Recent Developments in Catalytic Asymmetric Inverse-Electron

Review pubs.acs.org/CR

Recent Developments in Catalytic Asymmetric Inverse-ElectronDemand Diels−Alder Reaction Xianxing Jiang and Rui Wang* Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China 5.1. Combination of Organocatalysis with Metal Lewis Acid Catalysis 5.2. Bifunctional H-Bond-Directing Aminocatalysis 6. Summary and Perspective Author Information Corresponding Author Notes Biographies Acknowledgments Abbreviations References

CONTENTS 1. Introduction 2. Chiral Lewis Acid Metal Complexes-Catalyzed Asymmetric Inverse-Electron-Demand Diels− Alder (IEDDA) Reaction Based on LUMOdienesLowering Strategy 2.1. Catalytic Asymmetric IEDDA Reaction Using Chiral Titanium(IV) Complexes 2.2. Catalytic Asymmetric IEDDA Reaction Using Chiral Lanthanide Lewis Acid Complexes 2.3. Catalytic Asymmetric IEDDA Reaction Using Chiral Copper(II) Complexes 2.4. Catalytic Asymmetric IEDDA Reaction Using Chiral Nickel(II) and Chromium(III) Complexes 2.4.1. Using Chiral NiII-Complexes 2.4.2. Using Chiral CrIII-Complexes 2.5. Main Group Metal Complexes-Catalyzed Asymmetric IEDDA Reaction 2.5.1. Using Chiral AlIII-Complexes 2.5.2. Using Chiral InIII-Complexes 3. Chiral N-Heterocyclic Carbenes or Brønsted Acids-Organocatalyzed Asymmetric IEDDA Reaction Based on LUMO-Lowering Strategy 3.1. Chiral N-Heterocyclic Carbenes-Catalyzed Asymmetric Reaction 3.2. Chiral Brønsted Acids-Catalyzed Asymmetric Povarov Reaction 4. Chiral Amines-Catalyzed Asymmetric IEDDA Reaction Based on HOMOdienophiles-Raising Strategy 4.1. Enamine Catalytic Pathway 4.2. Dienamine Catalytic Pathway 4.3. Enolates Catalytic Pathway 5. Bifunctional HOMOdienophiles and LUMOdienes Strategies for Catalytic Asymmetric IEDDA Reaction © XXXX American Chemical Society

X Z AA AA AA AB AB AB AB AB

1. INTRODUCTION The Diels−Alder (DA) reaction, with its rich synthetic diversity, is recognized as one of the cornerstone reactions in modern organic chemistry.1 Since its discovery by Otto Diels and Kurt Alder in 1928,2 the DA reaction has undergone intensive development and is becoming a mainstay of organic synthetic methodologies.3 Moreover, these transformations as key steps have been frequently used for the construction of complex biologically active molecules and natural product synthesis.4 In general, DA reactions can be classified into two types of suprafacial [π4s + π2s] cycloadditions: (i) the normal and (ii) inverse-electron-demand DA reactions (Scheme 1), according

A

B C C F

J J J

Scheme 1. Classification of Diels−Alder Reactions

L L L

M M N

to the relative energies of the frontier molecular orbitals (FMOs) of the diene and the dienophile in the Hückel molecular orbital model.5 Based on the Woodward−Hoffmann rules, both of the two types could thermally be allowed.6 The frontier electron theory predicts that the normal [π4s + π2s] cycloaddition could be controlled by a HOMOdiene −

R S V W

Received: October 31, 2012

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dx.doi.org/10.1021/cr300436a | Chem. Rev. XXXX, XXX, XXX−XXX

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these asymmetric transformations, their important asymmetric synthetic applications are also illustrated in this Review. Despite all of the technical challenges, considerable progress has been made in catalytic enantioselective IEDDA reaction over the past two decades. This Review discusses in detail the results from the early 1990s to the present. The collective presentation of empirical reaction-discovery efforts herein is intended to accelerate the progress in this important field.

LUMOdienophile interaction between electron-rich dienes and electron-deficient dienophiles. In contrast, the DA reaction with inverse-electron-demand is dominated by the interaction of the HOMO of the dienophile and the LUMO of the diene. In the wake of the emergence of the first asymmetric version from Koga group7 in 1979, the catalytic asymmetric DA reactions have attracted much interest. In recent years, those elegant works have been achieved fruitfully in this area,8 and many powerful methods have been developed for these transformations with high efficiency, low ligand loading, and excellent selectivity.9 Among these reactions, the catalytic asymmetric inverse-electron-demand Diels−Alder (IEDDA) reaction has emerged as a powerful and atom-economical tool for the stereoselective construction of functionalized sixmembered rings with control of regio-, diastereo-, and enantioselectivity.10 It features mild reaction conditions, a tolerance of a diverse range of functional groups, and the easy construction of carbon−carbon and carbon−heteroatom bonds, which allows facile, stereospecific entry into the formation of functionalized ring systems.11 The high density of functional groups and up to four stereocenters of the resulting products renders them exceptionally versatile synthetic intermediates.

2. CHIRAL LEWIS ACID METAL COMPLEXES-CATALYZED ASYMMETRIC INVERSE-ELECTRON-DEMAND DIELS−ALDER (IEDDA) REACTION BASED ON LUMODIENES-LOWERING STRATEGY Metal-catalyzed asymmetric reactions play a prominent role in modern organic synthesis. They allow efficient access to various important enantiomerically rich molecules to meet the growing demands of both industry and academic researchers.29 Consequently, this particular research area has great economic potential and is becoming increasingly attractive. The Lewis acid metal-catalyzed asymmetric IEDDA reaction has received continuous attention from the chemical community in recent decades with the main focus on the synthetic aspects.9,10 The catalytic properties of Lewis acid metal for IEDDA reaction are due to the coordination of the Lewis acid to the functional groups of 1,3-diene, leading to a decrease of the LUMO energy of the diene (Figure 1). It could provide the chiral environment

Figure 1. LUMO energy of the diene by Lewis acid catalyst.

that forces the approach of a diene to the dienophile from the less sterically hindered face by the proper coordination, introducing stereoselectivity in the reaction. Usually, these reactions suffer from problems of the metal in combination with a chiral ligand because the inappropriate choice may lead to a deactivation of the catalyst. The Lewis acidity, the structural properties of the metal complex, and the electronic and structural properties of the chiral ligand all need to be considered. From the standpoint of reaction mechanism, it has usually been defined to a concerted process for those reactions. It was noted that the reaction sometimes was described by a stepwise or concerted process. For example, a stepwise process has been suggested to explain the mechanism of chiral Lewis acid metal complexes-catalyzed IED-imino Diels−Alder reaction. It has been pointed out that the IEDDA reaction could change from a concerted nonsynchronous mechanism to a stepwise mechanism depending on the substituents of the reacting species and also on the reaction conditions. On the basis of the current studies, we herein will use the broader definition in the following discussion, in part because it is often difficult to distinguish between concerted and stepwise mechanisms. As compared to the numerous theoretical calculations on normal DA reaction, only very few theoretical studies of Lewis acidcatalyzed IEDDA reactions have been performed. They will be elaborated in detail in the specific cases of this section.

Herein, we will present a systematic summary for the development and important synthetic application of asymmetric IEDDA reaction. This Review covers recent efforts and advances in asymmetric IEDDA reaction through catalytic methodologies including (i) the Lewis acidic metal complexes, or organic molecules-catalyzed asymmetric IEDDA reaction through the LUMO-lowering strategy (eq 1); (ii) the HOMOdienophiles-activation strategy by an enamine or enolate activation (eq 2); and (iii) the dual activation strategy of HOMO dienophiles and LUMO dienes (eq 3). Notably, the asymmetric Povarov reaction12 as an important type of IEDDA [4 + 2] cycloaddition between 2-azadienes and electron-rich olefins allows a rapid enantioselective construction of polysubstituted tetrahydroquinolines,13 which is discussed as well. Nowadays, IEDDA reactions have become the valuable tools in contemporary organic synthesis, especially for their synthetic utility in the synthesis of diversely heterocyclic entities and a wide variety of natural products14 such as (±)-strychnine,15 fredericamycin A,16 ent-(−)-roseophilin,17 (+)-absinthin (1),18 piericidin A1 and B1,19 taxol A-ring side chain,20 (−)-reveromycin B,21 (+)-mimosifoliol,22 (±)-leporin A,23 rhodexin A,24 (−)-halenaquinone,25 urolithin M7,26 (−)-xyloketal D,27 and 1,25-dihydroxyvitamin D3.28 To gain a better understanding of the synthetic potential and versatility of B


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As far as we can ascertain, the earliest report of the catalytic asymmetric IEDDA reaction with organometallics dates back to 1992. Tietze et al. described the first catalytic asymmetric IEDDA reaction using a diacetoneglucose-derived titanium(IV) complex.30 Ever since, a wide variety of organometallic complexes including those derived from titanium,31 copper,32 lanthanide,33 aluminum,34 nickel,35 and other metallic36 reagents have all been successfully applied to asymmetric IEDDA reaction. These Lewis acid metal complexes-catalyzed asymmetric IEDDA reactions have several unique characteristics: (1) the great range of efficient catalysts that are available; (2) high regioselectivities; and (3) the variety of functional groups that are tolerated. We herein will survey the literature in the area of catalytic asymmetric IEDDA reaction, with a focus on recent achievements using chiral Lewis acid metal complexes.

Almost at the same time, Posner and co-workers39 successfully extended the use of chiral Lewis acid titanium(IV) involving the (R)-(+)-Binol-TiCl2(iPrO)2 complex, prepared from titanium dichloride diisopropoxide (TiCl2(iPrO)2) and commercial (R)-(+)-1,1′-bi-2-naphthol ((R)-(+)-Binol) 10, to the asymmetric IEDDA reaction. After considerable experimentation, the reaction of 3-carbomethoxy-2-pyrone (3-CMP) 8 and vinyl ether 5 afforded the desired cycloadduct 9 with 90% yield in 98% ee and >99% de. This product was then converted into the A-ring phosphine oxide (−)-11 (eq 6), which is a useful building block for the synthesis of a range of biologically active compounds such as 1α-hydroxyvitamin D3 steroids.40 A drawback of the protocol is, however, the use of 1.3 equiv of stoichiometric (R)-(+)-Binol-TiCl2(iPrO)2 complex.

2.1. Catalytic Asymmetric IEDDA Reaction Using Chiral Titanium(IV) Complexes

Early asymmetric IEDDA reactions relied heavily on the use of chiral organometallic complexes as Lewis acid catalysts. The first asymmetric IEDDA reaction of a heterodiene was reported by Tietze and co-workers,37,30 who demonstrated that the intramolecular cycloaddition of heterodiene 1 could effectively be catalyzed by a diacetoneglucose-derived titanium(IV) complex 3. This reaction provided the cis-products 2 with enantioselectivity of up to 88% ee and moderate to high yields (eq 4). The selectivity of the reaction was influenced by the solvent as evidenced by the fact that the enantioselectivity in toluene or 1,2,3,5-tetramethylbenzene (88% ee) was better than that in CH2Cl2 (52% ee), THF (25% ee), and CHCl3 (0% ee). The catalytic enantioselective intramolecular IEDDA reaction also showed an interesting temperature effect. Product 2 was formed in 88% ee at 20 °C, while a racemic mixture was formed at 0 or 100 °C.

