Asymmetric Cycloaddition and Cyclization Reactions Catalyzed by

Oct 2, 2017 - Diastereodivergent asymmetric Michael-alkylation reactions using chiral N , N ′-dioxide/metal complexes. Yulong Kuang , Bin Shen , Li ...
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Article Cite This: Acc. Chem. Res. 2017, 50, 2621-2631

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Asymmetric Cycloaddition and Cyclization Reactions Catalyzed by Chiral N,N′‑Dioxide−Metal Complexes Xiaohua Liu, Haifeng Zheng, Yong Xia, Lili Lin, and Xiaoming Feng* Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China CONSPECTUS: Catalytic asymmetric cycloadditions and cascade cyclizations are a major focus for the enantioselective construction of chiral carbo- and heterocycles. A number of chiral Lewis acids and organocatalysts have been designed for such reactions. The development of broadly applicable catalysts bearing novel chiral backbones to meet the demands of various applications is an ongoing challenge. Approximately 10 years ago, we introduced a group of conformationally flexible C2-symmetric N,N′-dioxide amide compounds, which represent a new class of privileged ligands. The coordination of the four oxygens of a chiral N,N′-dioxide around a central metal generates an octahedral tricyclometalated Lewis acid catalyst that can carry out various enantioselective reactions. In this Account, we summarize our recent studies on asymmetric cycloadditions between various dienophiles and dienes, dipoles and dipolarophiles, and cascade cyclizations catalyzed by chiral N,N′-dioxide−metal complexes. In principle, these unique chiral catalysts lower the LUMO energy of electron-deficient 2π components or heterodienes by coordination with the functional groups via various binding modes. With N-Boc-3-alkenyloxindole and alkylidene malonate as the electron-deficient 2π components, N,N′-dioxide−metal complexes provided excellent catalytic activities and asymmetric inductions for a variety of transformations, including [2 + 1], [3 + 2], [4 + 2], and [8 + 2] cycloadditions. Mechanistically, these substrates could be efficiently activated through bidentate coordination. The strategy was also useful for asymmetric cascade cyclizations to form polycyclic adducts. Monodentate or bidentate coordination of other α,β-unsubstituted carbonyl compounds to metal centers enabled both normal Diels−Alder reactions and inverse-electron-demand hetero-Diels−Alder reactions as well as [2 + 2] additions. Furthermore, hetero-Diels−Alder reactions of aldehydes, ketones, and imines are well-tolerated and afford various heterocycles. This includes allowing the concise synthesis of the antimalarial compound KAE609. Asymmetric Michael/cyclization reactions of bidentate α,β-unsaturated pyrazolamides gave efficient access to the chiral drugs (−)-paroxetine and (R)-thiazesim. The formal [3 + 2] cycloadditions of donor−acceptor epoxides and aziridines enantioselectively gave a series of five-membered oxo- and aza-heterocycles. The reaction of cyclopropane diketones showed unprecedented reactivities and provided a new route for the synthesis of dihydropyrrole and benzimidazole derivatives. General models for the catalytic reactions emerged from knowledge of the absolute configurations of the products of several reactions and X-ray crystal structures of the catalysts. In the field of chirality created by the coordination of an N,N′-dioxide to a metal center, the bonding of one or two reactants establishes a perfect reaction template for generation of the target adducts. Representative examples have been used to demonstrate how the substructures of the ligands and other reaction components affect the stereoselectivity and how metal salts impact the reactivity. These results reveal the importance of tunability and compatibility of the ligands and metal precursors for achieving high stereoinduction and activity.

