[84]

The proposed mechanism and stereochemical rational is shown in Scheme [70]. The reaction begins with the nucleophilic attack of 3-substituted oxindole 379 on the iminium-activated α,β-unsaturated aldehyde 384 via TS-1. The Re-face under the catalyst control, by efficient shielding of the Si-face, affords the Michael addition adduct 385, which then reacts with 4-bromoaniline 380 (R³ = 4-Br) and TFA through condensation to provide iminium intermediate 386. This intermediate undergoes intramolecular Povarov reaction through an endo transition state (TS-2), preferring the stabilized π-π stacking and chairlike conformation, to provide the spiro compound with the observed diastereoselectivity.[84]

In 2018, Schneider and Hodík reported a one-step domino Michael addition/lactamization for the synthesis of spirobenzofuranone-hydroquinolones 387 from ortho-quinone methide imines, generated in situ from propargylic alcohols 388, and cyclic β-keto esters 389 as the nucleophile catalyzed by chiral phosphoric acid 390 (Scheme [71]). Mechanistic studies revealed the in situ generated chiral magnesium phosphate salt acts as the catalyst.[85]

Examples of domino reactions using alkylation and acylation are discussed below. The Wang group developed an organocatalytic asymmetric domino Michael/alkylation of methyleneoxindoles 391 and γ-halogenated β-keto esters 392 using a tertiary amine based on chiral thiourea 394 that gave various spirocyclopentanone-oxindoles 393 in high yields, good diastereoselectivities, and excellent enantioselectivities via α-alkylation (Scheme [72]).[86] Interestingly the reaction of N-alkyl-protected methyleneoxindoles with ethyl 4-chloroacetoacetate afforded an O-alkylated product with a tetronic acid scaffold 395. The mechanism is shown in Scheme [72].

Bartoli and co-workers developed the first enantioselective synthesis of 2-nitrospirocyclopropyl-oxindoles 401 through a Michael addition/alkylation sequence between bromonitromethane (402) and Boc-protected 3-alkylideneoxindoles 75 using a bifunctional thiourea derivative 403 catalyst that simultaneously activates the electrophilic oxindole and Michael donor bromonitromethane (Scheme [73]).[87] Mechanistically, the hydrogen bond interactions between the N–H bonds of the thiourea moiety and the imidic carbonyl groups of the oxindole place it in the correct position for nucleophilic attack on the Si-face of the C=C bond, so the reaction follows the alkylation route shown in Scheme [73], providing the desired spiro compound with high diastereo- and enantioselectivity.

Performing the same reaction using catalyst 404, a diastereomer of catalyst 403 acting as its ‘pseudo enantiomer’, gave the opposite enantiomers of the spirooxindoles, as expected, with an improvement of both the diastereo- and enantiocontrol. Additionally, starting from Boc-protected 3-alkylideneoxindoles 407 and 1-bromo-1-nitroethane 406 using catalyst 404 gave a series of highly substituted spirocyclopropyl-oxindoles 405 containing two quaternary stereogenic centers in an almost enantiomerically pure form in high yields, with good diastereocontrol (Scheme [74]).[87]

Hong and co-workers also used a Michael/alkylation domino sequence, this time between 2-(2-oxoindolin-3-ylidene)acetates 408 and 3-(2-bromoethyl)oxindoles 409 catalyzed by a chiral squaramide 410 in the presence of a base, to give biologically important dispirooxindole-cyclopentane-oxindoles 411 with high enantioselectivities (Scheme [75]).[88] The proposed activation mode of the substrates by the catalyst is shown in Scheme [75].[88]

In the next example, 7-azaspiro[4.5]decanones 412 were synthesized via a domino enantioselective organocatalyzed Michael/intramolecular acylation using β-ketoamides 413 with α,β-unsaturated acyl cyanides 414 as a bis-electrophile substrate and Takemoto’s thiourea catalyst 384 (Scheme [76]).[89] This is a rare example of direct enantioselective synthesis of glutarimide derivatives, a spirocyclic substructure found in several natural products, such as meloscandonine and lycoflexine alkaloids (Scheme [76]). In this reaction, the use of acryloyl cyanide (R³ = H) was not successful and the starting ketoamide was recovered.

Two possible activation modes can explain the observed stereochemical outcome (Scheme [77]). The enolate of the ketoamide 413′ coordinates to the thiourea moiety in a perpendicular fashion in both transition state (TS1 and TS2), exposing the Re-face of the enolate to the electrophile 414′. In TS1, activation of the α,β-unsaturated acyl cyanide 414′ through hydrogen bonding with the ammonium part of the organocatalyst is proposed. In TS2, the catalyst forms a covalent bond with 414′ by nucleophilic displacement of the cyanide ion. In both cases, the nucleophile reacts on the Re-face of the electrophile explaining the stereoselectivity. ¹H NMR studies led the authors to propose that TS1 should be the preferred path of reaction.[89]

Kumarswamyreddy and Kesavan developed the first enantioselective synthesis of spirooxindole-3,4′-dihydropyrano[2,3-c]pyrazole derivatives 417 by reacting pyrazolones 418 with 2-(2-oxoindolin-3-ylidene)acetate 419 (Scheme [78]).[90a]

A new bifunctional squaramide organocatalyst 420 derived from l-proline was used, surpassing the widely used thioureas and squaramides in yield and stereoselectivity. The stereochemical result of the reaction was explained by a transition state based on a Michael/hemiacetalization domino reaction (Scheme [78]), in which activation of both starting materials facilitates the Si-face attack of pyrazolone 418 to 2-(2-oxoindolin-3-ylidene)acetate 419 followed by aromatization of pyrazolone and hemiketalization leading to the desired product.[90a]

Spiro-3,4-dihydropyran structures 421 were synthesized by Ma and co-workers by a cinchona alkaloid catalyzed domino Michael/hemiacetalization reaction of cyclic β-keto aldehydes 422 and 4-aryl-2-oxobut-3-enoates 423 with high levels of diastereoselectivity and enantioselectivity (Scheme [79]).[90b]

Similarly, Ma and co-workers also developed a quinidine-derived squaramide catalyzed domino Michael/hemiacetalization reaction of cyclic β-keto aldehydes 426 and 4-(het)aryl-, 4-alkyl- and 4-cycloalkyl-substituted 2-oxobut-3-enoates 423 for the synthesis of spirocyclopentane- and spirocyclohexane-3,4-dihydropyrans 427 (Scheme [79]).[90c]

Starting from a Michael/Henry domino reaction between nitrostyrenes 429 and 3-(2-oxoethyl)oxindoles 430 organocatalyzed by a cinchona alkaloid 431, Albertshofer, Tan, and Barbas III synthesized highly substituted spirocyclopentane-oxindoles 432 in high yields and excellent enantioselectivities in a single step (Scheme [80]).[91a]

Wang and co-workers also developed a one-pot domino Michael/Henry reaction between 3-(2-oxoethylthio)oxindoles 433 and 1-(het)aryl-2-nitroethenes 429 for the synthesis­ of highly functionalized spirooxindole-tetrahydrothiopyrans 434 in good yields and diastereo- and enantioselectivities (Scheme [81]).[91b] Spirooxindole-tetrahydrothiophenes 436 were efficiently obtained through the same reaction, including a sulfonium-mediated rearrangement step. The proposed mechanism that rationalizes the stereochemical result is shown in Scheme [81].