Manickam and Sundararajan showed that the chiral 15− TiCl2 complex41 prepared from (R,R)-2,2′-(benzylazanediyl)bis(1-phenylethanol) 15 and TiCl4 could serve as a Lewis acid catalyst for promoting asymmetric IEDDA reaction between electron-rich dienophiles and the electron-poor diene benzylidene aniline 13.42 The reactions of different dienophiles 12 such as dihydropyrans, cyclopentadiene, and ethylvinyl ether were carried out using dichloromethane/toluene (2:1) solvent, 10 mol % of molecular sieves, and 20 mol % of catalyst (Scheme 2). Although only 51% ee was achieved for cyclopentadiene, tetrahydroquinoline derivatives 14 were formed in enantioselectivities of up to 92% ee in the cases of other dienophiles. However, the method suffers from low conversions (50−65%) and moderate diastereoselectivities (up to 4:1 dr). The authors proposed the mechanism of formation of tetrahydroquinolines, in which the nitrogen of the 2-azadiene group is coordinated to the 15−TiCl2 complex to promote the reaction.

Chiral α,α,α′,α′-tetraphenyl-2,2-dimethyl-1,3-dioxolan-4,5-dimethanol (TADDOL)-TiX2 (X = Cl, Br) complexes 7 were applied by Wade et al.38 to the IEDDA reaction of (E)-2-oxo-1phenylsulfonyl-3-alkenes 4 with vinyl ethers 5 (eq 5). The reaction proceeded well for enones 4 having both alkyl and aryl substituents, which reacted with various substituted vinyl ethers to afford the corresponding dihydropyrans 6 with up to 90% yield, 97% ee, and >98:2 dr in the presence of a catalytic amount of the chiral TADDOL-TiBr2 complex 7b. The results indicated that the stereoselectivity of the reaction was dependent on the bulkiness of the substituent of the vinyl ethers, with tert-butyl vinyl ether giving the best enantioselectivity.

2.2. Catalytic Asymmetric IEDDA Reaction Using Chiral Lanthanide Lewis Acid Complexes

Although lanthanide metal-catalyzed IEDDA reaction has shown many advantages and a range of catalytic reactions have been well documented to date,43 the development of asymmetric catalytic protocols in this field of research remains a highly desirable goal. The groundbreaking work of Kobayashi C


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Scheme 2. Asymmetric IEDDA Reaction of Various Dienophiles Catalyzed by 15−TiCl2 Complex

yield and diastereoselectivity of >95% de. It must be noted that this cycloaddition employed catalytic amounts of the lanthanide complex in contrast to an example reported by Posner that required more than stoichiometric quantities of the organometallic reagent.47 From kinetic and spectroscopic studies, the authors proposed a rationale that accounts for the stereochemical outcome of the reaction. It may proceed through chelate B, in which the sevenmembered ring renders the complex rigid and the pseudoaxial methyl substituent of the pantolactone auxiliary shields the 3Si, 6Si face of the diene. Selective attack of the dienophile at the other face leads to the formation of the observed major diastereoisomer 18 (Figure 2).

and co-workers opened the practical applications of chiral ytterbium(III) triflate complex-catalyzed Diels−Alder reaction between cyclopentadiene and acryloyl-1,3-oxazolidin-2-one derivatives with good enantioselectivity.44 On the basis of Kobayashi’s findings, Markó and Evans45 developed the first catalytic enantioselective IEDDA of 3-carbomethoxy-2-pyrone 8 with vinyl ethers and vinyl sulfides 12 using the chiral (R)(+)-Binol-ytterbium(III) triflate complex as the Lewis acid catalyst. As illustrated in Scheme 3, the reaction provided Scheme 3. Catalytic Asymmetric IEDDA Reaction of 3Carbomethoxy-2-Pyrone with Vinyl Ethers and Vinyl Sulfides Using Chiral (R)-(+)-Binol-Ytterbium(III) Triflate Complex

Figure 2. Proposed mechanism for europium(III) complex-catalyzed IEDDA reaction.

In 1996, the catalytic asymmetric IEDDA reaction of imine 19a48 with cyclopentadiene 12c and vinyl ethers was reported by Ishitani and Kobayashi using chiral (R)-(+)-Binol-ytterbium(III) complex 22 (eq 8), which was prepared from Yb(OTf)3, (R)-(+)-Binol, and diazabicyclo[5.4.0]undec-7-ene (DBU).49 The reaction of N-benzylidene-2-hydroxyaniline 19a with cyclopentadiene was performed under 20 mol % of a chiral ytterbium Lewis acid (R)-21, which was prepared from Yb(OTf) 3 , (R)-(+)-Binol, and 1,3,5-trimethylpiperidine (TMP).50 The reaction proceeded smoothly to afford the desired tetrahydroquinoline derivative 20a in high yield, but in low enantioselectivity of 6% ee. Surprisingly, the enantioselectivity could be increased to 62% ee when using chiral ytterbium Lewis acid 22. It was argued that the phenolic hydrogen of imine would interact with DBU to form a hydrogen bond with the hydroxyl groups of (R)-(+)-Binol ligand, causing the decrease of the enantioselectivity. To achieve the better results, other additives were also examined. It was noted that the tetrahydroquinoline 20a was obtained in 92% yield with good enantioselectivity (71% ee) when using 2,6-di-t-butylpyridine (DTBP) as an additive. The authors

corresponding cycloadducts 16 in excellent yields. Surprisingly, the enantioselectivity of this reaction was directly dependent upon the size of the alkyl substituent on the oxygen atom of the vinyl ether substrates. Thus, increasing the size of the alkyl substituent from ethyl to a bulkier tertiary substituent resulted in a gradual increase of the enantioselectivity from 27% to 71% ee. The cyclohexyl (Cy)- and adamantyl (Ad)-substituted vinyl ethers provided the corresponding bicyclic lactones in enantioselectivities of 82% and 85% ee, respectively. The substrate scope was then extended to vinyl sulfides, which also provided high enantioselectivities of 86% ee for the reaction of the cyclohexyl thiovinyl ether and >95% ee for that of the adamantyl thiovinyl ether. Later, Markó et al. also explored the stereochemical course of the intermolecular cycloaddition of pantolactone-derived 2pyrone 17 (eq 7).46 In this case, the stereochemistry of the cycloaddition was controlled by the europium(III) ligand. Reactions employing lanthanide complexes such as (+)-Eu(hfc)3, (−)-Eu(hfc)3, or Eu(fod)3 led to product 18 in high D


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the results, a series of N,N′-dioxide ligands that contained different sterically hindered amide substituents were tested. The L-ramipril-acid-derived N,N′-dioxide 24 exhibited superior enantioselectivity (98% ee), but only with a moderate diastereoselectivity compared with other ligands. However, when the molar ratio of ligand to central metal was changed to 2:1, a high diastereoselectivity was observed. Of particular mention is that this asymmetric process was also tolerant to air and moisture.

suggested that DTBP could competitively interact with the phenolic hydrogen of imine, thus avoiding the adverse interaction between 19a and (R)-(+)-Binol complex.

The authors proposed a transition state model for the observed stereochemistry of the reaction (Figure 3). The imine

Using the optimized conditions, regardless of the electronic properties or steric hindrance of the substituents on the aromatic ring of aldehydes 26, promoted by 5 mol % of N,N′dioxide 24/Sc(OTf)3 complex (eq 9), the reaction between substrates 12c, 25, and 26 afforded ring-fused tetrahydroquinoline derivatives 20 in moderate to high yields, excellent diastereoselectivities (up to >99:1 dr), and enantioselectivities (90−>99% ee). Importantly, this asymmetric reaction could afford the ring-fused tetrahydroquinolines with three contiguous stereocenters in a one-pot manner under mild conditions. As an effective Lewis acid metal complexes catalyst, the N,N′dioxide 24/Sc(OTf)3 complex has also been successfully applied to synthesize enantiopure tetrahydroquinoline derivatives by the catalytic asymmetric IEDDA reactions. Feng et al.51a reported a highly enantioselective IEDDA reaction of αalkyl alkenes 27 and N-aryl aldimines 19 using 10 mol % of N,N′-dioxide 24/Sc(OTf)3 complex in CH2Cl2 at 30 °C (eq 10). A wide variety of α-alkyl styrenes and N-aryl aldimines were tolerated in the reaction, to give the corresponding tetrahydroquinoline derivatives 28 bearing a quaternary stereocenter at the C4 position in excellent diastereo- (up to 99:1 dr) and enantioselectivities (92% to >99% ee). In addition, the reaction could be performed on the gram scale without any loss of yield, diastereo-, and enantioselectivities.

Figure 3. Transition state mode.

coordinated in a bidentate fashion to ytterbium, and the axial chirality of (R)-(+)-Binol could be transferred through hydrogen bonds to amine parts. The additive interacted with the phenolic hydrogen atom of the imine, which is fixed by the bidentate coordination to the metal. Because the top face of the imine was shielded by the amine, the dienophile approached from the bottom face. More recently, Feng and co-workers developed a series of chiral ligands based on N,N′-dioxides scaffolds51 (Figure 4) and

Figure 4. Chiral N,N′-dioxides ligands.

successfully applied these ligands to an asymmetric threecomponent IEDDA reaction with cyclopentadiene as the dienophile.52 Initially, various lanthanide metals with N,N′dioxide 23a were examined through the three-component model reaction between benzaldehyde, 2-aminophenol 25a, and cyclopentadiene. The use of La(OTf)3, Y(OTf)3, and Yb(OTf)3 led to the corresponding racemic ring-fused tetrahydroquinoline in trace yield. Only Sc(OTf)3 afforded the desired product 20 with improved results. Encouraged by

On the basis of the above results, Feng et al. further extended the scope of the chiral N,N′-dioxide-metal complexes-catalyzed IEDDA reaction. The reactions of β,γ-unsaturated α-ketoesters and a broad range of electron-rich alkenes were investigated using chiral N,N′-dioxide ligands with a variety of lanthanide E


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(III) metal salts such as La(OTf)3,53 Eu(OTf)3, Er(OTf)3, Ho(OTf)3,54 Y(OTf)3, Tb(OTf)3,55 Lu(OTf)3,56 and Sc(OTf)3.57 The chiral N,N′-dioxide 23b/Er(OTf)3 complex was proved to be the most promising Lewis acid catalyst in terms of chemical yield and enantioselectivity for this catalytic asymmetric process. The results showed that when various β,γunsaturated α-ketoesters 29 were reacted with 2,3-dihydrofurans 12a and 12b using a low catalyst loading of N,N′-dioxide 23b/Er(OTf)3 complex (0.5 mol %), the corresponding 3,4dihydro-2H-pyrans 30 were formed in moderate to high yields, with excellent enantioselectivities (up to >99% ee) and diastereoselectivities (up to >99:1 dr, eq 11). As part of an expansion of the reaction, the catalytic cycloaddition with other electron-rich alkenes was carried out. Cyclopentadiene 12c was found to be an efficient dienophile in this reaction (61% yields, 99% ee, and 99:1 dr, eq 12). It is notable that the more sterically hindered alkene 32, which afforded product 33a with a quaternary carbon center, gave excellent results (>99% yield, 99% ee, and >98% de, eq 13). Vinyl sulfides 34 also functioned efficiently as dienophiles to give products 33b in up to 99% yield and 97% ee, with an excellent diastereoselectivity (eq 14). The low catalyst loading and inexpensive starting materials and catalyst for this reaction offered a practical way to scale up production. The potential biological activities exhibited by the 3,4dihydro-2H-pyrans and the derived ring-fused tetrahydropyrans58 suggested that the structural elaboration of this core is extremely important. As illustrated in eq 15, the ring-fused bicyclic product 30 could be converted smoothly into tetrahydropyran 35 as a single isomer in 81% yield without any loss of enantioselectivity by hydrogenation in the presence of Pd/C. This compound might lead to the formation of 36 through a series of steps,59 which was a suitable intermediate target for blepharocalyxin D.60 This representative example demonstrated the inherent synthetic potential of this type of 3,4-dihydro-2H-pyrans. In addition, the combination of a bisoxazoline ligand and Sc(OTf)3 also proved to be efficient for catalytic IEDDA reaction of cyclopentadiene and β,γ-unsaturated α-ketoesters 29 (eq 16). Desimoni and co-workers61 reported the reaction between cyclopentadiene 12c and methyl (E)-2-oxo-4-aryl-3butenoates 29 using the 10 mol % of (S,S)-bisoxazoline 38/ Sc(OTf)3 complex in CH2Cl2, which provided the corresponding DA adducts 37 along with IEDDA adducts 31 in excellent enantioselectivities of 99% ee, albeit moderate diastereoselectivities of ≤34% de. Under a comparative experiment between the thermal and the scandium(III) triflate-catalyzed conditions, the authors found that the reaction prefers to furnish the desired 31 as major products when using the Sc(OTf)3catalyzed condition. 2.3. Catalytic Asymmetric IEDDA Reaction Using Chiral Copper(II) Complexes