1. INTRODUCTION Catalytic asymmetric cycloaddition and cyclization reactions have figured prominently as fundamental synthetic methodologies for the enantioselective construction of various useful carbocycles and heterocycles.1,2 Chiral organocatalysts and ligand−metal complexes for cyclic framework synthesis have been thoroughly studied for years, as evidenced by the publication of many books and reviews.3−7 As discussed in the review by Moyano and Rios,3 approximately 150 different chiral organocatalysts have been used; however, many exciting challenges still lie ahead. Interest in developing general and powerful methods for asymmetric syntheses of cyclic structures © 2017 American Chemical Society

is continuing to grow as a means of meeting a variety of demands. Lewis acid activation occupies a preeminent position in cycloaddition and cyclization reactions. The use of privileged chiral ligands, such as oxazoline, salen, and TADDOL derivatives, coordinated with metal ions, such as Ni(II), Mg(II), Cu(II), Cr(III), and Ti(IV), was able to accelerate the formation of stereoisomeric cyclic compounds.8−10 Lanthanides and other metal salts can also give rise to racemic Received: July 28, 2017 Published: October 2, 2017 2621

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Accounts of Chemical Research

Figure 1. Structures of relevant N,N′-dioxide ligands.

described in our previous publications.12,13 In this Account, we discuss new developments in chiral N,N′-dioxide−metal complex-catalyzed asymmetric cycloaddition and cyclization reactions. Figure 2 shows superimposed crystal structures of several N,N’-dioxide−metal complexes. It provides a representation of the geometries of the metal centers (Figure 2b), the orientations of the chiral N,N′-dioxide ligands, the steric bias inherent in the ligands (Figure 2a), and the locations of vacant sites that can be attached or recognized upon binding of one or two substrate molecules to generate the reactive intermediate that generates the cyclization product (Figure 2c). Generally, N,N′-dioxides act as tetradentate ligands that securely bind a metal ion through two amine oxide oxygens and two amide oxygens, forming distorted octahedral complexes.5 The counterions of the metal precursors are weakly coordinating ions such as TfO−, BF4−, NTf2−, and ClO4−, which is beneficial for the coordination of ligands and substrates. Each of these components impacts the reaction. The malleability inherent in N,N′-dioxide−metal complexes12,13 leads to their extensive use in a wide variety of cyclization reactions, such as [2 + 1], [2 + 2], [3 + 2], [4 + 2], and [8 + 2] additions and cascade cyclizations. These reactions occur under mild conditions with excellent stereocontrol. Wherever possible, working mechanistic models in terms of substrate activation are presented.

with metal salts, including main-group metals, rare-earth metals, and transition metals. Our results suggested that conformationally rigid ligands are not always preferred over flexible ligands for asymmetric catalytic transformations. The synthesis, coordination chemistry, and representative applications of chiral N,N′-dioxides in asymmetric catalysis have been

2. CYCLOADDITION AND CYCLIZATION OF 2π COMPONENTS BEARING ELECTRON-DEFICIENT SUBSTITUENTS Most cycloaddition reactions involve an electron-rich component and an electron-deficient 2π component. Mechanistically,

products, but in general, matched chiral ligands are limited to enantioselective reactions.11 In recent years, we demonstrated that chiral N,N′-dioxides (Figure 1) could efficiently coordinate

Figure 2. Superimposed crystal structures of chiral N,N′-dioxide−metal complexes. The central metal atoms and the metal-bound atoms were taken from references and were aligned.14 Counterions and coordinated solvent molecules in (a) and (b) have been omitted for clarity. 2622

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Accounts of Chemical Research Scheme 1. Asymmetric Cycloadditions of N-Boc-3-alkenyloxindoles