Both starting materials are activated by the catalyst 435. The intermolecular Michael reaction between the nucleophilic C3 of the oxindole and the β-carbon of the nitroalkene proceeds through Re-face attack. Then, the generated carbanion attacks the Re-face of the carbonyl group of 433 to afford the Henry products 434, which when treated with SOCl₂ and pyridine, undergo rearrangement.

The Enders group developed a domino oxa-Michael/1,6-addition reaction of o-hydroxyphenyl-substituted p-quinone methides 437 and 2-(2-oxoindolin-3-ylidene)acetates 283 organocatalyzed by 5 mol% of a bifunctional thiourea 438 for the synthesis of 4-substituted spirochromane-oxindoles 439 in good to excellent yields and with very high stereoselectivities (Scheme [82]).[92a] In the transition state proposed to explain the stereochemical of the reaction, the catalyst 438 activates the olefinic oxindole 283 through hydrogen-bonding interactions and its tertiary amino group activates 437. Then, the Si-face of 283 is attacked by the phenolic oxygen atom in an oxa-Michael addition and a subsequent intramolecular 1,6-addition provides the desired product 439 (Scheme [82]).

Also starting from a domino oxa-Michael/1,6-addition methodology between o-hydroxyphenyl-substituted p-quinone methides 440 and unsaturated isoxazolones 441, catalyzed by Et₃N, Zhou and co-workers synthesized new spirochromane-isoxazolones 442 in good yields and with excellent diastereoselectivities (Scheme [83]).[92b] The structure of one of the compounds was determined by single crystal X-ray analysis and the remaining compounds had their structures determined by analogy. This methodology was extended to asymmetric organocatalysis using a quinine as a chiral catalyst; the product 445 was obtained with moderate diastereoselectivity and enantioselectivity (Scheme [83]).

The Yuan group reported the domino asymmetric Michael/Friedel–Crafts reactions of 3-pyrrol-1-yloxindoles 447 with α,β-unsaturated aldehydes 220 catalyzed by diphenylprolinol silyl ether 61a and 2-fluorobenzoic acid, followed by dehydration with p-toluenesulfonic acid to afford spiro-5,6-dihydropyrido[1,2-a]pyrrole-3,3′-oxindoles 449 in high yields and diastereo- and enantioselectivities (Scheme [84]).[93] According to the proposed mechanism (Scheme [84]), the catalyst 61a reacts with aldehyde 220 to give iminium 450. Then, Michael addition between 450 and 447 provides intermediate 451, which after hydrolysis results in adduct 452 and regenerates the catalyst. Finally, intramolecular Friedel–Crafts reaction of 452 generates the spirocycle 448, which after dehydration gives the desired spirooxindole 449. The synthetic usefulness of the spiro compounds 449 was proven from the reduction by Pd-catalyzed hydrogenation. The product of this reaction was obtained in good yield and without decreasing ee or dr.

Marini and co-workers obtained spirocyclopropyl-oxindoles 453 with excellent diastereoselectivities through a domino Michael/intramolecular nucleophilic substitution reaction using substituted vinyl selenones 454 and enolizable oxindoles 455 in aqueous sodium hydroxide solution, using CTAB as catalyst (Scheme [85]).[94] Based on the proposed mechanism, the stereochemistry of the cyclization reaction is independent of the relative configuration of the initially formed Michael adduct, due to the formation of an oxindole enolate by proton transfer. This intermediate allows the formation of both diastereomers (cis and trans) by rotation around a single C–C bond. However, π–π stacking interactions between oxindole and the neighboring aromatic ring in the transition state may be responsible for the high diastereoselectivity (trans) observed in the presence of aryl groups (Scheme [85]). Some of the synthesized compounds were selected for biological evaluation and showed anti-HIV-1 activity.

In a final example, α-spiro-δ-lactams 458 were obtained by Rios and co-workers through a domino Michael/hemiaminal annulation reaction of cyclic β-ketoamide 459 and α,β-unsaturated aldehyde 220 (Scheme [86]).[95] The combination of trifluoromethyl-substituted Jørgensen–Hayashi catalyst 460 and 2,3-dinitrobenzoic acid enabled excellent enantioselectivities with both aromatic and aliphatic α,β-unsaturated aldehydes, while lower diastereoselectivities were obtained with aromatic enals. The proposed mechanism (Scheme [86]) begins with Michael addition of the ketoamide in its enol form 459′, to the iminium ion 461. Then, the intramolecular hemiacetalization generates the spiro compound 458. The enantioselectivity of the reaction is controlled by the catalyst in the Michael addition step. The bulky group on the catalyst, blocks the bottom face of the iminium intermediate, allowing nucleophilic attack only on the Si-face. The nucleophile 459′ can attack the iminium ion in different trajectories. In trajectory A, the bulky ketoamide stays away from the catalyst, giving rise to the major diastereomer. In the case of aliphatic enals, steric hindrance between the enal and the ketoamide is small, which increases diastereoselectivity. On the other hand, in the case of aromatic enals, which have greater volume, steric hindrance of both trajectories A and B have similar energies, explaining the lower diastereoselectivity. Since the control of the reaction is thermodynamic, the R and OH substituents are in the equatorial position on the formed six-membered ring.