As described in the previous section, the inverse-electrondemand hetero-Diels−Alder (IED hetero-DA) reaction of α,βunsaturated carbonyl compounds with electron-rich alkenes gives easy access to substituted 3,4-dihydro-2H-pyrans that are very useful precursors for the synthesis of carbohydrates and natural products. The reaction is mainly controlled by the LUMO of α,β-unsaturated carbonyl compound through using a chiral Lewis acid metal-complex catalyst.62 Undoubtedly, CuIIcatalyzed reaction is one of the most important achievements among these reactions. Considerable progress has been

achieved in this field as a result of contributions from the groups of Evans,63 Jørgensen,64 Wada,65 Pedro,66 and Feng.67 These elegant works were featured by operational simplifications including lower catalyst loadings, facilitate short reaction times, and a catalyst recycling procedure.9a Moreover, their works led to a large step forward in the catalytic enantioselective IEDDA reaction of α,β-unsaturated carbonyl compound. F


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Evans and Johnson68 discovered that α,β-unsaturated acyl phosphonates 39 underwent enantioselective IED hetero-DA reactions with a variety of vinyl ethers and cyclopentadiene in the presence of chiral C2-symmetric bisoxazoline (BOX)69-CuII complexes. This BOX-CuII catalyst exhibits a high efficiency over a wide range of substrates, and the starting material is also easily available. The initial studies focused on effect of chiral [Cu(S,S)-BOX)](X)2 complexes 41 in catalytic asymmetric IEDDA reaction of α,β-unsaturated acyl phosphonate (Table 1). The stereochemistry for [Cu(S,S)-BOX)](X)2 complexes

Scheme 4. Catalytic Asymmetric IEDDA Reaction of Acyl Phosphonates Using Chiral [Cu((S,S)-BOX)](X)2 Complexes

Table 1. Effect of Chiral [Cu((S,S)-BOX)](X)2 Complexes in Catalyzed Asymmetric IEDDA Reaction

entry

R

X

dr (endo/exo)

ee (%)

1 2 3 4 5 6

t-Bu (41a) t-Bu (41b) i-Pr (41c) Bn (41d) Ph (41e) Ph (41f)

OTf SbF6 SbF6 SbF6 SbF6 OTf

99:1 69:1 32:1 60:1 >99:1 >99:1

99 93 39 58 93 94

41 varied with the pendant oxazoline substituent R and counterion X. The authors found that a substantial change of the substituent R and counterion has a significant effect on stereoselectivity. The subtle electronic effects generated from coordination between the counterions OTf or SbF6 and copper(II) center could play an important role in Lewis acidic regulation of chiral copper(II) complexes. High enantioselectivity, diastereoselectivity, and yield were observed for the product 40a from substrates 39a and 12d by using Cu(S,S)-tBu-BOX (41a and 41b, entries 1 and 2, Table 1) and Cu(S,S)-Ph-BOX complexes (41e and 41f, entries 5 and 6, Table 1 as catalysts), while [Cu(S,S)-tBu-BOX](SbF6)2 41b resulted in a slight diminution in diastereoselectivity. When the oxazoline substituent R was changed from tert-butyl to isopropyl or benzyl, lower stereoselectivities were observed (entries 3 and 4, Table 1). Subsequently, a variety of vinyl ethers including vinyl sulfides were investigated using 10 mol % of BOX-Cu(II) complexes as catalysts, as shown in Scheme 4.63 Their reactions with 39 proceeded not only with aliphatic chain vinyl ethers but also with cyclic vinyl ethers to give the adducts 40 in high yields, diastereo-, and enantioselectivities. As expected by the authors, cyclopentadiene was also a suitable substrate for this asymmetric process. The reaction still provided 95% ee, although a moderate yield was obtained. Evans’ group extended the scope of electron-rich alkenes to silyl enol ethers in the asymmetric IEDDA reaction of α,βunsaturated acyl phosphonates by using the chiral BOX-Cu(II) complex 41b as a catalyst. The cycloaddition of crotonyl phosphonate 39a with silyl enol ethers of acetophenone 42 (R1 = TMS or TBS) assessed the viability of reaction by employing chiral [Cu(S,S)-tBu-BOX](SbF6)2 41b (eq 17). The major reaction pathway was the formal cycloaddition to form both cis-

and trans- dihydropyrans endo-43 and exo-43, while the minor pathway resulted in the formation of Michael adduct 44. The formal cycloaddition pathway became dominant by changing the oxygen protecting group from TMS to the bulkier silyl group TBS. The endo-isomer 43 was formed preferentially, with virtually complete enantioselectivity observed (99% ee).

Following the initial works, Evans also showed that a novel aquo BOX-CuII complex 47 bearing a C2-symmetric bisoxazoline ligand63,70 was a highly effective catalyst for the enantioselective IED hetero-DA reaction of α,β-unsaturated carbonyl compounds 45 with electron-rich alkenes 12, which provided cycloadducts 46 (eq 18). The results demonstrated that the excellent enantioselectivities and yields could be achieved (up to 98% yield and 99% ee) when [Cu(S,S)-tBuBOX](H2O)2(OTf)](OTf) 47a was used as catalyst in the presence of 3 Å molecular sieves in THF. G


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ethers 12 afforded the corresponding products 51 in good yields and high diastereo- and enantioselectivities, with full control of the stereocenter at the amino carbon atom (eq 20). These carbohydrate precursors containing nitrogen atoms are interesting compounds in relation to the synthesis of carbohydrates as inhibitors of glucosidases for the treatment of diabetes and drugs against influenza.73

Almost at the same time, the same catalytic system was applied by Jørgensen et al.71 to enantioselective IED hetero-DA reactions of α,β-unsaturated acyl esters with different electronrich alkenes. The reaction of α,β-unsaturated acyl ester 45a with vinyl ether 12d in CH2Cl2 at −78 °C was catalyzed by a series of BOX-Cu(OTf)2 complexes (eq 19). In their investigations, the bidentate BOX-CuII-complexes were found to be more effective than tridentate CuII-complexes. The use of preformed [Cu(S,S)-tBu-BOX](OTf)2 complex 41a allowed product 46a to be achieved in enantioselectivity of >97% ee and 100% conversion rate. Although the reaction gave high levels of conversion rate in the presence of chiral BOX-Cu(II) complexes 41f or 41g, it led to lower enantioselectivities (64% ee and 72% ee, respectively). Other chiral tridentate BOXCu(II) complexes such as 48 and 49 provided poor results as compared to bidentate CuII-complexes. The low effectiveness of tridentate BOX-Cu(II) complexes may be affected by several factors such as steric hindrance, low flexibility of copper(II) center, five-coordination in complexes leading to CuIIpassivation, and stability under kinetic control. These adverse properties of tridentate BOX-Cu(II) complexes caused a decrease of the ability of LUMO-activating α,β-unsaturated acyl ester.

The high efficiency of this reaction was applied to the stereoselective synthesis of β-D-mannopyranosides,74 which has been a long-standing problem in carbohydrate chemistry, attracting the attention of numerous groups.75 For example, Jørgensen et al. developed the synthesis of ethyl β-D-mannoside tetraacetate 55 from optically active dihydropyran 52, which was obtained through an asymmetric IEDDA reactions (eq 21).75a It is an alternative to the use of carbohydrates for the synthesis of these types of compounds.

The scope of BOX-CuII-catalyzed asymmetric IED heteroDA reactions using electron-rich alkenes as dienophiles has been extended even further to unsaturated alcohols. Wada and co-workers65 reported a novel asymmetric tandem transetherification-intramolecular hetero Diels−Alder reaction of methyl (E)-4-methoxy-2-oxo-3-butenoate 56 with δ,ε-unsaturated alcohols 57 by using BOX-Cu(II) complexes (eq 22). The chiral [Cu(S,S)-tBu-BOX](SbF6)2 41b in the presence of 5 Å molecular sieves was highly effective to afford corresponding trans-fused hydropyranopyran derivatives 58 in good yield (up to 90%) with high enantiomeric excess (up to 98% ee). The sense of asymmetric induction can be rationalized by assuming that the vicinal carbonyl functionalities of transetherified products coordinate to the copper(II) center in bidentate fashion leading to a square-planar intermediate, in which the reface of the reacting enone is available for an intramolecular approach of the si-face of alkene with an exo-E-anti conformation. The concept of this facial tandem reaction is outlined in Scheme 5.76 The process involves first the conjugate

The asymmetric IEDDA reaction of α,β-unsaturated acyl esters with electron-rich alkenes catalyzed by chiral tBu-BOXCu(II) complex 41a has also been used for the synthesis of optically active amino carbohydrates.72 The reaction of γamino-protected β,γ-unsaturated α-keto ester 50 and vinyl H


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recycled by simple extraction of the ionic liquid with a relatively nonpolar organic solvent after reaction. Using [Bmim]PF6 as reaction media, the BOX-Cu(II) complex 62 was recovered and recyled up to eight times, still exhibiting high activity with almost the same stereoselectivity (96:4 dr and 94% ee) in the reaction of β,γ-unsaturated α-ketoester 29b with ethyl vinyl ether 12d. Moreover, the stability of copper complex in ionic liquid was also verified; thus these results could be extended to a practical application.

Scheme 5. Catalytic Asymmetric Tandem Transetherification−Intramolecular IEDDA Reaction

addition of unsaturated alcohols to β-alkoxy-substituted α,βunsaturated esters and then a reversible elimination of alcohols, followed by the catalytic enantioselective hetero-Diels−Alder reaction, leading to the fused hydropyranopyran derivatives. Pedro et al. described a highly enantio- and diastereoselective IED hetero-DA reaction using 2-alkenoylpyridine N-oxides as oxo-heterodienes (eq 23).66 2-Alkenoylpyridine N-oxides 59 reacted very efficiently with alkene 12d in the presence of [Cu(S,S)-Ph-BOX](OTf)2 complex 41f to give chiral dihydropyrans 60 bearing a pyridine ring at the 6-position with high yields (up to 90%) and excellent diastereo- and enantioselectivities (up to 96% ee and >99:1 dr). These oxo-heterodienes exhibited higher reactivity and enantioselectivity than the corresponding nonoxidized 2-alkenoylpyridines according to the detailed studies of the authors. As compared to 2alkenoylpyridines, the N-oxide group of oxo-heterodienes could provide a second “docking point” for bidentate coordination to the chiral copper(II) Lewis acid, thus conferring reasonable levels of enantioselection through the intervention of the illustrated catalyst−substrate complex in the cycloaddition event.