structures, the major enantiomers of these cycloadducts show similar stereoarrangements, implying that the two-point bonding of the N-Boc 3-alkenyloxindole to the metal center provides a precise platform for the facially selective binding of different dipoles and dienes. In these cases, the excellent enantioselectivity of N,N′dioxides can be attributed to the well-defined asymmetric template generated by the two protruding sterically hindered amide substituents. Take, for example, the cycloaddition of 3benzylideneoxindole with nitrile oxide17 and a Brassard-type diene19 (Table 1). The less sterically hindered N,N′-dioxide LPiPh provides much lower stereoselectivity, and as the steric hindrance of the amides increases, the enantioselectivity of the reactions gradually improves. The type of moderately Lewis acidic metallic cation has a somewhat influence on the reactivity and stereoselectivity. These results are consistent with the structural features depicted in Figure 2. The coordination of the N,N′-dioxide to various metal cations provides little steric bias (Figure 2b); however, the complexes of a given metal salt with N,N′-dioxides with various amide units or amino acid backbones produce noticeably different results (Figure 2a). Thus, together the metal salts and the chiral ligands control the diastereo- and enantioselectivities of these transformations. The efficiency of the N-Boc-3-alkenyloxindole catalytic template was observed in an asymmetric Michael/Friedel− Crafts/Mannich cascade reaction with 2-isocyanoethylindole.22 A chiral L-PrPr2−Mg(OTf)2 complex accelerated the reaction and gave polycyclic 3-spirooxindoles with four contiguous stereocenters. The β-Re face of the methyleneindolinone is shielded by the amide group underneath the ligand, which leaves the β-Si face open for selective attack by the isocyanide group of the 2-isocyanoethylindole (Scheme 2). Friedel−Crafts and dearomative annulation then give the desired isomers. The facial selectivity in this case is consistent with that shown in Scheme 1.

chiral Lewis acid catalysts can lower the LUMO energy of the electron-deficient 2π component through coordination to its functional groups, and then the catalyst can induce chirality in the products. By using 3-alkenyloxindoles, alkylidene malonates, and other α,β-unsaturated carbonyl compounds as the 2π components, we succeeded in developing diastereo- and enantioselective [2 + 1], [2 + 2], [3 + 2], [4 + 2], and [8 + 2] cycloadditions with a variety of dienes and dipoles. Several cascade cyclizations could also be triggered by the activation of α,β-unsaturated carbonyl compounds in a similar manner. 2.1. 3-Alkenyloxindole Substrates

The asymmetric cycloaddition of 3-alkenyloxindoles is one of the most straightforward methods for quickly constructing various chiral spirooxindoles, which represent an attractive structural motif found in a number of natural products. We envisioned an elegant strategy to make 3-alkenyloxindoles suitable for cycloadditions. As described in Scheme 1, introducing N-Boc-group to 3-alkenyloxindoles permits the direct bidentate coordination of their two carbonyl groups to the metal center. The metal cations, including Mg(II), Ni(II), and Zn(II), which are commonly used as moderate Lewis acids and can form strong bidentate chelates with α-alkoxycarbonyl compounds, proved efficient for LUMO activation of N-Bocprotected 3-alkenyloxindoles. The two amide groups and two amine oxides of chiral N,N′-dioxides provide steric hindrance and bias to ensure efficient asymmetric induction by the propeller-type scaffold. The α-Re face of the 3-alkenyloxindoles was blocked by the amide unit below, and a number of reactants, including phenyliodonium ylide,15 nitrile imine,16 nitrile oxide,17 azomethine imine,18 Brassard’s diene,19 3vinylindole,20 and azaheptafulvene,21 could perform diastereoand enantioselective cycloadditions from the opposite face. With respect to this catalytic model, we could obtain three-, five-, and six-membered spirooxindole derivatives in high yields and stereoselectivities. As verified by multiple X-ray crystal 2623

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Accounts of Chemical Research Table 1. Effect of Ligands and Metal Salts

Figure 3. Proposed catalytic model for an asymmetric domino reaction.