Domino Reactions Initiated by Mannich Reactions

The intermolecular Mannich reaction has become a classic method for the preparation of β-amino carbonyl compounds,[96] and it is one of the most important and applicable C–C bonds forming reactions in organic syntheses as it is the key step in the synthesis of numerous pharmaceuticals and natural products.[96]

The domino reaction initiated by Mannich reaction can be an interesting strategy in forming ring systems, although it is little explored in the literature. An example from 2016 is the Enders group highly stereoselective synthesis of functionalized dispirooxindole-pyrrolidine-oxindoles 465 with three stereogenic centers, including two vicinal spiro-stereocenters, achieved through an organocatalytic Mannich/Boc-deprotection/aza-Michael sequence (Scheme [87]).[97]

This new protocol was effective for the synthesis of various dispirooxindole-pyrrolidine-oxindoles 465 in good yields (41–87%) and with good to excellent diastereo- and enantioselectivities. This one-pot sequence could be scaled up without any loss of its efficiency and stereoselectivity.

In 2013, Huang and co-workers synthesized a series of functionalized spiro-1,4-benzoxazine-oxindoles 469 in moderate to good yields via a Mannich/alkylation domino process using α-halocarbonyl compounds 471 and 3-(2-hydroxyphenylimino)oxindoles 470 under mild conditions (Scheme [88]).[98] Their methodology made it possible to obtain several bioactive spiro-1,4-benzoxazine-oxindoles with two new heterocyclic rings and up to two quaternary carbon centers.

In 2015, the Yuan group obtained a range of structurally diverse chiral spirooxindole-imidazolidine-2-thiones 472 via a domino Mannich/cyclization reaction of 3-isothiocyanatooxindoles 266 and imines 473 with quinine (474) as catalyst under mild conditions (Scheme [89]).[99] This protocol is characterized by a simple process, easily available catalyst, high reactivity, low catalyst loading (1 mol%), and good to excellent diastereo- and enantioselectivities (up to >99:1 dr and 97% ee).

Based on experimental results and previous related work regarding to α-isothiocyanato compounds with imines, a plausible dual activation working model was proposed to account for the stereochemistry of the domino Mannich-cyclization process (Scheme [90]). The imine is activated by a hydrogen bond involving the hydrogen atom of quinine and the nitrogen atom of tosyl-protected imine. Then, the 3-isothiocyanatooxindole is synchronously enolized by deprotonation at C3 by the tertiary amine of quinine. The Si-face of the imine is attacked by the Si-face of the enolate of the incoming nucleophile. Next, nucleophilic attack of the nitrogen anion onto the electron-deficient carbon atom of the isothiocyanato group in the 3-isothiocyanatooxindole leads to the optically active spirocyclic oxindole product.

Alternatively, Xie and co-workers developed an efficient protocol for the synthesis of multifunctionalized spirooxindole-imidazolidine-2-thiones 475 via a catalyst-free domino Mannich/cyclization between 3-isothiocyanatooxindoles 266 and bis(arylmethylene)hydrazines 476 (Scheme [91]).[100] The domino reaction proceeded smoothly under environmentally benign conditions and provided pure spirooxindole-imidazolidine-2-thiones with excellent diastereoselectivities in moderate to excellent yields.

According to the proposed mechanism, the bis(arylmethylene)hydrazine 476 is activated by hydrogen bonding with an ethanol molecule to give an imine that undergoes a Mannich reaction with the enol form of 266. Subsequently, the Mannich adduct 477, also activated by hydrogen bonding with ethanol, undergoes intramolecular cyclization providing the desired product 475 (Scheme [92]).

In 2018, Zhao and Du demonstrated that novel 2-isothiocyanatoindan-1-ones 478 are useful building blocks in heteroannulation reactions with 3-iminooxindoles 479. The domino Mannich/cyclization reaction serves as a powerful tool for the enantioselective construction of dispiroindanone-imidazolidine-2-thione-oxindoles 480 (Scheme [93]) bearing two adjacent spiro-quaternary stereocenters in good to excellent yields (up to 95%) with excellent diastereo- and enantioselectivities (up to >25:1 dr, >99% ee).[101]

Domino Reactions Initiated by Knoevenagel Reactions

Knoevenagel condensation is one of the most useful reactions for C=C bond formation. The electron-deficient alkenes resulting from this reaction can be used in subsequent reactions as optimal Michael acceptors, dienes, dipolarophiles, etc. Thus, Knoevenagel reactions are an excellent tool for developing domino and multicomponent reactions.[102]

A hetero-domino Knoevenagel/Diels–Alder/epimerization reaction of enones 481, arenecarbaldehydes 482, and indane-1,3-dione (483), catalyzed by l-proline (484) or pyrrolidine (485), was developed by the Barbas group for the synthesis of highly substituted symmetric prochiral spirocyclohexane-1,2′-indane-1′,3′,4-triones 486 and 486′ in a highly diastereoselective fashion in excellent yields (Scheme [94]).[103] According to the proposed catalytic cycle, l-proline (or pyrrolidine) catalyzes the domino Knoevenagel condensation of aldehyde 482 with indane-1,3-dione (483) to provide 2-arylideneindane-1,3-dione 487. This then undergoes concerted [4+2] cycloaddition with 2-aminobuta-1,3-diene 488, generated in situ from enone 481 and proline or pyrrolidine, to form substituted spirocyclohexane-1,2′-indane-1′,3′,4-triones 486 and 486′ in a diastereoselective manner.

Epimerization of the minor diastereomer trans-spirane 486′ to the more stable cis-spirane 486 occurred under the same reaction conditions via deprotonation-reprotonation or retro-Michael/Michael reactions, also catalyzed by l-proline and pyrrolidine (Scheme [95]).

The prochiral spiranes 486 were used as excellent starting materials for the synthesis of benzoannulated centropolyquinanes.

In complementary work, the Barbas group used various amino acids and amines in the synthesis of symmetrical and nonsymmetrical spirocyclohexane-1,2′-indane-1′,3′,4-triones 488 via hetero-domino Knoevenagel/Diels–Alder/epimerization reactions (Scheme [96]). These compounds were also used as starting materials in the synthesis of benzoannulated centropolyquinanes.[104]

The Yuan group reported the first asymmetric organocatalytic two- and three-component reactions via a domino Knoevenagel/Michael/cyclization sequence, catalyzed by cupreine (490), that provided a series of spiro-4H-pyran-3,3′-oxindoles 491 in excellent yields and with good to excellent ee values, from simple and readily available starting materials (Scheme [97]).[105] According to the proposed mechanism, isatin 492 reacts with malononitrile (493) by Knoevenagel­ condensation generating 494. Subsequently, the Michael addition of 495 to 494 catalyzed by cupreine proceeds through transition state TS1 to generate TS2, which coexists with TS3 as a keto–enol tautomerism equilibrium in the reaction system. Then, the intramolecular cycloaddition, involving the CN group activated by the phenolic OH as the electrophile, occurs via TS3 to form TS4. Finally, molecular tautomerization leads to the formation of the desired product 491 and concurrently releases catalyst cupreine back into the catalytic cycle.