Mechanistic studies on the IED hetero-DA reactions of α,βunsaturated carbonyl compounds with vinyl ethers using BOXCu(II) complexes have also been investigated by Evans’ group (Figure 5).32,63 The diastereoselective preference for the cis-2,4-

Figure 5. Transition structures using chiral (S,S)-Cu(II)-BOX complexes.

disubstituted dihydropyrans products is in agreement with an endotransition state. This is consistent with a secondary orbital interaction between the LUMO at the carbonyl atom of the α,β-unsaturated acyl system (A, Figure 5). On the basis of their obtained experimental results, the authors proposed two possible transition structures that differ in metal center geometry (B and C, Figure 5). The substrate in these reactions coordinates in a bidentate fashion to the copper(II) center. The bidentate coordination has two purposes: (i) to activate the carbonyl functionalities for reaction, and (ii) for the chiral ligand to discriminate one of the faces of the carbonyl functionality. A change in geometry at copper from square planar to tetrahedral was expected to expose an opposite sense of asymmetric induction for reaction, by virtue of the altered spatial relationship between the pendant oxazoline substituent (R2) and the heterodienophile π-system.78 In the chiral (S,S)Cu(II)-tBu-BOX complex, the Cu(II) center was characterized by a distorted square-planar geometry (C, Figure 5). There is

In addition, as compared to the wasteful and tedious isolation processes for homogeneous catalysis, the immobilization of catalysts presents an attractive alternative due to its readily recoverable and recyclable properties. Hydrophobic ionic liquids such as [Bmim]PF6 and [Bmim]SbF6 were used successfully as powerful media for [Cu(S,S)-iPr-BOX](OTf)2 complex-catalyzed asymmetric IED hetero-DA reaction by Kim and co-workers (eq 24).77 The immobilized catalyst could be I


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evidence supporting this distorted square-planar Cu(II)-tBuBOX-substrate complex, in which the angle of the plane of the coordinated α,β-unsaturated carbonyl compounds and the plane of Cu(II)-tBu-BOX ligand is about 45°. The authors also suggested that the use of the (S,S)-Cu(II)-tBu-BOX complex will thus lead to a new complex in which the tert-butyl substituent could shield the α-Si-face of the coordinated α,βunsaturated acyl system. Pedro and co-workers also reported a new series of hydroxy oxazoline ligands derived from (+)-(S)-ketopinic acid,79 which could combine Cu(II) trifluoromethanesulfonate to successfully catalyze the asymmetric IED hetero-DA cycloaddition of β,γunsaturated α-keto esters 29 and enol ether 12d (eq 25). A survey of screening of hydroxy oxazoline ligands 63a−d indicated that catalyst 63d was found to be the most effective ligand for this enantioselective Diels−Alder cycloaddition in terms of chemical yield and stereoselectivity. The combination of hydroxy oxazoline ligand 63d and Cu(OTf)2 in ethyl acetate at 0 °C efficiently allowed the corresponding enantiomerically enriched 2,4-trans-disubstituted 2,3-dihydropyrans 61 to be achieved with enantioselectivity of up to 88% ee and 84%→ 98% yield. Notably, the observed stereochemistry of the products of this enantioselective Diels−Alder cycloaddition indicated that the reaction pathway proceeded via an exostereoselective manner.

2.4. Catalytic Asymmetric IEDDA Reaction Using Chiral Nickel(II) and Chromium(III) Complexes

2.4.1. Using Chiral NiII-Complexes. The enantioselective IEDDA reaction of enol ethers has also been achieved by using chiral NiII-complexes. Carretero et al.80 reported a highly enantioselective catalytic IED hetero-DA reaction of Nsulfonyl-1-aza-1,3-dienes 64 and enol ethers 5 using a DBFOX-Ph/Ni(ClO4)2·6H2O complex as catalyst, providing highly functionalized piperidine derivatives 65 in good yields with excellent endo-selectivity and enantioselectivity (up to 92% ee, eq 27). These authors also demonstrated that the use of different N-(heteroaryl)sulfonyl groups could dramatically affect the reactivity of N-sulfonyl imines, allowing the reaction to give better reactivity and stereoselectivity. The key success of this reaction relied on the use of the Kanemasa’s chiral ligand DBFOX-Ph 6681 and the choice of the N-(8-quinolinesulfonyl) group at the iminic nitrogen.

Recently, Feng’ group67 developed a highly enantioselective IED hetero-DA reactions of β,γ-unsaturated α-keto esters with cyclopentadiene catalyzed by chiral N,N′-dioxide-Cu(OTf)2 complexes. The authors suggested that temperature may play an important role in the chemoselective control of the reaction, providing a degree of chemoselectivity. They described a catalytic method that achieved good to high chemoselectivity for the DA adducts and moderate chemoselectivity for the IEDDA adducts by regulating temperature. As outlined in eq 26, chiral N,N′-dioxide 23b/Cu(OTf)2 complex promoted the reaction, providing the DA adducts 37 along with IEDDA adducts 31 through an chemoselective manner. Using 1.5 mol % of N,N′-dioxide 23b/Cu(OTf)2 complex in CH2Cl2 at −20 °C, the reaction provided the desired major IEDDA products 31. Excellent enantioselectivities (up to >99% ee) were observed for a broad range of substrates. Both aromatic and aliphatic β,γ-unsaturated α-keto esters were found to be suitable substrates for the reaction, although the chemoselectivity was less satisfactory.

Density functional theory (DFT) calculations showed that the proS oxygen might coordinate to Ni and E-configuration at the imine, which could account for the main product of the reaction by the endo approach of the enol ether to the re face of the N-sulfonyl-1-aza-1,3-diene in the complex B as outlined in Figure 6.35 The equivalent proR-oxygen-coordinated complex that would afford the other less stable enantiomer. The authors also suggested that the H2O in the starting nickel salt Ni(ClO4)2·6H2O might have a key role in the reaction outcome. 2.4.2. Using Chiral CrIII-Complexes. As described above, although numerous catalytic enantioselective IED hetero-DA reactions using chiral ligands/CuII or NiII-complexes have been identified, the scope of reported methods is limited to oxabutadiene derivatives bearing electron-withdrawing groups such as phosphonate groups, ester groups, or sulfone groups. These ancillary groups could serve both to activate the oxadiene J


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Scheme 6. CrIII-Complexes-Catalyzed IEDDA Reactions in Enantioselective Synthesis of Iridoid Natural Productsa Figure 6. Stereochemical model for reaction using DBFOX-Ph/ Ni(ClO4)2·6H2O complex.

electronically and to anchor the substrates to the metal catalyst by two-point binding (A, Figure 7). Chelation in this manner

Figure 7. Mode for binding of dienes to a Lewis acid (M = Lewis acid).

appears to be essential for attaining efficient reactivity and stereoselectivity. Jacobsen and co-workers showed that a chiral tridentate Schiff base-CrIII complex82 could be identified as a highly diastereoselective and enantioselective catalyst in IED hetero-DA reactions between α,β-unsaturated aldehydes and vinyl ether.83 The crucial feature of this chiral Schiff base-CrIII catalytic system lies in its ability to effect activation enantiofacial discrimination of the carbonyl solely through one-point binding to the metal catalyst (B, Figure 7), while simultaneously avoiding unproductive decomposition of the sensitive oxadiene and electron-rich dienophile partners. Using chiral Schiff base-CrIII complex 69 (5−10 mol %) combined with a certain amount of 4 Å molecular sieves, the scope of the reaction was extended to a wide range of α,βunsaturated aldehydes bearing aliphatic and aromatic βsubstituents 67, which reacted with ethyl vinyl ether 12d to give the corresponding cycloadducts 68 in high diastereo- and enantioselectivities (up to 98% ee and >97:3 dr, eq 28). Although this catalytic asymmetric method needs a long reaction time, it still has some advantages such as mild reaction conditions, good functional group compatibility, and experimental simplicity. All of these advantages make it a useful protocol in enantioselective total synthesis of a range of natural products. Later, Chavez and Jacobsen84 extended the scope of the chiral Schiff base-CrIII complex catalyzed IEDDA reaction, thus providing direct stereoselective access to the fused cyclopenta[c]pyran bicyclic ring system characteristic of iridoids, an important class of naturally occurring compounds.85 As outlined in Scheme 6, the reaction of 5-methyl-1-cyclopentene-1-carboxaldehyde 70 and ethyl vinyl ether 12c was catalyzed by chiral Schiff base-CrIII complex 69 (5 mol %) at

a

(a) H2, PtO2, EtOAc, 12 h, quant; (b) (i) cat, p-toluenesulfonic acid, acetone/H2O (1:1), (ii) PCC, CH2Cl2, 16 h, 80% over three steps.

room temperature to afford a 1.2:1 mixture of diastereomers (71a:71b) with the complete conversion of aldehyde. The results revealed that the major diastereomer 71a was generated in 80% ee with >99:1 dr, while the minor diastereomer 71b was afforded in 98% ee with 8:1 dr. Each diastereomer was subsequently hydrolyzed and the resulting lactols oxidized into (−)-boschnialactone and (+)-7-epi-boschnialactone, which were further converted through standard chemical manipulations into other targets such as teucriumlactone, iridomyrmecin, and isoiridomyrmecin. Thiomarinol A86a and derivative 7686b are marine natural products isolated from the bacterium Alteromonas rava sp. nov. SANK 73390 in 1992. These natural compounds were found to be much more potent than their parent compound pseudomonic acid A87 and possess a wider spectrum of activities. Gao and Hall88 achieved the first total synthesis of a member of the thiomarinol class of marine antibiotics, and thiomarinol A derivative 76, which was reached in a remarkable global yield of 22% (Scheme 7). The highlight of this stereoselective synthesis is the efficient catalytic enantio-, regio-, E/Z-, and diastereoselective three-component IEDDA/ allylboration reaction sequence using the chiral Schiff base-CrIII complex 69 (3 mol %), in which the desired pyran 75 was obtained in 76% yield as a single diastereomer in 95% ee and K


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Scheme 7. CrIII-Complexes-Catalyzed IEDDA Reactions in Enantioselective Synthesis of Thiomarinol A Derivative

2.5. Main Group Metal Complexes-Catalyzed Asymmetric IEDDA Reaction

2.5.1. Using Chiral AlIII-Complexes. As compared to transition metals, the application of main group metal in the field of asymmetric catalysis represents a challenge, and the main group metal-complexes-catalyzed enantioselective IEDDA reactions are scarce to date. Indeed, there are still several lessthan-ideal aspects, for example, low enantioselectivity, low chemical yields, and narrow substrate scope. It means that there is an opportunity to develop other even more efficient main group metal-chiral ligands catalytic system with a view to achieve better stereocontrol and chemical yield. Nevertheless, there are still some impressive works achieved by several groups in the aluminum- and indium-catalyzed asymmetric IEDDA reaction. Davies and Dai34 discovered a novel formal IED hetero-DA reaction occurring between 2-aryl-α,β-unsaturated aldehyde and cyclopentadiene (eq 29), in which the dihydropyran derivative is derived from a Diels−Alder reaction, and followed by a retro-Claisen rearrangement.92 The reaction of 80 with cyclopentadiene catalyzed by a (R)-Binol-modified aluminum(III) Lewis acid complex 83 (10 mol %) at −40 °C in CH2Cl2, afforded the corresponding dihydropyran 81 as a major product along with normal [4 + 2] adduct 82 both in 44% ee. Surprisingly, when toluene was used as solvent, the IEDDA product 81 (25% ee) and DA product 82 (56% ee) were obtained with different enantiomeric excess. The authors suggested that the major pathway for the transformation is a Lewis acid-catalyzed tandem Diels−Alder reaction/retroClaisen rearrangement by the detailed mechanism studies.