2.2. Alkylidene Malonate Substrates

Alkylidene malonate is a perfect electron-deficient 2π component, as it enables two-point bonding to form an activated six-membered ring with chiral Lewis acid catalysts (Scheme 3). This activation allows efficient cycloadditions25−29 and conjugate additions. As for enantioselective cycloadditions, we developed chiral Ni(II)-promoted [3 + 2] cycloadditions with nitrone25 and azomethine imine 26 and [8 + 2] cycloadditions with azaheptafulvene27 (paths a−c); Mg(II)accelerated Michael/Friedel−Crafts-type cascade reactions with isocyanoethylindoles (paths d and e);28 and Co(II)-catalyzed hydride transfer-initiated cyclizations of o-dialkylamino-substituted alkylidene malonates (path f).29 In these examples, the nucleophile prefers to attack the β-Si face of the alkyl- or arylsubstituted alkylidene malonate in the first step. The exception to this is the [3 + 2] cycloaddition of alkylidene malonate with nitrone or azomethine imine as the dipole (path b),26 which gives the opposite facial selectivity under identical conditions (path a vs b). This driving force might come from the secondary orbital interactions between the π-orbital overlap of the azomethine imine and alkylidene malonate,26 which indicates that the interaction between the reactants might impact the selectivity of asymmetric reactions. Metal salts control both the reactivity and the stereoselectivity. For example, a chiral N,N′-dioxide−Mg(OTf)2 complex could promote all of the [3 + 2] reactions shown in Scheme 3 but with outcomes inferior to those of Ni(BF4)2.25−29 Nevertheless, in the cascade reaction of alkylidene malonates with isocyanoethylindole, the choice of metal salt is critical (Table 2).28 Chiral Ni(BF4)2 and Zn(OTf)2 complexes were inert in the reaction, but alkaline-earth metal salts were effective. This may be due to the nature of the metal cations; hard metal ions such as Mg(II) prefer to coordinate to the alkylidene malonate, but borderline metal ions such as Ni(II) and Zn(II) may interact with the isocyanate, which would inhibit the cascade reaction. Moreover, the counterion of the Mg(II) complex affects the reactivity; the strongly coordinating Cl− ions of MgCl2 are detrimental to the substitution of the alkylidene malonate and lower the reaction yield.

Scheme 2. Asymmetric Cascade Reaction

When N-Bn-protected 3-alkenyloxindole is used in a domino thia-Michael/aldol cycloaddition, the coordination mode of the substrates varies, which results in the opposite stereoarrangement for the spirocyclic oxindole-fused tetrahydrothiophene adducts (Figure 3).23 The reaction proceeds via the L-PiPr2− Ni(OTf)2 complex simultaneously activating 3-alkenyloxindole and mercaptoacetaldehyde. After an enantioselective intermolecular thia-Michael reaction, the chiral catalyst continues to facilitate the intramolecular aldol reaction via a chairlike transition state to afford the final adduct. Moreover, the N,N′-dioxide−metal complex could induce good enantioselectivity when only one substrate was bound, as demonstrated by the enantioselective tandem 1,5-hydride shift/ring closure of 3alkenyloxindole derivatives.24 These examples show that the N,N′-dioxide Lewis acid catalysts are compatible with the activation of reactants via bidentate or monodentate coordination of one or two reactants.

2.3. Other α,β-Unsaturated Carbonyl Substrates

Chiral N,N′-dioxides are also the ligands of choice for the cycloaddition of α,β-unsaturated carbonyl compounds via either monodentate or bidentate coordination modes (Scheme 4). The bidentate coordination of 2,3-dioxopyrrolidines or 2alkenoylpyridines with Ni(OTf)2 complexes results in the 2624

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Accounts of Chemical Research Scheme 3. Asymmetric Cycloadditions and Cascade Cyclization of Alkylidene Malonates

metal salts, including Ni(OTf)2, Cu(OTf)2, Zn(OTf)2, and Mg(OTf)2. This indicates that the Lewis acidity and ionic radius of the metal affect the reactivity. Asymmetric [2 + 2] and [4 + 2] cycloadditions of alkynones are another method of incorporating electron-rich alkenes in an enantioselective manner by monodentate binding of the carbonyl group of the alkynone to N,N′-dioxide−Zn(NTf)2 complexes (Scheme 5).32,33 However, the cycloadditions with cyclic enol silyl ethers32 and cyclopentadiene33 required N,N′dioxides with the same functionalities but different chain lengths.