Similarly, Zhao and co-workers developed a highly enantioselective synthesis of chiral spirooxindole-pyranonaphthoquinones 496 through organocatalytic three-component domino Knoevenagel/Michael/cyclization reactions between isatins 497, malononitrile (493), and 2-hydroxynaphthalene-1,4-diones 498 using a cinchona-thiourea 499 as catalyst (Scheme [98]).[106] The products were obtained with excellent yields and high enantioselectivities.

A dinuclear zinc cooperative catalytic asymmetric three-component reaction of α-hydroxy ketones 500, isatins 501, and malononitrile (493), also involving a domino Knoevenagel/Michael/cyclization sequence, was developed by Wang and co-workers for the synthesis of a series of chiral spirodihydrofuran-3,3′-oxindoles 502 in excellent enantioselectivities and yields under mild conditions (Scheme [99]).[107] This protocol has been reproduced on a large scale without any loss in reactivity and stereoselectivity. The proposed mechanism begins with the reaction of ligand 503 with ZnEt₂ to give dinuclear Zn catalytic species 504. Next, α-hydroxyacetophenone (500′) is deprotonated by ethylzinc to form the bidentate bridging enolate 505. Then the Knoevenagel condensation product 506 coordinates to the less hindered zinc atom of 505 to afford intermediate 507, which after asymmetric Michael addition and tautomerization results in intermediate 508. Finally, the proton transfer with another α-hydroxyacetophenone (500′) nucleophile liberates the unstable product 509, completing the catalytic cycle. This unstable product 509 undergoes a Pinner reaction/isomerization, affording the final product 502′.

A method for the catalytic enantioselective 1,3-dipolar cycloaddition of the Seyferth–Gilbert reagent (SGR) 511 to (2-oxoindolin-3-ylidene)malononitriles 512 using a cinchona alkaloid derivative 513 as a catalyst was developed by Peng and co-workers.[108] This method allowed the synthesis of a series of chiral spirooxindole-phosphonylpyrazolines 514 in good yields with excellent enantioselectivities. The synthetic utility of this method was demonstrated by its use in a three-component domino reaction involving isatins 501′, malononitrile (493), and SGR 511 based on sequential Knoevenagel condensation and 1,3-dipolar cycloaddition reactions with no decrease in the yields or enantioselectivities (Scheme [100]).

He, Guan, and co-workers developed a domino Knoevenagel/Michael/Michael reaction for the synthesis of spirooxindole derivatives 515 and 515′ in methanol biocatalyzed by pepsin 516 from porcine gastric mucosa as a sustainable and environmentally friendly biocatalyst.[109] A wide range of isatins 501 and α,β-unsaturated ketones 517 reacted with malononitrile (493) to provide 515/515′ in high yields and diastereoselectivities (Scheme [101]).

According to the literature,[110] [111] the active site of pepsin 516 from porcine gastric mucosa contains Asp32 and Asp215 residues. The function of aspartic acid (32nd residue) has been confirmed to act as a base. Thus, based on the literature, in control experiments and kinetic experiments, the authors proposed a mechanism for the pepsin-catalyzed domino reaction of isatin 501, malononitrile (493), and benzalacetone (517′) (Scheme [102]). First, the carbonyl of benzalacetone is stabilized via a hydrogen bond with Asp215 in pepsin, and Asp32 acts as a base to abstract a proton from benzalacetone to form enol 518 that in turn reacts by intermolecular Michael addition with the intermediate (2-oxoindolin-3-ylidene)malononitrile 519, which spontaneously formed by Knoevenagel condensation of isatin 501 with malononitrile. Finally, intramolecular Michael addition occurs forming the spirocyclic oxindole skeleton 515 or 515′.

Domino Reactions Initiated by Cycloaddition Reactions

Cycloadditions are reactions in which two π bonded molecules come together to make a new cyclic molecule with the formation of two new σ bonds. These reactions are one of the main strategies employed in the synthesis of spiro compounds.[1] [3] [5]

A chemo- and enantioselective [3+2] annulation between the Morita–Baylis–Hillman carbonate of isatins 520 and propargyl sulfones 521 catalyzed by a chiral tertiary amine 522 was developed by Chen and co-workers for the synthesis of spirooxindoles 523 that incorporate an unusual cyclopentadiene motif in good yields and excellent enantiomeric excesses (Scheme [103]).[112] The reaction takes place through the dipolar cycloaddition of an in situ generated allylic N-ylide and allenyl sulfone, followed by a C=C bond domino isomerization sequence.

The Yan group developed a domino cycloaddition of N-phenacylbenzothiazolium bromides 524 with 3-(2-oxo-2-phenylethylidene)oxindoles 525 or ethyl 2-(2-oxoindolin-3-ylidene)acetates 526 in ethanol at room temperature in the presence of triethylamine for the synthesis of functionalized spirobenzo[d]pyrrolo[2,1-b]thiazole-3,3′-oxindoles 527 and 527′, respectively, in good yields and high diastereoselectivities. Moreover, spirooxindole-3,7′-pyrrolo[2,1-b]thiazoles 528 were obtained in satisfactory yields and with high diastereoselectivities through the reaction of N-phenacylthiazolium bromides 529 with 3-(2-oxo-2-phenylethylidene)oxindoles 525 (Scheme [104]).[113]

The proposed mechanism is shown in Scheme [105]. First, triethylamine deprotonates the N-phenacylbenzothiazolium bromide 524 to give a nitrogen ylide A with canonical form B. Then, the nitrogen ylide reacts by a stepwise process (path a) or a concerted process (path b). In path a, Michael addition of nitrogen ylide A to 3-(2-oxo-2-phenylethylidene)oxindole 525 results in intermediate C, which undergoes intramolecular addition to provide spirooxindole-3,7′-pyrrolo[2,1-b]thiazoles 527. In path b, the addition of nitrogen ylide A to the C=C bond of 3-(2-oxo-2-phenylethylidene)oxindole 525 directly results in the formation of 527.[113]

Similarly, Mukhopadhyay and co-workers developed a three-component reaction via domino 1,4-dipolar cycloaddition of isatins 492′ with acetylenedicarboxylates 532 and pyridine 531 in aqueous ethanol at room temperature using ultrasound-assisted methodology to obtain spirooxindole-pyrido[2,1-b][1,3]oxazines 530 in good yields and diastereoselectivities (Scheme [106]).[114]

In 2021, the Siva group also developed an asymmetric one-pot 1,3-dipolar cycloaddition domino sequence of chalcones 533, isatin 501′, and proline (484) organocatalyzed by a bipyridine-based chiral quaternary ammonium bromide 534 for the synthesis of spirooxindole-3,3′-pyrrolizine derivatives 535 in excellent yields and with excellent enantiomeric excesses (Scheme [107]).[115]

Toffano and co-workers described an auto tandem catalysis (ATC) process including an enantioselective vinylogous formal [4+2] cycloaddition followed by a kinetic resolution (KR). The reaction passes through a 1,3-prototropic shift between ketone-derived benzylidene Meldrum’s acid 536 and α-ketolactone 537 to provide enantioenriched spirolactone-dihydropyranones 538 and 538′ (Scheme [108]).[116] This process results from the dual and complementary role of (DHQ)₂PHAL organocatalyst 539.