98:2 dr (Scheme 7). This key operation provides a rare example of an enantioselective IEDDA reaction involving acyclic 2substituted enol ethers. Similar catalytic stereoselective three-component IEDDA/ allylboration reaction sequence using the chiral Schiff base-CrIII complex 69 as catalyst has also been successfully applied to the total synthesis of natural compounds from styryllactone family by Carreaux group.89 The styryllactones isolated from the plant family Goniothalamus have shown potent antitumor, antiedema, and antirheumatism biological activities.90 Carreaux et al. reported the stereoselective total synthesis of several members of the styryllactone family such as (+)-goniodiol,91b (+)-goniotriol,91a and (−)-goniofupyrone.91b As shown in Scheme 8, the Scheme 8. Total Synthesis of (+)-Goniodiol, (+)-Goniotriol, and (−)-Goniofupyrone Using Catalytic Asymmetric IEDDA Reactions

The aluminum(III)-catalyzed enantioselective IEDDA reaction of tropone derivatives 84 with the ketene diethyl acetal 85 was established by Li and Yamamoto by utilizing an airstable dinucleus Binol-AlIII complex 87, prepared from the tris(mxylyl)silyl substituted Binol ligand and diisobutylaluminum hydride at room temperature in dichloromethane.93 This afforded synthetically useful chiral functionalized bicyclo[3.2.2] ring structures 86 with good to excellent ee values (eq 30). Although only modest enantioselectivity (46% ee) was obtained for tropone itself, the protocol generally showed good tolerance toward a variety of substituted tropone derivatives to give excellent results (up to 97% ee). Surprisingly, halogenated tropones were also suitable substrates for this reaction, giving the corresponding cycloadducts with good enantioselectivities. In addition, one noteworthy application of this asymmetric method is that this reaction could be applicable for asymmetric synthesis of highly substituted chiral sevenmembered rings. 2.5.2. Using Chiral InIII-Complexes. Very recently, Luo’s group developed the first peri-, regio-, and enantioselective IED

CrIII-complex 69 (1 mol %) catalyzed the three-component IEDDA/allylboration reaction sequence of substrates 12d, 77, and 78 to give dihydropyran 79 as a unique stereoisomer with 65% yield, 96% ee, and >95% de. The transformation of 79 into α,β-unsaturated lactone led to the preparation of (+)-goniodiol in a reduced number of steps. The epoxidation reaction was used to generate the remaining stereogenic centers on the lactone moiety of (+)-goniodiol, and these intermediates were then converted into (+)-goniotriol and (−)-goniofupyrone by an isomerization or cyclization step. L


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3. CHIRAL N-HETEROCYCLIC CARBENES OR BRøNSTED ACIDS-ORGANOCATALYZED ASYMMETRIC IEDDA REACTION BASED ON LUMO-LOWERING STRATEGY Since about 2000, the research area of asymmetric organocatalysis has grown rapidly and become one of the most dynamic fields in organic chemistry. Usually, small chiral organic molecules act as catalytically active species to promote reactions through different activation modes.95 Organocatalysis offers alternatives to the activation of substrates, and can deliver unique, orthogonal, or complementary selectivities as compared to metal-catalyzed asymmetric processes. In 2003, Juhl and Jørgensen reported the first organocatalytic asymmetric IEDDA reaction.96 Ever since, many enantioselective IEDDA reactions using chiral organocatalysts, including proline amide derivatives,95e N-heterocyclic carbenes,97 and chiral phosphoric acids,95d have been successfully developed. These organocatalyzed asymmetric IEDDA reactions have several unique characteristics: (1) the great range of efficient catalysts that are readily available; (2) metal free and usually nontoxic catalysts; (3) high regio- and stereoselectivities; and (4) the variety of functional groups that are tolerated. In recent years, the chiral Brønsted acids-catalyzed IEDDA reaction mainly benefits from the progress and development of catalytic asymmetric Povarov reaction by using chiral cyclic phosphoric acids derived from Binol. Importantly, the introduction of substituted aryl groups onto the 3,3′-positions of chiral phosphoric acids is essential for both excellent reactivity and enantioselectivity of reactions. The remarkable ability of Brønsted acids to form hydrogen bonds with reactants provides a solid base for their high catalytic activities in asymmetric IEDDA reaction. From the perspective of the mechanism, the Brønsted acids-catalyzed IEDDA reaction features a catalytic stepwise Friedel−Crafts process, wherein the Brønsted acids could activate the reaction components and intermediates by hydrogen-bonding interaction. In addition, the chiral N-heterocyclic carbenes-catalyzed IEDDA reaction also made a considerable success, despite the reports are relatively rare. In this section, we will survey the literature in the field of catalytic asymmetric IEDDA reaction, with a focus on recent achievements using chiral N-heterocyclic carbenes or Brønsted acids.

hetero-DA reaction of mono- and bisubstituted cyclopentadienes catalyzed by unique binary acid-InBr3 complexes (eq 31).94 A salient feature of this reaction is ascribed to the identification of an extremely active binary acid 89-InBr3 complex that enables the reactions of substituted cyclopentadienes with β,γ-unsaturated α-ketoesters 29 to give the corresponding cycloadducts 88 in good yields (86−99% yields) and with high enantioselectivities (up to 99% ee). A tentative transition state has been suggested to account for the regio- and stereoselectivity (Figure 8). Accordingly, the reactions occur

Figure 8. Proposed transition state for binary-acid 89/InBr3-catalyzed IEDDA reaction.

through bidentate activation of an α-ketoester by the catalytic active complex formed from chiral phosphoric acid 89 and InBr3 (1:1). Approach of cyclopentadiene from the more accessible upper space by the aid of attractive π-interactions between fluorobenzene and cyclopentadiene and subsequent [a,b]-endo addition lead to the chiral HDA product.

3.1. Chiral N-Heterocyclic Carbenes-Catalyzed Asymmetric Reaction

Asymmetric carbon−carbon bond forming processes mediated by N-heterocyclic carbenes (NHC) have witnessed recent progress in the discovery of new asymmetric reaction.98 Although the NHC-catalyzed enantioselective Diels−Alder reactions are challenging and elusive, two successful works were still achieved by Bode’s group.97 In 2006, Bode and coworkers made a great contribution in advancing this field, reporting the first example of NHC-catalyzed generation of a highly reactive dienophile that participates in LUMOdienecontrolled IEDDA reaction with α,β-unsaturated imines under mild conditions (eq 32).97a When the enal reactants 90 reacted with a variety of N-sulfonyl imines 91 in the presence of 10 mol % of N-mesitylsubstituted azolium salt 93b, and a catalytic amount of DIPEA in 10:1 toluene/THF at room temperature, the corresponding chiral cis-3,4-dihydropyridinone products 92 were obtained in excellent yields, diastereo-, and enantioselectivites (97−99% ee). The friendly reaction conditions did not require heating, cooling, or additional reagents. M


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α-chloroaldehydes 94 as the dienophile precursors to afford the corresponding 3,4,6-trisubstituted dihydropyran-2-ones 95 with good yields and excellent stereochemical outcomes (eq 34). This catalytic reaction provided a simple and efficient one-pot synthesis for trisubstituted dihydropyran derivatives. Significantly, the loading of the chiral organocatalyst could be reduced to 0.5 mol % without compromising the reaction rate, enantioselectivity, and chemical yield. 3.2. Chiral Brønsted Acids-Catalyzed Asymmetric Povarov Reaction

Among the catalytic asymmetric IEDDA, IED-imino Diels− Alder reaction (Povarov reaction)12 between 2-azadienes and electron-rich alkenes allows a rapid construction of polysubstituted tetrahydroquinolines attracting the interest of both synthetic and medicinal chemists. Early catalytic asymmetric Povarov reactions relied heavily on the use of chiral Lewis acid organometallic complexes such as aminodiol-titanium(IV),42 and Binol-ytterbium(III),49 as discussed in the previous sections. However, these Lewis acid metal-catalyzed reactions still suffer from the narrow scope of substrates, relatively harsh reaction conditions, and the expensive chiral organometallic reagents. Although organocatalytic methods have shown many advantages and a range of catalytic asymmetric reactions have been well documented,95a,b the catalytic version of the asymmetric Povarov reaction only first appeared in 2006 when Akiyama et al.98 reported the first example of a chiral Brønsted acid99-catalyzed reaction of aldimines with electronrich alkenes. Akiyama and co-workers showed that the chiral phosphoric acid 97 derived from (R)-Binol could serve as a catalyst in the Povarov reaction of a variety of N-aryl aldimines 19 with electron-rich alkenes (eq 35). The reaction afforded tetrahydroquinoline derivatives 96 in good yields with high to excellent enantioselectivities (87−97% ee) and excellent diastereoselectivities (99:1 dr) in favor of the cis-isomer. Not only ethyl ether, but also butyl and benzyl ethers proved to be good substrates. The nine-membered cyclic transition state was depicted to rationalize the stereochemistry, wherein phosphoryl oxygen formed a hydrogen bond with the hydrogen of the imine OH moiety with the nucleophile attacking the re-face of the imine preferentially. The high efficiency of this reaction was demonstrated by its useful application in the synthesis of poly rings fused quinolone derivatives. For example, the tetrahydroquinoline could be converted to an optically active compound bearing a 2-aryl-2,3dihydro-4-quinolone core structure 98 in two steps (eq 36). Zhu and co-workers demonstrated the first example of a successful catalytic enantioselective three-component Povarov reaction.100 These efforts were built upon studies by the Zhu group, who identified the Binol-derived phosphoric acid (R)104 as an effective chiral Brønsted acid catalyst for threecomponent Povarov reaction involving aldehyde 101, anilines, and benzyl N-vinylcarbamate (eq 37). The authors suggested that the N−H function in carbamate 102 could form a

The key to the success of this approach is that the Breslow intermediate or its homoenolate resonance structure can undergo a protonation to generate the reactive enolate.99 The key Breslow intermediate could be formed via the nucleophilic addition of NHC catalysts to aldehydes, followed by a further protonation or trapping to lead to the formation of the catalystbound enolate poised for carbon−carbon bond formation (eq 33). The formation of dihydropyridinones relies on a LUMOdienecontrolled IEDDA cycloaddition reaction. It was proposed that the observed absolute stereochemistry of the products (Figure 9) is achieved through an endo-transition state intermediate. In

Figure 9. Stereochemical model for endo-cycloaddition using chiral Nheterocyclic carbenes.

this NHC-catalyzed reaction, the stereoselectivity is further enhanced by the presence of a bulky triazolium moiety in the active dienophile. The conformation of the enol-triazolium bond is a key determinate of the stereochemical outcome, and the Breslow intermediate could occur only in a fully conjugated arrangement that necessarily leads to the (Z)-enolate structure. The cis-stereoselectivity would arise from a (Z)-enolate reacting as the dienophile. In addition, the scope of NHC-catalyzed asymmetric IEDDA reaction was further extended using the N-mesityl-substituted azolium salt 93b as an exceptionally effective catalyst. Bode et al.97b reported a NHC-catalyzed, highly enantioselective IEDDA reaction of a broad range of enones 29, using racemic N


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Scheme 9. Enantioselective Brønsted Acid-Catalyzed ThreeComponent Povarov Reaction with β-Substituted (E)Enecarbamates

hydrogen bond with the catalyst, potentially avoiding the need for the OH function in the anilines 100. It is essential not only for the enantioselectivity but also for the reactivity. Cyclization of a wide variety of aromatic and aliphatic aldehydes as well as anilines with carbamate 102 formed the (2,4-cis)-4-amino-2aryl(alkyl)-tetrahydroquinolines 103 with high yields in excellent enantio- and diastereoselectivities (92→99% ee, and up to >95:5 dr). It is interesting to note that the absolute configuration of the tetrahydroquinolines 103 is different from that obtained by Akiyama, although the chiral phosphoric acids used in both cases were derived from (R)-Binol. A possible Siface attacking transition state was proposed to explain the observed reversal of enantiofacial selectivity.