Table 2. Effect of Metal Salts

Metal salt

Yield (%)

ee (%)

Ni(BF4)2 or Zn(OTf)2 Ca(OTf)2 Ba(OTf)2 Mg(OTf)2 Mg(ClO4)2 MgCl2

no reaction 50 24 97 90 12

− 38 69 76 76 70

Scheme 5. Asymmetric [2 + 2] and [4 + 2] Cycloadditions of Alkynones

Scheme 4. Asymmetric Diels−Alder Reactions

α,β-Unsaturated pyrazolamides are attractive electrophilic cyclization acceptors because of the potential for secondary coordination to the pyrazole group, which allows the facile preparation of rings bearing leaving groups. We explored this substrate in combination with N,N′-dioxide−Yb(OTf)3 catalysts for enantioselective conjugate addition/cyclization processes.34,35 The reaction with amidomalonates gave a series of chiral substituted glutarimides, and one of those glutarimides was used to synthesize (−)-paroxetine (Scheme 6a).34 The reaction with 2-aminobenzenethiol allowed the synthesis of (R)-thiazesim (Scheme 6b).35

formation of five-membered catalyst−substrate complexes, which are advantageous for controlling the stereoselectivity of Diels−Alder reactions with cyclopentadiene (Scheme 4a, b).30 Similarly, β,γ-unsaturated α-keto esters could participate in cycloaddition reactions with silyloxyvinylindoles to give tetrahydrocarbazole derivatives in the presence of L-PiPr3− Y(OTf)3 (Scheme 4c).31 In the latter reaction, the rare-earth metal salts gave much higher yields than other more common

3. HETERO-DIELS−ALDER REACTIONS OF ALDEHYDES, KETONES, AND IMINES The exceptional suitability of the catalysts was exploited to achieve asymmetric hetero-Diels−Alder reactions of carbonyl compounds and imines to form six-membered heterocycles. We 2625

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Accounts of Chemical Research Scheme 6. Asymmetric Reactions of α,β-Unsaturated Pyrazolamides

4. INVERSE-ELECTRON-DEMAND HETERO-DIELS−ALDER REACTIONS Inverse-electron-demand hetero-Diels−Alder reactions are controlled by the interactions of the HOMOs of the dienophiles and the LUMOs of the dienes. Heterodiene substrates, such as α,β-unsaturated carbonyl compounds and NBoc-3-alkenyloxindoles, react with ketenes or electron-rich dienophiles to generate dihydropyran derivatives. In these reactions, the chiral N,N′-dioxide−metal complex activates the heterodiene through bidentate coordination (Figure 4), which

were initially pleased to observe that an N,N′-dioxide− In(OTf)3 catalyst was perfect in hetero-Diels−Alder reactions of various aldehydes with Danishefsky’s dienes and Brassard’s dienes.36,37 This confirms that the monodentate binding of an aldehyde to this catalyst could give rise to perfect enantioselectivity. Later we demonstrated that isatin38,39 and 2-hydroxyphenyl-protected imines40,41 were good bidentate coordination candidates that could accept asymmetric [4 + 2] cycloadditions of both Brassard’s dienes and Danishefsky’s dienes. Inspired by the Diels−Alder reactions of 3-vinylindoles with 3-alkenyloxindoles,20 we designed an aza-Diels−Alder reaction for the concise synthesis of KAE 609, a highly active antimalarial compound (Scheme 7).42 N-Boc-isatin-derived ketimine was activated by an L-RaPr3−Ni(OTf)2 complex via bidentate coordination similar to that of the corresponding 3alkenyloxindole derivatives (Scheme 1) and participated in enantioselective cycloadditions of 3-vinylindoles to give spiroindolone derivatives. Compared with the reaction of 3alkenyloxindoles,20 the regioselectivity for 3-vinylindoles is reversed. This phenomenon might stem from the stabilizing π−π stacking interaction between the two indole rings in the substrates, as evidenced by a theoretical study.43

Figure 4. Asymmetric inverse-electron-demand hetero-Diels−Alder reactions.

facilitates the attack of the dienophile regardless of whether the cycloaddition involves concerted or stepwise ionic reactions. Nevertheless, the facial selectivity of the diene depends on the steric hindrance of both of the amide substituents of the N,N′dioxide and the type of dienophile.