The proposed catalytic sequence is shown in Scheme [109]. The catalytic cycle I is related to the asymmetric formation of the spiro stereogenic center leading to the non-conjugated lactone 538 and 538′ as an enantioenriched mixture. The second cycle (catalytic cycle II) consists of the isomerization of 538 to conjugated lactone 538′ via a kinetic resolution process, which proceeds through a 1,3-prototropic shift, on which basic catalyst deprotonates the weakly acidic α-position of 538 to form the intermediate 540. A regioselective reprotonation of the enolate 540 then occurs preferentially at the γ-position to afford the product 538′.

Domino Reactions Initiated by Metal Insertion

Enantioselective metal catalysis is a powerful tool for many types of reactions. In particular, the combination of enantioselective metallic catalysis with the concept of domino reactions allows high molecular complexity to be achieved with remarkable levels of stereocontrol based on simple and economical one-pot procedures. Since 2010, many enantioselective domino processes have been successfully catalyzed by a wide variety of chiral metal complexes. Especially, the considerable impact of the advent of asymmetric transition-metal catalysis has allowed the immense development of many highly efficient enantioselective metal-catalyzed domino reactions. The wide variety of these processes well reflects the variety of metals used to promote them.[117] [118]

In 2014, Chen, Xiao, and co-workers reported an efficient access to various synthetically important polycyclic spirooxindoles 545 in a highly stereoselective manner under mild conditions using an unprecedented zinc-catalyzed asymmetric domino Michael/cyclization reaction of 3-nitro-2H-chromenes 546 with 3-isothiocyanatooxindoles 266 (Scheme [110]). These complex and densely functionalized chiral products 554, bearing three consecutive stereocenters, were obtained in good to quantitative yields (72–99%) and with excellent stereoselectivities (>95:5 dr) and enantioselectivities (91 to >99% ee). The spiro compounds were obtained using a combination of Zn(OTf)₂ and chiral bisoxazoline (S,S)-547 bearing a free NH group that could act as a Lewis base through hydrogen bonding interaction.[119]

Xu, Yuan, and co-workers[120] developed related asymmetric domino Michael/cyclization reactions using the (R,R)-enantiomer 548 of the ligand used by Chen, Xiao, and co-workers.[119] Reaction between 3-isothiocyanatooxindoles 266 and 3-nitroindoles 549 in the presence of (R,R)-548 as ligand with Zn(OTf)₂ as precatalyst in toluene at 50 °C gave highly functionalized polycyclic spirooxindole derivatives 550 with three contiguous stereocenters in quantitative yields with excellent diastereo- and enantioselectivities (>98% de and >99% ee) (Scheme [111]).[120]

In 2012, the Franz group reported the enantioselective [3+2] annulation of allylsilanes 551 with isatins 492 as a novel strategy to obtain a chiral biologically interesting spirooxindoles 552 in moderate to good yields and, in most cases, with remarkable enantioselectivities (97–99% ee) and complete diastereoselectivity (Scheme [112]).[121] The reaction was promoted by an in situ generated scandium catalyst from ScCl₂(SbF₆) and chiral Pybox ligand 555 in the presence of TMSCl as a additive. Mechanistically, the domino process between allylsilanes and isatins begins with allylation to produce intermediates 553 that undergo 1,2-silyl migration to give 554, which further undergoes cyclization to afford the final chiral spirooxindoles.

The Franz group also reported the first enantioselective formal 1,3-dipolar cycloaddition of unsaturated carbonyl compounds 556 with allylsilane 557 using a combination of 10 mol% of Sc(OTf)₃ and Pybox ligand 555 in the presence of NaBArF as an additive. The reaction proceeded through asymmetric scandium-catalyzed domino Michael/1,2-silyl shift/cyclization reaction of alkylideneoxindoles 556 with allyltriisopropylsilane (557) to afford highly functionalized chiral spirocyclopentane-oxindoles 558 bearing three stereogenic centers in high yields and with high diastereo- and enantioselectivities (Scheme [113]). Mechanistically, it is proposed that the Michael addition of allyltriisopropylsilane to alkylideneoxindole gives intermediate 559, which further undergoes 1,2-silyl shift followed by cyclization to provide the final spirocyclopentane 558.[122]

Alternatively, Li and Shi used an asymmetric domino bromination/aminocyclization reaction of 2-benzofuranylmethyl N-tosylcarbamates 560 with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 562) to give a novel class of chiral spirobenzofuran-oxazolidinones 561 in good to excellent yields of 62–97% and excellent enantioselectivities of 91–97% ee in the presence of Na₂CO₃ as an additive (Scheme [114]).[123]

In the same way, Feng and co-workers reported a novel enantioselective scandium-catalyzed 1,5-hydride shift/ring closure domino reaction using 3-alkylideneoxindoles 564 to provide various chiral spirooxindole-tetrahydroquinolines 565 bearing contiguous quaternary or tertiary carbon stereocenters in good to excellent yields (up to 97%) and good to high enantioselectivities (up to 94% ee) (Scheme [115]). Mechanistically, it is proposed that in the presence of a combination of N,N′-dioxide chiral ligand 565 (10 mol%) and Sc(OTf)₃ (10 mol%) 3-alkylideneoxindole 564 undergoes a 1,5-hydride shift to give intermediate 566 which subsequently undergoes a ring-closure reaction to provide 565.[124]