withdrawing as well as electron-donating groups on both the anilines and the aldehydes proved to be suitable substrates for the reaction. Importantly, this reaction provided a convenient asymmetric method for the preparation of 4-amino-1,2,3,4tetrahydroquinolines with various substitution patterns at C-2, C-3, and C-4. A stepwise process has been suggested to explain the reaction mechanism. It proceeded via protonation of the imine, forming chiral ion pair A, followed by hydrogen bonding between the enecarbamate NH and the Lewis basic phosphoryl oxygen. A pseudointramolecular Si-face attack of (E)-enecarbamate on the iminium carbon of the chiral contact ion pairs via the transition state B would then afford iminium C, with concurrent proton shift within the phosphoric acid sphere. A subsequent intramolecular aza-Friedel−Crafts reaction would finally furnish the observed cis-4-amino-2-aryl(alkyl)-1,2,3,4-tetrahydroquinolines 106 (Scheme 10). This evidence also indicated that the free NH function of enecarbamates plays a key role in the success of this transformation. In addition, the mechanistic Scheme 10. Proposed Mechanism and Stereochemical Issue Using Chiral Brønsted Acid

Later, Zhu and Masson’s groups extended the scope of the Brønsted acid-catalyzed asymmetric three-component Povarov reaction to include β-substituted acyclic enecarbamates as dienophiles by using the same chiral phosphoric acid (R)-104 (Scheme 9).101 With β-substituted acyclic enecarbamates 105 as a key reaction partner, in general, the cyclization afforded the corresponding cis-4-amino-2-aryl(alkyl)-1,2,3,4-tetrahydroquinolines 106 in good yields with excellent diastereo- and enantioselectivities (up to 98% ee and >99:1). ElectronO


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investigation was also supported by including NMR spectroscopy studies, linear effects, and control experiments. On the basis of those findings, the scope of asymmetric three-component Povarov reaction using enecarbamates as dienophiles has been extended even further to five-membered endocyclic enecarbamates. They also found that the chiral phosphoric acids could effectively catalyze the three-component Povarov reaction of cyclic ene-(thio)ureas with anilines and aldehydes.102 Zhu et al. considered the activation of both the imine and the ene-(thio)ureas by hydrogen bonding is crucial to achieve high enantioselectivity in Figure 10. To explore the

ature, it still has some advantages such as good functional group compatibility, experimental simplicity, and commercial availability of inexpensive chiral reagents. Figure 10. The activation of ene-(thio)urea and imine by a chiral phosphoric acid.

efficiency of the proposed asymmetric three-component cyclization, various substituted chiral phosphoric acids were rescreened for the three-component reaction of ene-(thio)ureas with aniline 107a and 4-azidobutanal 109 (Scheme 11). The 4Scheme 11. Three-Component Synthesis of Hexahydropyrroloquinolines Using Chiral (R)-TRIP

All of these advantages make it a useful protocol in organic synthesis. For example, the guanidine-containing pyrroloquinoline is a core structural feature of martinelline and martinellic acid,103 and represents a new entry to synthetic analogues of these biologically active natural products. The N-thiocarbamoyl hexahydropyrroloquinoline could be easily converted to Nunprotected hexahydropyrrolo[3,2-c]quinoline 113 (eq 39).

chlorophenyl-disubstituted phosphoric acid (R)-104 gave low yield and stereoselectivity. After having screened various 3,3′substituted chiral phosphoric acids, the 2,4,6-triisopropylphenyl disubstituted phosphoric acid (R)-111 was found to be the best catalyst in terms of yield and stereochemical outcome (72% yield, 88% ee, and 5:1 dr). With cyclic ene-thiourea 108b, the reaction furnished the corresponding endo-hexahydropyrroloquinoline 110b in high yield with excellent diastereo- and enantioselectivities (81% yield, >95:5 dr, and 92% ee). The cyclic ene-thiourea 108b reacted with various aldehydes and anilines in the presence of chiral phosphoric acid (R)-111 to produce the hexahydropyrrolo[3,2-c]quinolines 110 in high yields (up to 93% yield) with excellent diastereo- and good to excellent enantioselectivities (up to >95:5 dr, and 75−98% ee) as shown in eq 38. A wide variety of aromatic and aliphatic aldehydes, as well as anilines with different electronic properties, are all suitable substrates for this catalytic asymmetric three-component Povarov reaction. Although the established asymmetric method needs low reaction temper-

In recent years, the enantioselective construction of CF3- or CF2-substituted stereogenic centers has attracted considerable attention because chiral organofluorine compounds usually exhibit many unusual properties that have found widespread application in dyes, agrochemicals, and pharmaceuticals.104 Following the initial works and the above results, Liu and coworkers described an efficient asymmetric method that allowed P


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hydroxystyrenes were used, and led to the generation of desired products in 54−95% yields with high stereoselectivity (eq 42). Interestingly, the α-alkyl 2-hydroxystyrenes (R3 = Et, Me) provided a cleaner reaction than 2-hydroxystyrenes, providing much higher yields. The absolute configuration of the products was determined as (2S,4S). This is consistent with the proposed transition state as shown in Scheme 12. It

for introduction of CF3 or CF2 groups into tetrahydroquinolines based on the Povarov reaction of N-arylimines 114 with benzyl N-vinylcarbamate 102 using a chiral phosphoric acid (eq 40).105 N-Arylimines 114 reacted very efficiently with benzyl Nvinylcarbamate 102 in the presence of chiral phosphoric acid (R)-115 to give the corresponding enantioenriched CF3- or CF2-substituted tetrahydroquinolines with high yields (81− 94%) and excellent diastereo- and enantioselectivities (97−99% ee and >97:3 dr). In light of this work and previous mechanistic studies, the authors suggested that chiral phosphoric acid acted as a bifunctional catalyst that activated both the nucleophile and the electrophile. The acidic proton and phosphoryl oxygen of the catalyst could form the hydrogen bond with imine and benzyl N-vinylcarbamate. On the basis of previous works, Masson et al. recently further extended the substrate scope of the chiral phosphoric acidcatalyzed three-component Povarov reaction to a variety of substituted isoeugenol derivatives.106 Using chiral phosphoric acid (R)-111 as the Brønsted acid catalyst in 1,2-DCE (1,2dichloroethane) at 50 °C proved to be the optimal reaction conditions. The reaction of isoeugenol derivative 116, aldehydes 101, and anilines 107 yielded the corresponding 2,3,4-trisubstituted 4-aryl-tetrahydroquinolines 117 in 70−92% yields with enantioselectivities of 90% to >99% ee (eq 41). It must be noted that the reactivity and stereoselectivity of reaction was sensitive to dienophile geometry. For example, the cycloadduct was obtained as a 2:1 mixture of diastereomers in only 11% yield when using Z-dienophile. A transition state model, wherein the phosphoric acid forms H-bonds with the phenol and imine, was proposed to explain the stereochemical outcome of the reaction.

Scheme 12. Proposed Mechanism for Chiral Phosphoric Acid (R)-120-Catalyzed Reaction

revealed that the Povarov reaction proceeded through a sequential vinylogous Mannich reaction and an intramolecular Friedel−Crafts reaction, wherein the phosphoric acid acted as a bifunctional catalyst to activate the reaction components and intermediates involved by hydrogen-bonding interaction. This conclusion was also supported by density functional theory calculations (DFT)108 for the model reaction. The DFT calculations showed that the 2-hydroxystyrene may approach the E-imine through cis or trans orientations from its Re-face or Si-face. Both 2-OH of the styrenes and key intermediate Eimine were activated simultaneously by the chiral phosphoric acid (R)-120 by means of hydrogen-bonding interaction, thereby accelerating the vinylogous Mannich reaction and the subsequent intramolecular Friedel−Crafts reaction.

As an extension of the chiral Brønsted acid-catalyzed enantioselective Povarov reaction, Ricci and co-workers also investigated the asymmetric Povarov reaction of N-arylimines with 2- and 3-vinylindoles.109,110 Using chiral phosphoric acid (S)-TRIP 111 as a catalyst, and toluene as solvent in the presence of 3 Å molecular sieves at 45 °C, the reaction furnished the Povarov cycloadducts containing an indole moiety in high diastereo- and enantioselectivities. The reactions of 2-vinylindole 121 with a range of N-arylimines 123, derived from the condensation of anilines with various aldehydes, all furnished the corresponding cycloadducts 124 with excellent

As a result of the above demonstrated studies by Zhu and Masson, the chiral phosphoric acid-catalyzed three-component Povarov reaction was made practicable. Very recently, Gong and co-workers reported that the 2-hydroxystyrenes 118 efficiently reacted as dienophiles with aldehydes 101 and anilines 107, leading to the corresponding enantiomerically enriched tetrahydroquinolines 119 by using chiral phosphoric acid (R)-120 as catalyst.107 This protocol is fully regioselective and tolerates a wide range of aldehydes, anilines, and 2hydroxystyrenes. Both 2-hydroxystyrenes and α-alkyl 2Q


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Scheme 13. Asymmetric Cooperative Catalysis of Brønsted Acid-Promoted IEDDA Reactions Using Chiral Ureas

results in terms of yields, diastereo-, and enantioselectivities, irrespective of the steric or electronic properties of the Narylimines employed (eq 43). Yields of 44−96% with 73−98% ee for the corresponding products 125 were obtained by using the same phosphoric acid (S)-111 as catalyst when employing 3-vinylindole 122 and N-arylimines 123 as substrates (eq 44). This reaction also features a catalytic stepwise Friedel−Crafts process. In the reaction with 2-vinylindole, the typical nucleophilic reactivity of the C3 carbon of the indole nucleus111 is overridden by the Povarov cycloaddition at the C2 olefinic moiety. This reaction outcome is rather impressive as evidenced by the fact that the experimental data perfectly supported the obtained result. The design and application of chiral phosphoric acids in catalytic enantioselective Povarov reaction has been proven particularly useful as the above description. In contrast with a single Brønsted acid-catalyzed Povarov reaction, Jacobsen and co-workers described an asymmetric cooperative catalytic strategy for Povarov reaction, wherein a chiral urea catalyst could interact with the highly reactive intermediate through a network of noncovalent interactions.112 Through the optimization of the reaction conditions, Jacobsen et al. found that the combination of the bifunctional sulfinamido urea derivative 126a and ortho-nitrobenzenesulfonic acid (NBSA) could effectively catalyze the Povarov reaction of a wide variety of N-arylimines 123 with electron-rich alkenes (Scheme 13). The tetrahydroquinoline derivatives exo-129 were obtained in high enantio- and diastereoselectivities (95−99% ee and >20:1 dr) with 72−92% yields by the reaction of 123 with vinyllactam 127. Under the same catalytic system, the cycloaddition of 123 with N-Cbz-protected 2,3-dihydropyrrole 128 also provided high enantioselectivities (90−98% ee), despite the moderate diastereoselectivities were observed. Yields of 45−73% for the corresponding tricyclic hexahydropyrrolo[3,2-c]quinoline derivatives exo-130 could be isolated. The authors suggested that the tight binding between a chiral urea and a highly reactive cationic intermediate through multiple, specific H-bonding interactions as well as these noncovalent interactions113 was maintained in the stereodetermining cycloaddition event. In a subsequent detailed experimental and computational analysis, they demonstrated that four energetic minima of comparable stability were identified (Scheme 14), with the 126a-triflate

Scheme 14. Geometry and Energy-Minimized Structures for Intermediates by DFT

complex acting as a dual H-bond acceptor through the triflate and sulfinamide groups, and the iminium ion acting as a dual Hbond donor through the iminium nitrogen and formyl protons. These analytical results also showed that the enantioselective reaction occurred preferentially with complex A, leading to the experimentally observed (R)-enantiomer of product, which was consistent with the experimental data.