Scheme 7. Concise Synthesis of KAE609 and Possible Catalytic Model Based on Computational Analysis

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Accounts of Chemical Research For example, Gd(OTf)3 complexes of N,N′-dioxide L-PiPr2 or L-PiAd promoted the reaction between N-tosyl-3alkenyloxindoles and ketenes with reversed diastereoselectivity and high enantioselectivity (Figure 4a).44 1-Adamantyl and 2,6diisopropylphenyl groups on the ligands create different chiral pockets, and the ketene approaches the heterodiene from the opposite face. Nevertheless, in cycloadditions using mono- or disubstituted acyclic vinyl ethers, vinyl sulfides, 3,4-dihydro-2Hpyrans, and enecarbamates, the dienophiles showed uniform facial selectivity in the presence of the chiral L-PiMe3− Ni(BF4)2 complex.45 With β,γ-unsaturated α-keto esters as the dienes via bidentate coordination to the Lewis acid (Figure 4b), the dienophiles mentioned above were tolerated in [4 + 2] cycloadditions.46−48 Notably, the approach of vinyl ethers and ketenes came from different sides, and their approaches were governed by the chiral pocket created by the L-PiPr2− Er(OTf)3 and L-PiPr2−Y(OTf)3 catalysts, respectively.48 Additionally, asymmetric reactions between o-quinone methide and azlactone mediated by a chiral L-RaMe2tBu−Sc(OTf)3 complex gave dihydrocoumarin derivatives,49 and the binding of two monodentate substrates to the Sc(III) center was suggested to control the stereochemistry. Asymmetric cycloadditions catalyzed by N,N′-dioxide−metal complexes were extended to relay catalysis. We discovered a new dual-metal relay catalyst that exploits the preferential binding affinity of different ligands for specific metal centers to promote the desired sequence of transformations (Scheme 8).50 During our studies, we found that N,N′-dioxide could

cyclization, giving spiroketals and spiroaminals in good yields and enantioselectivities rather than the bicyclo[4.n.0]aminal products seen in the achiral Au(I)/Gd(III) dual-metal systems of the racemic reaction.51 Thus, the structurally tunable and stable chiral N,N′-dioxide−metal complexes are capable of catalyzing more complicated relay transformations in which asymmetric catalysis is independently or cooperatively transferred to chiral Lewis acid catalysts. An N-aryl imine could act as a diene in a formal cycloaddition with an electron-rich alkene in a Povarov reaction. Asymmetric Povarov reactions between cyclopentadiene and α-alkyl styrenes rely on the use of a chiral L-PrPr2− Sc(OTf)3 catalyst (Scheme 9).52,53 A one-pot three-component strategy was used in some instances, and the outcomes were on par with those of the prepared imines.52 Using o-hydroxyaniline to form the imine is essential for both the reactivity and stereoselectivity, and the convenient formation of fivemembered metallacycles was assumed to facilitate the coordination of the alkenes.

5. CYCLIZATION OF DONOR−ACCEPTOR EPOXIDES, AZIRIDINES, AND CYCLOPROPANES Donor−acceptor (DA) epoxides and DA aziridines favor C−C bond heterolytic cleavage to form transient carbonyl ylide and azomethine ylide intermediates, respectively, that undergo cycloadditions with various dipolarophiles, especially in the presence of Lewis acids. Control experiments showed that the chirality of the DA epoxides and aziridines has no obvious effect on the outcome of the cycloaddition, which indicates a dynamic kinetic resolution process. Like alkylidene malonates (Scheme 3), 2,2-dicarbonyl-substituted epoxides and aziridines and their related ylide intermediates can form six-membered rings through the coordination of two carbonyl groups to the metal center (Figures 5 and 6) and then undergo enantioselective formal [3 + 2] cyclizations.54−58 We carried out the asymmetric catalysis of formal [3 + 2] cyclizations of racemic aryl oxiranyl diketones (Figure 5), which are chiral L-PiPr2−Gd(OTf)3 complex-mediated transformations with aldehydes that lead to enantiomerically enriched 1,3dioxolanes.54 Other dipolarophiles such as alkynes and alkenes55 could efficiently participate in similar [3 + 2] cycloaddition reactions with DA epoxides, and the corresponding chiral dihydrofurans and tetrahydrofurans, respectively, were generated via L-PrPr3−Ni(II) catalysis. Moreover, on the basis of the absolute configurations of the two products, aldehydes and alkynes are selective for the Re face of the carbonyl ylide intermediate. However, for cycloadditions with indoles, aryl oxiranyl diketones are sluggish, and only 2,2diester-substituted epoxides gave satisfactory results.56 In a subsequent application, we demonstrated a relay catalyst system for the asymmetric cycloaddition of DA aziridines to aldehydes and a variety of cyclic and acyclic enol ethers (Figure 6).57,58 Initially, LiNTf2 promoted C−C bond cleavage to form azomethine ylide intermediates. Chiral N,N′-dioxide−Nd-