In 2015, Feng and co-workers reported an asymmetric dearomatization of indoles through a domino Michael/Friedel–Crafts-type/Mannich reaction between 3-(2-isocyanoethyl)indole (568) and alkylidenemalonates 569 to provide a range of fused functionalized polycyclic chiral indolines 570 as single diastereomers (>99% de) exhibiting three stereocenters in good yields of up to 98% and high enantioselectivities of 81–95% ee (Scheme [116]). The process was catalyzed with a combination of Mg(OTf)₂ and chiral N,N′-dioxide ligand 571 in the presence of NaBArF₄ as an additive.[125]

Performing the same reaction using 2-substituted 3-(2-isocyanoethyl)indoles 573 with arylidenemalonates 569 resulted in a simple domino Michael/Friedel–Crafts-type reaction to give chiral spiroindoles 572 in good to quantitative yields (70–99%), high enantioselectivities of 85–96% ee, and moderate to excellent diastereoselectivities of up to >90% de (Scheme [117]).[125] While reaction of 3-(ω-isocyanoalkyl)indoles 575 with 3-(2,2-dimethylpropylidene)oxindoles with catalyst 571 and Mg(OTf)₂ in DCE at 0 °C gave a series of chiral polycyclic 3-spirooxindoles 574 bearing cyclopenta[b]indole units with four contiguous stereocenters in high yields (75–96%), and enantioselectivities of 73–93% ee, combined with moderate to high diastereoselectivities of 38 to >90% de (Scheme [118]). In most cases, higher diastereoselectivity was observed for the electron-withdrawing substituted compounds compared to the electron-donating ones.[126]

Matsunaga, Kanai, and Kato used a chiral dinuclear nickel Schiff base as catalyst to develop the first catalytic asymmetric addition of 3-isothiocyanatooxindoles 577 with aliphatic aldehydes 489 through an aldol-type/cyclization domino reaction to give spirooxindoles 578 in high yields and diastereo- and enantioselectivities (Scheme [119]). The reaction was carried out using 10 mol% of chiral dinuclear Ni₂-Schiff base 579 in the presence of molecular sieves at room temperature and 1,4-dioxane as solvent. Notably, the catalyst loading could be reduced to 0.1 mol% while still providing an enantioselectivity of 98% ee. Catalyst 579 was more effective than the corresponding dinuclear copper and cobalt complexes which both provided low enantioselectivities (2–21% ee).[127]

In 2014, Gandon and co-workers used a Au/Lewis acid bimetallic system to expand the field of asymmetric Conia-ene-type reactions (Scheme [120]). The hydroalkylation of N-allyl-2-oxocyclohexanecarboxamide 581 using digold complex (R)-[DTBM-SEGPHOS(AuCl)₂] 582 with indium activator gave spirocyclohexane-pyrrolidinone 583. No reaction took place with the gold complex alone, but the spiro compound was obtained in enantioenriched form after addition of In(OTf)₃; indium(III) triflimidate was equally selective.[128]

The Enders group reported a one-pot stereoselective synthesis of spiroindane-pyrazolones 584 via an organocatalytic asymmetric Michael addition and Conia-ene reaction starting from pyrazolones 313 and 2-alk-1-ynyl-β-nitrostyrenes 585. The syntheses proceed under mild conditions and results in high yields and stereoselectivities (Scheme [121]). The mechanistic pathways were investigated using computational chemistry and mechanistic experiments. The sequential procedure can be described as a combination of a squaramide-catalyzed Michael addition and a silver-catalyzed Conia-ene reaction. The organocatalyzed asymmetric reaction may proceed through the formation of a ternary complex in which the 2-alk-1-ynyl-β-nitrostyrene undergoes electrophilic activation by hydrogen bond formation to the squaramide scaffold 586 (Scheme [121]).[129]

Also exploring the Michael/Conia-ene reaction, the study by Veselý and co-workers report a highly stereoselective synthesis of spirocyclopentene-pyrazolones 587 (Scheme [122]). This novel synthetic strategy combines metallic catalysis and organocatalysis to promote a synergism between proline 61a and the Pd catalyst. A detailed computational study showed that the substituent of the proline catalyst 61a changes its function during the reaction. In the Michael reaction this group acts as a bulky blocking group, but also the same group generates π-Pd interactions and plays as a driver in the subsequent Pd-catalyzed Conia-ene reaction.[130]

The proposed mechanism is divided in two parts based on the two different C–C bond forming reactions (TS-I and TS-II). The reaction occurs during the whole process with Part 1, including the Michael addition reaction that produces intermediate Int-Ald 589; and Part 2, including the final Conia-ene reaction that generates product 587 (Scheme [123]).[130]

Veselý, Rios, and co-workers reported the first ring contraction-formal [6+2] cycloaddition using synergistic Pd(0)-proline derived 61a catalysis to give spirocyclopentane-pyrazolones 590 in excellent yields and stereoselectivities (Scheme [124]). The key palladium activated intermediate in its protonated form was determined by mass spectrometry, infrared spectroscopy, and DFT calculations.[131]

The proposed mechanism is initiated by activation of both reactants to yield highly reactive palladium complex 592 and iminium ion 593, where the Jørgensen–Hayashi catalyst efficiently blocks the upper face of the ion during coupling between 594 and 593 to produce the enamine intermediate 595 that contains the palladium-coordinated allyl cation. Ring-closure between the enamine moiety and the allyl cation in 595 gives an iminium complex 596 that is hydrolyzed to regenerate the secondary amine catalyst 61a and provides the palladium complex 597. After palladium recovery the final compound 590 is obtained and the catalysts is regenerated for another synergistic cycle (Scheme [125]).[131]

Córdova and co-workers also used palladium for the construction of spirooxindoles 598 based on the combination of imine-enamine activation of diphenylprolinol silyl ether 61a with Pd-allylation (Scheme [126]). Oxindoles 599 containing an allylic acetate were reacted with enals 220 via Michael/Tsuji–Trost allylation to give spirocyclopentane-oxindoles 598 in good yields (90–76%), with moderate diastereoselectivities (up to 5:1 dr) and excellent enantioselectivities (up to 99% ee).[132]

The proposed mechanism begins with the reversible stereoselective conjugate addition of 599, by the less hindered Si-face of the intermediate 600, generated in situ, resulting in formation of the major stereoisomers 601 and 602 over the minor stereoisomers ent-602 and ent-602′ which are in slow equilibration via the corresponding enamine intermediates (601a–c). Then, the oxidative addition of Pd to enamine 601 occurs, resulting in the π-allyl-palladium 603 complex; intermolecular nucleophilic attack by the chiral enamine followed by protonation and reductive elimination, releases the catalyst and forms iminium 604. Finally, hydrolysis of 604 generates spirocyclic oxindole 598 and reconstitutes catalyst 61a. Additionally, it was shown that the faster reaction pathway via enamine 601 as compared with the pathway via 602 is due to lower steric repulsion between the aryl group and the R-O group in its transition state (Scheme [127]).[132]