4. CHIRAL AMINES-CATALYZED ASYMMETRIC IEDDA REACTION BASED ON HOMODIENOPHILES-RAISING STRATEGY Intense research over 10 years by several groups has been expended in an effort to achieve the organocatalytic asymmetric DA reaction. MacMillan and Jørgensen’s groups are recognized as having made the most significant contribution in advancing this field respectively. In 2000, MacMillan and co-workers reported the first example of an organocatalytic DA reaction R


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IEDDA reaction only first appeared in 2003 when Jørgensen et al. reported the first example of a chiral enamine-catalyzed IEDDA reaction of aliphatic aldehydes with β,γ-unsaturated αketoesters (eq 46). Indeed, these authors showed that the chiral pyrrolidine 138 derived from (S)-proline could serve as a catalyst in the reaction of aldehydes 135 with enones 29. The reaction afforded the corresponding pyran-2-one derivatives 137 with 80−94% ee and high diastereoselectivity after PCC (pyridinium chlorochromate) oxidation of hemiacetals 136. Jørgensen et al. found that the possible reaction mechanism could involve an enamine species A, generated in situ from amine 138 and aliphatic aldehydes. It could act as HOMOraised dienophiles in the IEDDA reaction with enones 29 (Scheme 15). Silica gel played a key role in the catalytic cycle,

using chiral secondary amines (eq 45).114 Alternatively, Jørgensen and co-workers described the first amine-catalyzed IEDDA reaction with the characteristics of HOMO of dienophiles via an enamine activation.96 Recent developments in chiral amine-catalyzed asymmetric IEDDA reactions have recognized the power of the alternative HOMO-raising strategy.

Scheme 15. Catalytic Cycle for Organocatalytic IEDDA Reaction Using Chiral Enamine

To date, these amine-catalyzed asymmetric IEDDA reactions included two HOMO-activating approaches: (1) an in situ enamine or dienamine catalytic pathway, and (2) an in situ enolates controlling pathway. These HOMO-activating modes were based on covalent active intermediates (Figure 11)

causing the hydrolysis of N,O-acetal cycloadducts to give hemiacetals 136. This ground-breaking work clearly demonstrated that asymmetric IEDDA reaction could be efficiently catalyzed by a chiral amine via a HOMO activation pathway. Figure 11. HOMO-activating approaches in amine-catalyzed asymmetric IEDDA reactions.

generated by the condensation of chiral amines with a carbonyl group. This reversible condensation could lead to form nucleophilic enolate intermediates or electron-rich enolate equivalents (enamine or dienamine). Thus, the energy of the highest occupied molecular orbital (HOMO) of the system is effectively raised, resulting in activation of the carbonyl compounds as dienophiles. From the above three activating pathways, we will discuss the development of asymmetric IEDDA reactions based on the HOMO-raising effects of chiral amines in this section. These reactions generally occurred with high chemo-, regio-, and stereoselectivity. These successful examples proved that the HOMO-activating approach via aminocatalysis could become a significant tool in asymmetric IEDDA reactions. 4.1. Enamine Catalytic Pathway

Enamines can act as useful equivalents of the α-carbanions of carbonyl compounds and consequently have proved to be useful in organic synthesis. As early as 30 years ago, the electron-rich CC bond generated by enamine has been used in DA-type reactions, and the first such pyrrolidine-catalyzed DA reaction based on the formation of enamine was reported by Boger in 1982.115 However, the catalytic version of the

Despite obtaining an impressive success, this promising catalytic protocol has not caused too much attention at that S


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α,β-unsaturated trifluoromethyl ketones 144 with aliphatic aldehydes 135 was catalyzed by the Jørgensen−Hayashi catalyst α,α-diphenylprolinol O-TMS ether 146a,120 furnishing the 6trifluoromethyl-3,4-dihydropyan-2-ones 145 with moderate to good yields, high enantio-, and diastereoselectivities (up to 97% ee and >95:5 dr) after further transformations. Surprisingly, a big drop in the enantioselectivity (46% ee) was observed for 3phenylpropionaldehyde. In this field, considerable advances have recently been achieved by several groups. Notably, the effort made by Chen and co-workers in the catalytic enantioselective IEDDA reaction via the enamine HOMO-raising strategy should be recognized.121 On the basis of those findings, Chen group successfully extended the use of chiral enamine HOMO-raising catalytic system. They found that enamine intermediates generated in situ from chiral amine 146a and aliphatic aldehydes 135 as HOMO-raised dienophiles could be applicable to Boger’s IED hetero-DA reaction.122 As an effective promoter, the α,α-diphenylprolinol O-TMS ether 146a catalyzed the reaction of N-Ts-1-azadienes 147 and aldehydes 135 to afford hemiaminals 148 in excellent enantioselectivities of up to 99% ee and 74−95% yields (eq 49).123 In general, a wide range of N-Ts-1-azadienes with aryl, heteroaryl, alkyl, and ester groups were well tolerated for combination with aliphatic aldehydes. It is noted that the addition of a small amount of water turned out to be crucial for this asymmetric conversion.

time. In 2007, employing the same enamine HOMO-raising strategy, Zhao et al. showed that an available and highly tunable L-prolinal dithiolacetal 140 was a highly effective catalyst for the enantioselective IEDDA reaction of β,γ-unsaturated αketophosphonates 45 with aliphatic aldehydes 135, providing the corresponding cycloadducts 139 (eq 47).116 High enantioselectivities and yields could be achieved (up to 91% yield, and 94% ee) for 140-catalyzed reaction in the presence of SiO2 in CH2Cl2. Almost at the same time, Dixon and coworkers reported an enantioselective IEDDA reaction of in situ generated enamines with o-quinone reagents 141 by using the tert-butyl imidazolidinones 143b (eq 48).117 This protocol tolerates a variety of readily available linear and β-branched aldehydes 135. Under the optimized reaction conditions, both o-chloranil and o-bromanil were used, and led to the generation of desired products 142 with good enantioselectivities and yields (up to 75% yield, and 81% ee). The stereochemical outcome of the reaction is consistent with the favored Si-face attack of the o-quinone reagent to the less hindered face of the in situ generated enamine. Accordingly, the tert-butyl group is responsible for fixing the conformation and providing the facial bias on approach of the o-quinone.

In addition, the same catalytic strategy was applied by Liu’s group118 to enantioselective synthesis of trifluoromethylsubstituted dihydropyrans, as shown in Scheme 16. Among the various fluorine-containing compounds, trifluoromethylsubstituted dihydropyran derivatives are important ones, and some of them have been used as drug intermediates such as antibiotics.119 In general, the IEDDA reaction of a variety of

With the above success, other types of 1-azadienes such as NTs-1-aza-1,3-butadienes 149 derived from 3-argiocarbonylcoumarins were also studied by Chen’s group.124 The reaction of 149 and aqueous acetaldehyde 135a could provide the tricyclic chroman-2-one derivatives incorporating a piperidine motif 150 in high enantioselectivities and yields after reduction with Et3SiH/BF3·Et2O (eq 50). The use of α,α-diarylprolinol ethers 146a, and 146d−146f as catalysts gave low enantioselectivities, whereas that of 146g, bearing the bulkier tert-butyl substituent, yielded the (S)-product with a much higher ee. On the downside, a longer reaction time and 5 °C were needed. Optimum enantioselectivities of between 84% and 95% ee were obtained for azadienes bearing various electron-withdrawing or electron-donating substitutions on the aryl ring.A possible catalytic endo-selective mode was proposed to rationalize the generation of the observed stereocontrol, and the Si-face attack on the azadienes would afford the cyclic products 150 with (S)configuration at the benzylic carbon. In a further work, Chen group employed the established HOMO-enamine catalytic protocol to construct versatile fused heterocycles with diverse skeletons through a sequential IEDDA reaction and Friedel−Crafts (FC).125c As illustrated in Scheme 17, aldehydes 151 tethered to an arene motif have been used in the IEDDA reaction with N-Ts-1-azadienes 147.

Scheme 16. Synthesis of 6-Trifluoromethyl-3,4-dihydropyan2-ones through Asymmetric IEDDA Reaction of α,βUnsaturated Trifluoromethyl Ketones and Aldehydes

T


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Scheme 18. Sequential IEDDA and Cation-Olefin Cyclization Using Prolinol Ether 146a

Scheme 17. Sequential IEDDA and Friedel−Crafts Reaction Using Prolinol Ether 146a

domino cation-olefin/Friedel−Crafts reaction in their studies. In addition, employing a similar catalytic strategy, asymmetric IEDDA and O-Michael addition sequence reaction was also investigated by Chen’s group.125b Wang and co-workers also reported a PPh3-catalyzed addition/all-carbon-based asymmetric IEDDA sequence reaction.126 Notably, as compared to other classic reactions, DA reaction presents more difficulties due to the governing strict principle of generation of DA reaction including the suitable matching of diene with dienophile in accordance with the electronic orbital theory.114 Indeed, a long-standing limitation for the progress of asymmetric DA reaction is the lack of appropriate and effective dienes. In their study, a novel type of electron-poor dienes 157 could be generated via a PPh3catalyzed cascade reaction of propiolates and α,α-dicyanoolefins 158, which could then undergo asymmetric cycloaddition with enamine species (Scheme 19). This approach has been used to generate a broad spectrum of highly substituted cyclohexenols 159 with 43−86% yields in high stereoselectivities (up to 86% yield, 99% ee, and >20:1 dr). Scheme 19. PPh3-Catalyzed Addition/All-Carbon-Based Asymmetric IEDDA Sequence Reaction Using Prolinol Ether 146a

The corresponding hemiaminals 152 were subsequently converted into electrophilic iminium ions under strongly acidic conditions, which underwent intramolecular Friedel−Crafts cyclization with the tethered arene motif to give fused tetrahydropyridine frameworks. Using this approach, a range of enantioenriched fused piperidines 153 were produced in excellent enantioselectivities (up to 99% ee). On the basis of those findings, Chen and co-workers further discovered that N-Ts-1-azadienes 147 could undergo an asymmetric IEDDA and cation-olefin cyclization sequence with a variety of aldehydes 154 to construct cyclopenta[b]piperidine skeletons (Scheme 18).125a Consequently, chiral hemiaminals 155 were initially provided from IEDDA reaction of N-Ts-1-azadienes 147 with a variety of aldehydes 154 catalyzed by α,α-diphenylprolinol O-TMS ether 146a and ofluorobenzoic acid. Under acidic conditions, the corresponding DA adducts were subsequently converted into electrophilic iminium ions, which could undergo cation-olefin cyclization to give fused cyclopenta[b]piperidines 156 with 35−64% yields and excellent stereoselectivities (95→99% ee and >95:5 dr). The authors verified that the cyclization of N-Ts iminium ion underwent a stepwise cationic process through a designed U


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4.2. Dienamine Catalytic Pathway