Scheme 8. Bimetallic Relay Asymmetric Catalysis

discriminate ions based on hardness, which means that the combination of an achiral π-acidic gold(I) catalyst and a chiral L-PiPr2−nickel(II) catalyst worked well in the cascade reaction between β,γ-unsaturated α-keto esters and alkynyl alcohols and amides. Interestingly, the incorporation of N,N′-dioxide changed the regioselectivity of the reaction. The asymmetric [4 + 2] cycloaddition occurred preferentially with the initially formed enol ether or enamide intermediate of the 5-exo-dig Scheme 9. Asymmetric Povarov Reaction

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complex catalyst preferentially recognize the S enantiomer of the cyclopropane, which then undergoes a formal cycloaddition in which the stereocenter is reversed via an SN2 pathway (Scheme 10).59 A dynamic kinetic resolution process Scheme 10. Asymmetric Reactions of Cyclopropyl Ketones

Figure 5. Activation models of donor−acceptor epoxides.

(OTf)3 complexes bound to dipolar intermediates to mediate concerted [3 + 2] cycloadditions with aldehydes, which afforded cis-1,3-oxazolidine derivatives (path a). Furthermore, the cooperativity of LiNTf2 and L-PiPr2−Dy(OTf)3 complexes enabled efficient cyclizations of 3,4-dihydropyran and 6substituted 3,4-dihydropyrans, which showed reversed diastereoselectivity in the final ring-closure step (path b vs c). In general, the cycloaddition proceeded via a concerted enantioselective [3 + 2] pathway to give cis product. If 3,4dihydropyran participated in the cycloaddition, it might go through an anomeric epimerization to form the thermodynamically more stable trans product. In addition, the methodology was further applied in the highly diastereo- and enantioselective synthesis of D-galactal derivatives (path e). The excellent performance of the chiral Lewis acids was further exploited to realize the catalytic asymmetric ring opening and closing of DA cyclopropanes. Compared to previous DA epoxides and DA aziridines,54−58 the stereochemistry of DA cyclopropanes in ring-opening reactions is quite different.59−61 In these cases, the chiral L-PiPr3−Sc(III)

accompanies this reaction as well. Furthermore, unlike for the reactions of cyclopropyl diesters, the transformation observed for cyclopropyl diketones is interesting in that one ketone participates in an intramolecular condensation reaction.59,60 In addition, the reaction is sluggish in the absence of the chiral N,N′-dioxide ligand. As depicted in Scheme 10, the asymmetric reaction between racemic cyclopropyl diketones with anilines occurs via a ringopening/cyclization cascade to deliver 2,3-dihydropyrroles as the final products.59 Moreover, the reaction between cyclopropyl diketones and aryl 1,2-diamines was an interesting ringopening/cyclization/retro-Mannich process that gave benzimidazole derivatives.60 A diastereo- and enantioselective [3 + 3] annulation of cyclopropanes with mercaptoacetaldehyde to generate tetrahydrothiopyranols was also readily achieved.61 The activation mode of cyclopropyl diketones is unclear at

Figure 6. Activation models and reactions of donor−acceptor aziridines. 2628

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Accounts of Chemical Research present, and mono- or bidentate coordination of the ketone to the metal center might be involved.