Chogii and Njardarson reported an interesting application of metallic insertion in the synthesis of spirocycles through stereoselective domino reaction in the preparation of the natural product (+)-elacomine (605), an intriguing spirooxindole structure (Scheme [128]). A substrate-controlled Heck cyclization step was used to form the spirooxindole core.[133]

Initially, deprotonated ethyl 4-bromobut-2-enoate was trapped with imine 606 to give ester 607 that was converted into 2-iodophenyl-3-pyrroline-3-carboxamide 608 using aniline 609. Then, Heck cyclization was used to form the spirooxindole core 610 in good yield which was further manipulated to give elacomine (605).[133]

Sekar and co-workers reported palladium catalysis in an efficient diastereoselective synthesis of spirooxindole-α-tetralones 612. A novel Pd-catalyzed carbene migratory insertion-conjugate addition strategy was used to access spirooxindoles with contiguous quaternary and tertiary carbon centers in a diastereoselective fashion. This operationally simple protocol represents the first example of the use of isatin-derived N-tosylhydrazones 613 in a metal-carbenoid involving domino process, thus opening a new way to construct novel complex molecular spirocycles from readily accessible starting materials with a broad scope. In addition, a transition-state model has been proposed to understand the observed stereoselectivity (Scheme [129]).[134]

NMR reaction profiling and deuterium-labeling investigations provide insight into the mechanistic pathway; the proposed mechanism is outlined in Scheme [130]. Initially, oxidative addition of 614 to Pd(0) generates ArPd(II) species A that reacts with in situ formed diazo compound to give the Pd–carbenoid complex B, which undergoes migratory insertion of the aryl group into the carbenic carbon atom to generate the C- or O-bound Pd-enolate existing as π-oxoallyl Pd-intermediate C. Then, the Pd-enolate undergoes an intramolecular 6-endo-trig mode of conjugate addition to form intermediate D. Since syn-β-H elimination is precluded by the conformationally rigid nature intermediate D, it, or its corresponding O-bound tautomer E, undergoes protonolysis to furnish the product 612. The resultant Pd(II) is reduced to active Pd(0) with the aid of DIPEA. The formation of 615 via a 5-exo-trig mode of closure is disfavored presumably due to increased steric hindrance involved in the approach of the Pd to α-position of the double bond.[134]

In 2018, Xu and co-workers developed a new palladium-catalyzed domino approach for the synthesis of attractive spirocyclic indolines and dihydrobenzofurans. The reaction proceeds through a sequential intramolecular Heck spirocyclization, remote C–H activation, and diazocarbonyl carbene insertion. The optimized methodology enabled efficient access to a broad range of spiroindane-indolines 616 and spiroindane-dihydrobenzofurans 617 containing two quaternary stereogenic centers in good to excellent yields. In the reaction of N-(2-arylallyl)-2-iodoanilines 619 with α-diazo esters 620 the best catalytic activity was exhibited by Pd(OAc)₂ while monophosphoramidite ligand 618 displayed unique catalytic activity and furnish the spiroindoline product 616 in excellent yield (up to 94%) with up to 71:29 dr (Scheme [131]).[135]

The reaction of 2-arylallyl 2-iodophenyl ether 621 and α-diazo esters 620 also used Pd(OAc)₂ but this time the reaction proceed smoothly in the presence of PPh₃ as ligand, Cs₂CO₃ as the base, and THF as the solvent, enabling access to the expected spiroindane-dihydrobenzofurans 617 in good yields (Scheme [131]).[135]

The asymmetric spirocyclization of N-(2-arylallyl)-2-iodoanilines 619 with α-diazo esters 620 with Pd(OAc)₂ using chiral monophosphoramidite 622 as a ligand enabled access to highly valuable chiral spiroindolines 623 with up to 80% ee (Scheme [132]).[135]

In 2019, the Miesch group used an intramolecular electrophilic aromatic substitution of ketospiro-enesulfonamides 626 followed by allylation catalyzed by Zr and Ti to form diastereoselectively 624 and 625, respectively. Treatment of ketospiro-enesulfonamides 626 with ZrCl₄ and allylsilane 627 resulted in intramolecular electrophilic aromatic substitution and subsequent allylation is observed. Similarly, treatment of ketospiro-enesulfonamides 626 with TiCl₄ resulted in a double enamine-type reaction to diastereoselectively create four contiguous stereogenic centers (Scheme [133]).[136] The Miesch group then explored the reaction of keto-ynesulfonamides with quaternary ammonium salts to access azaspiro compounds.[137]

The proposed mechanism for the formation of these spiro-polycyclic-fused ring systems is shown Scheme [134]. Firstly, the Lewis acid activates ketone 626 to provide 628. Subsequent intramolecular electrophilic aromatic substitution affords intermediate 629 that through a process of rearomatization affords 630. Next, the ionization of 631 complex leads to tertiary carbocation 632.[136] So far, the mechanism is the same for both catalysts, however two pathways can be considered depending on the Lewis acid chosen. Pathway A involves allylsilane addition on the convex face of molecule 632. Because zirconium(IV) has an ionic radius much larger than that of titanium(IV), the Zr–Cl bond may be more labile, promoting β-silyl elimination to form polycyclic system 624. On the other hand, in pathway B, allylsilane adds to 632, providing 634. In this case, the enamine-like reactivity of 634 is faster than β-elimination of the silicon moiety, thus leading to bridged compound 635. A second molecule of allylsilane subsequently adds to the iminium ion from the less hindered side of 636, thus ending with the production of 625 after β-silyl elimination.[136]

Other Mechanisms

Some examples of domino reactions for the asymmetric synthesis of spiro compounds where several different reactions initiate the domino processes are presented in this section.