Yong Xia received his B.S. in 2012 and Ph.D. in 2017 from Sichuan University under the supervision of Prof. Feng. Lili Lin received her B.S. in 2003 and Ph.D. in 2008 from Sichuan University. She joined the faculty of Prof. Feng’s group at Sichuan University, where she is now a professor. She is interested in the development of new methodologies in asymmetric catalysis.

6. CONCLUSIONS The examples described above demonstrate that chiral N,N′dioxide−metal complexes are excellent Lewis acid catalysts for asymmetric cycloaddition and cyclization reactions and can tolerate either bidentate or monodentate substrate coordination. The optimization of the structure of the catalysts to meet the requirement of various reactants can be readily achieved through steric tuning of the amino acid and amide subunits. In most cases, the ligands exerted asymmetric induction through the bulky o-iPr groups of the amide units. The Lewis acidity could be adjusted by using different metal salts. The use of rareearth metal complexes enhanced the efficiency of the chiral N,N′-dioxides, which gave several surprising results. A chiral pocket could be constructed through the coordination of N,N′dioxides to specific metal salts (Figure 2), and then the chirality of the N,N′-dioxides could be efficiently transmitted to the adducts. To date, we have demonstrated the power of N,N′dioxide−metal complexes for the activation of a wide range of substrates, including aldehydes, ketones, imines, 3-alkenyloxindoles, alkylidene malonates, 2,3-dioxopyrrolidines, 2-alkenoylpyridines, alkynones, α,β-unsaturated pyrazolamides, β,γunsaturated α-keto esters, o-quinone methides, donor−acceptor epoxides, donor−acceptor aziridines, and cyclopropyl diketones. More than 20 kinds of dienes, dienophiles, dipolarophiles, and nucleophiles could be introduced to the chiral architectures of the catalysts and deliver the target carbocyclic and heterocyclic products in high yields, diastereoselectivities, and enantioselectivities. Optically pure molecules with important biological activities were synthesized via the developed methodologies. Intensive research in chiral N,N′dioxide−metal complex-mediated asymmetric transformations will focus on discovering novel activation modes and constructing complex and useful chiral molecules. As discussed above, several representative catalytic templates have been established, but unfortunately, there are still gaps. We anticipate that the systematic study of the outcomes brought about by N,N′-dioxide−metal complexes could enable the establishment of an asymmetric library. If we could build several general templates for a number of asymmetric transformations, it would be possible to achieve rational asymmetric catalytic synthesis.

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Xiaoming Feng was born in 1964. He received his B.S. in 1985 and M.S. in 1988 from Lanzhou University. Then he worked at Southwest Normal University from 1988 to 1993, becoming an associate professor in 1991. In 1996, he received his Ph.D. from the Chinese Academy of Sciences (CAS) under the supervision of Professors Zhitang Huang and Yaozhong Jiang. He went to the Chengdu Institute of Organic Chemistry, CAS, from 1996 to 2000 and was appointed a professor in 1997. He did postdoctoral research at Colorado State University in 1998−1999 with Professor Yian Shi. In 2000, he moved to Sichuan University as a professor. He was selected as an Academician of the Chinese Academy of Sciences in 2013. He focuses on the design of chiral catalysts, development of new synthetic methods, and synthesis of bioactive compounds.

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ACKNOWLEDGMENTS We are sincerely indebted to a highly talented group of coworkers whose names are listed in the relevant references. We also thank the National Natural Science Foundation of China (21432006, 21625205 and 21290182) and the National Program for Support of Top-Notch Professionals for financial support.

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xiaoming Feng: 0000-0003-4507-0478 Notes

The authors declare no competing financial interest. Biographies Xiaohua Liu received her B.S. in 2000 from Hubei Normal University and her M.S. in 2003 and Ph.D. in 2006 from Sichuan University. She joined the faculty of Prof. Feng’s group at Sichuan University, where she is now a professor. Her current research interests include asymmetric catalysis of chiral guanidines and organic synthesis. Haifeng Zheng received his B.S. from Sichuan University in 2013 and is currently pursuing his Ph.D. studies under the supervision of Prof. Feng. 2629

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