Wu and co-workers developed the first enantioselective vinylogous aldol/cyclization domino reaction of N-but-3-enoylpyrazoles 637 with isatins 492 for the asymmetric construction of spirooxindole-dihydropyranones 638 in excellent yields and good-to-excellent enantioselectivities, in the presence of only 1 mol% of Takemoto catalyst 351.[138] Similarly, Han and Chang also synthesized a series of spirooxindole-dihydropyranones 639 via a vinylogous aldol-cyclization cascade reaction of 3-alkylideneoxindoles 640 to isatins 641, using cinchona alkaloid-squaramide bifunctional organocatalysts 77 or 167 (Scheme [135]).[139]

A stereoselective synthetic approach to spirooxindole-4H-pyran-2-ones 642 was developed by the Du group via a NHC-catalyzed three-component domino reaction of alk-2-ynals 643 with oxindoles 455 in good yields and with good to high diastereoselectivities (Scheme [136]).[140] According to the proposed mechanism, the domino reaction starts with the addition of the NHC catalyst deprotonated by t-BuOK 644 to the aldehyde 643, providing the Breslow intermediate 645. After a redox reaction and protonation the α,β-unsaturated acyl azolium 646 and intermediate 647 are formed; conjugate addition followed by H-migration gives adduct 649, this one in turn undergoes aldol reaction with another molecule of alkynyl aldehyde 643 and subsequent lactonization to form 642 and regenerate the catalyst. The stereochemistry of the product is explained by the chair-transition state 650 in the lactonization step. Steric hindrance between the alkynyl group and the carbonyl group of the oxindole leads to anti-orientation. The other group R¹, being bulky, must also be anti to the alkynyl (Scheme [136]).

Gravel and co-workers also described a domino NHC-catalyzed spirocyclization via Stetter/aldol/Michael (SAM) reaction, for the synthesis of a variety of spiroindane-indenes 651, with high diastereoselectivity, from simple o-phthaldialdehydes 652 (Scheme [137]).[141] According to the proposed mechanism, the Breslow intermediate I participates in a Stetter reaction to form the enolate intermediate II. This enolate undergoes an aldol reaction prior to the release of the NHC as proposed by Ye and co-workers.[142] Then, β-hydroxy ketone IV is deprotonated to give intermediate V, which undergoes intramolecular Michael addition, forming the spiro bis-indane 651′′. In the Michael addition step, Si-face of the Michael acceptor is attacked by the Re-face of the favored Z-enolate thanks to a hydrogen bond between the carbonyl and the alcohol initially formed (see Scheme [137b]). Finally, dehydration of 651′′ provides the final product 651′.

In 2018, Samanta and co-workers reported an efficient, organocatalytic, environmentally friendly, and stereoselective [3+3] one-pot allylic alkylation-oxa-Michael reaction using a wide range of Morita–Baylis–Hillman (MBH) carbonates of isatins 654 and cyclic carbonyl compounds 313 in a biomass-derived 2-MeTHF as green solvent catalyzed by DABCO as a solid Lewis base catalyst. This protocol delivers a unique class of medicinally promising spirooxindole-dihydropyran scaffolds 655 (Scheme [138]).[143] The proposed mechanism for the formation of 655 is given in Scheme [138]. An S_N2′ reaction between MBH carbonate 654 and DABCO gives allylammonium intermediate 656. Then, a tert-butoxide anion (formed in situ) removes a methylene proton from 313 to give 657, which then reacts with 656 via an S_N2′ reaction to give the adduct 658. In the presence of base, adduct 658 is converted into enolate 659, which after intramolecular oxa-Michael reaction provides 660. Finally, protonation of 660 on the same side of the C–C=O bond (i.e., in the axial direction of the half-chair conformation), leads to the thermodynamically more stable trans-product 655. Theoretical calculations using DFT/B3LYP/6-311G++(d,p) indicated that the relative thermodynamic stability of the trans isomer is 30.98 kJ mol^–1 more stable than the minor cis isomer.

Samanta and co-workers also performed a reaction of the MBH carbonate of isatin 661 with 1,3-diphenyl-1H-pyrazol-5(4H)-one 662 using optically active quinidine-based organocatalyst 663 (Scheme [139]). The reaction produced major isomer 664 in 53% yield and with 44% ee and excellent dr.[143]

In 2019, Hajra and co-workers developed a highly efficient regio- and stereoselective domino aziridine ring opening and lactamization reaction between aziridines 665 and oxindole-3-carboxylates 666 for the one-pot asymmetric synthesis of 4-arylspiropyrrolidine-3,3′-indole-2,2′-diones 667 with excellent selectivity (dr >99:1 and up to >99% ee) (Scheme [140]).[144]

Also in 2019, Chen and co-workers reported the stereoselective domino Rauhut–Currier/Michael addition process of benzofuran-3-yl vinyl ketones 668 and 3-alkylidene(7-aza)oxindoles 669 using a chiral bifunctional phosphine 670 to give the previously unreported direct asymmetric dearomative reaction of benzofuran substrates tethered to a carbonyl group in a formal [4+2] cycloaddition manner. A range of hydrodibenzofuran derivatives 671 were obtained with excellent diastereoselectivities and enantioselectivities (up to >19:1 dr, >99% ee) (Scheme [141]).[145]

Liu and co-workers synthesized spirooxindole-3,3′-pyrrolidines 672 via a silica gel and alumina-mediated diastereoselective cascade cyclizations based on tryptamine-derived ynesulfonamide substrates 673 under neat conditions (Scheme [142]).[146] The mechanism of this process was examined by isotope-labeled experiments. Initially, activation of the carbonyl group in 674 by a proton-promoted Michael addition of the indole to the ynone provides spiro intermediate 675, followed by isomerization to afford 676, which is then captured by water to provide hemiaminal 677 after proton exchange. The coordination of the carbonyl group with water through a hydrogen bond is made possible the syn-stereochemistry of the addition. The formation of 678 from hemiaminal 677 is proposed to happen via a stereospecific 1,5-hydride migration promoted by alumina.[147] The diastereoselectivity of the hydride migration is totally controlled by the stereochemistry of the hemiaminal (Scheme [142]). This strategy was further applied in the formal syntheses of indole alkaloids coerulescine and horsfiline.

In this way, the exploration of alternative reactions could give a new insight into the world of spirocycles. Zheng and You have summarized systematic studies of the chemistry of spiroindolenines, including their enantioselective syntheses, their relationship with catalytic asymmetric Pictet–Spengler-type reactions, and their diverse transformations beyond classic asymmetric Pictet–Spengler reactions.[148]

Conclusion

Spiro compounds are promising structures for drug development, in addition to being used in organic optoelectronics and asymmetric synthesis. The synthesis of spiro compounds is quite challenging, especially the control of the absolute stereochemistry. However, domino reactions have emerged as an interesting and versatile methodology of wide applicability for the asymmetric synthesis of these compounds.

Conflict of Interest

The authors declare no conflict of interest.

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Corresponding Authors

Publication History

Received: 20 December 2021

Accepted after revision: 14 February 2022

Accepted Manuscript online:
14 February 2022

Article published online:
16 May 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

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