Chiral dienamine species derived from α,β-unsaturated carbonyl compounds and amines also proved to be effective catalytic intermediates for DA-type reaction by Barbas,127 Jørgensen,128 Christmann,129 and Xu groups.130 The HOMO-raised dienamines may react either with electron-deficient dienophiles in normal DA reactions or with electron-poor dienes in IEDDA reactions. Chen and co-workers131 discovered that dienamine species of α,β-unsaturated aldehydes 160 and amine 146a exhibited high reactivity in the IED hetero-DA reaction with NTs-1-azadienes 147 (Scheme 20). These asymmetric transScheme 20. Asymmetric IED Hetero-DA Reaction of N-Ts1-Azadienes with α,β-Unsaturated Aldehydes through Dienamine HOMO-Raising Strategy

discovered that these dienes were highly reactive with the HOMO-dienamine species of β,β-disubstituted α,β-unsaturated aldehydes 160.134 The catalytic ability of dienamine species was established in the enantioselective IEDDA reaction of chromone-fused dienes 168 with α,β-unsaturated aldehydes 160 (Scheme 21). The reaction gave the corresponding DA Scheme 21. Asymmetric IEDDA Reaction of β,βDisubstituted Enals and Domino Vinylogous Aldol Reaction formations have been shown to occur with remarkable ipso, αregioselectivity in very high enantioselectivities, providing the hemiaminals 161 containing an alkene moiety with 85−96% yields. The resulting chiral hemiaminals were oxidized directly to the corresponding lactams, and the major E-isomers 162 were isolated in 66−72% yields without almost any loss of enantioselectivity. This particular reaction exhibits a high efficiency and can be carried out under mild reaction conditions. Although currently examples of the asymmetric reaction of unsaturated aliphatic aldehydes are still somewhat limited, this dienamine HOMO-activated reaction clearly represents a new strategy for chiral amine-catalyzed asymmetric IEDDA reactions of unsaturated aldehydes. Subsequently, Chen and co-workers extended the scope of HOMO-dienamine species-catalyzed IEDDA reaction to an allcarbon-based IEDDA reaction of electron-deficient dienes 164 and crotonaldehyde 163 (eq 51).132 Using 146a as a catalyst, various substituents at the different position of the dienes 164 could be well tolerated, providing cycloadducts 165. Excellent enantioselectivities (91−99% ee) combined with high diastereoisomeric ratios were obtained for a number of dienes bearing electron-withdrawing or -donating aryl and heteroaryl groups. The high efficiency of this asymmetric DA-type reaction makes it a highly suitable methodology in organic synthesis. The partial hydrolysis of one cyano group and subsequent decarboxylation could be conducted by the treatment of alcohol 165a with aqueous NaOH solution, thus affording a conjugated nitrile 166 without affecting the enantiopurity. In addition, this approach was also used to synthesize a caged polycyclic compound 167 after some simple derivations (eq 52). Expanding on the IEDDA reaction of chromone-fused dienes and electron-rich ethenes described by Bodwell,133 Chen’s group further extended the application of dienamine intermediates to cascade and sequential catalytic processes. They

products 169. This valuable moiety is found widely in natural products and biologically active compounds.135 A domino vinylogous aldol reaction occurred after the desired IEDDA reaction, affording an array of the caged tetrahydroxanthone skeletons 171 bearing an ethoxycarbonyl in high enantioselectivities (94−98% ee). In addition, the ethoxycarbonyl group of diene was replaced by an electron-withdrawing phenylsulfonyl group, and a similar cascade reaction was performed to furnish the caged product in 85% ee and 89% yield. The authors suggested that the HOMO energy of a dienamine V


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intermediate from a β,β-disubstituted α,β-unsaturated aldehyde could be efficiently raised, which could overcome the reaction barrier for generating fused tetrahydroxanthones in this catalytic sequential transformations. In contrast, as illustrated in eq 53, a different domino reaction occurred when a chromone-fused diene 168c incorporating an acetyl group was employed. By using catalyst 172, a tetracyclic hemiacetal product 173, rather than the vinylogous aldol adduct, was obtained as a diastereomeric mixture in 90% yield and 91% ee. This result is in good agreement with the previously proposed model shown in Scheme 20.

general, the aromatic or aliphatic aldehydes with different steric parameters were tolerated, affording the quinoxalines 176 with excellent enantioselectivities (90−99% ee). It must be noted that quinoxalines and related scaffolds exist in a number of pharmaceutical agents. Notably, low temperature (−78 °C) was necessary to ensure high stereocontrol. On the basis of the above results, Lectka et al. further extended the scope of useful heterodienes from o-benzoquinones to o-benzoquinone imides,139 thus providing direct enantioselective access to α-amino acid derivatives. As shown in Scheme 23, under the same catalytic system, the reaction of acyl Scheme 23. Catalytic Asymmetric Synthesis of 1,4Benzoxazinones and Enantioselective Route to α-Amino Acid Derivatives from o-Benzoquinone Imides

4.3. Enolates Catalytic Pathway

The use of chiral, catalytically in situ derived zwitterionic ketene enolates has brought forth powerful methodology for the synthesis of a diverse variety of optically enriched products.136 Chiral ketene enolate intermediates have been widely recognized for undergoing highly enantioselective cycloadditions with both aldehydes and imines to produce βlactones and β-lactams, respectively.137 Inspired by the utilization of in situ generation of enolates from ketenes and tertiary amines for asymmetric transformations, Lectka and coworkers developed an elegant IEDDA reaction of obenzoquinones with ketene enolates formed in situ from acyl chlorides (Scheme 22).138 During their investigations, the authors discovered that the chiral zwitterionic ketene enolate species generated in situ from cinchona alkaloid derivative 177 and acyl chlorides 174 acted as HOMO-raised dienophiles in the IEDDA-type reaction with o-benzoquinones 175. In

chlorides 174 and a variety of readily available o-benzoquinone imides 175 furnished the chiral 1,4-benzoxazinones 179 with excellent enantioselectivity (>99% ee). Moreover, the authors illustrated that these chiral 1,4-benzoxazinones could serve as flexible precursors for the efficient synthesis of highly enantiomerically enriched α-amino acids and related derivatives. The cycloadducts could be converted directly into the αamino acid derivatives 180 in 59−90% yields and enantioselectivity of >99% ee by further nucleophilic addition from various nucleophiles in one pot manner. The highly optically active α-amino acid methyl esters 181 were obtained in moderate to good yields (58−74%) through further conversion of the resulting 180. In addition, the chiral enolate equivalents directly generated in situ from chiral amines and readily available carboxylic acids acted as HOMO-raised dienophiles, which have also been proved to be feasible. Very recently, an interesting IEDDA-type reaction was accomplished by Smith and co-workers as shown in Scheme 24.140 Using benzotetramisole 184 as chiral aminecatalyst, the reaction of N-Ts-1-azadienes 147 with arylacetic acids 182 in the presence of a certain amount of pivaloyl chloride and N,N-diisopropylethylamine afforded the corresponding dihydropyridones 183 in 53−79% yields with high diastereo- and enantioselectivities (up to 9:1 dr, and 99% ee). A stepwise Michael/lactamization process has been suggested to explain the reaction mechanism. The reaction proceeded through the initial formation of the mixed anhydride from the arylacetic acid and pivaloyl chloride, followed by formation of the corresponding acyl ammonium ion. Deprotonation of the acyl ammonium ion generated the Z-enolate, which then underwent stereoselective Michael addition, followed by

Scheme 22. Enantioselective IEDDA Reaction of Ketene Enolates and o-Quinones by in Situ Enolate HOMO-Raising Strategy

W


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Scheme 24. Enantioselective Reaction of N-Ts-1-Azadienes and Arylacetic Acids by in Situ Enolate HOMO-Raising Strategy

cycloaddition to be achieved efficiently through simultaneous activation of the HOMO of the dienophile and the LUMO of the diene. Although research on bifunctional catalytic enantioselective IEDDA reaction has lagged somewhat behind that on the single activated asymmetric variants by Lewis acid or base catalysts, there has still been some significant progress achieved. 5.1. Combination of Organocatalysis with Metal Lewis Acid Catalysis

As discussed in the previous section, although to date the catalytic enantioselective IEDDA reaction by using Lewis acidic metal complexes or organic molecules has been well developed, the use of metal/organic molecules cooperative catalytic system,144 however, as the efficient bifunctional catalytic strategy in such reaction has received much less attention. Among the possible reasons is the fact that the metal Lewis acid/Lewis base catalytic systems might potentially result in catalyst inactivation because of the acid−base self-quenching reaction. In addition, the rational coordination is also a difficulty in controlling the stereochemistry of the reaction. The key to overcoming this challenge is the judicious selection of appropriate catalyst combinations. Despite these difficulties, however, two successful examples of the metal/organic molecules bifunctional catalytic asymmetric IEDDA reaction have been reported in recent years.

intramolecular cyclization, to generate the corresponding cycloadducts.

5. BIFUNCTIONAL HOMODIENOPHILES AND LUMODIENES STRATEGIES FOR CATALYTIC ASYMMETRIC IEDDA REACTION Bifunctional catalytic strategy has emerged as a potentially powerful tool in catalytic asymmetric synthesis.141 Although the single catalysis strategy has successfully delivered vast numbers of asymmetric organic transformations to date, bifunctional catalysis concepts have recently began to emerge in many transformations enabling chemical reactions that are impossible or inefficient using traditional monocatalytic strategies. This concept aims to efficiently achieve asymmetric transformations that cannot be approached by using either a Lewis acid or a base catalyst alone.142 As the simplest forms shown in Figure 12, the concept of bifunctional catalysis involves the concurrent

Lectka and co-workers145 developed a highly enantioselective bifunctional catalyst system, deriving from the combination of a chiral amine 177 or 187 with a metal Lewis acid, which was applied to the IEDDA reaction of o-benzoquinone diimides 185 and acyl chlorides 174. Nearly optically pure various substituted quinoxalinones 186, which are found in some bioactive compounds, were afforded in 71−93% yields (eq 54). It was observed that the Lewis acid cocatalyst Zn(OTf)2 could increase the electrophilicity of the diimide without interfering with the nucleophilic enolate through putative coordination to the diimide. The proposed mechanism was depicted as involving a Lewis acid−base cooperative catalytic transition state to rationalize the observed results (eq 55). Later, Lectka et al. realized that the chiral amine 177 also could combine Sc(OTf)3 to effectively catalyze this kind of Lewis acid−base cooperative catalytic IEDDA cycloaddition under similar catalytic conditions.146 At the same time, this useful asymmetric methodology has been successfully applied to synthesize enantiopure non-natural α-amino acid derivatives by Lectka’ group (eq 56). The reaction of a variety of acyl chlorides 174 with o-benzoquinone imide 188 was catalyzed by the 177/Sc(OTf)3 complex, furnishing the highly optically

Figure 12. Concept of bifunctional catalysis involves the concurrent activation.

activation of both a nucleophile and an electrophile using the same (A) or different catalysts (B). Under the bifunctional catalytic system, two reactive species could be generated simultaneously, one with a lowering of the LUMO energy and the other with a raising of the HOMO energy (C), in comparison to the respective starting substrates. To date, great effort has been focused on the development of bifunctional catalytic approaches to achieve asymmetric organic reactions, and impressive results have been obtained.143 Notably, as compared to the progress of other important addition reactions, the bifunctional catalytic asymmetric IEDDA reaction has been much less studied. As a more effective catalytic mode, it allows asymmetric [4 + 2] X


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of the higher stereochemical outcome of the resulted IEDDA reaction. The combination of Y(OTf)3 with 193 was used to successfully catalyze the asymmetric IEDDA reaction of several cyclic ketones 191 with enones 29 at 4 °C. The corresponding cycloadducts 192 were obtained in yields of 60−87%, enantioselectivities of 92−99% ee, and diastereoisomeric ratio of up to 9:1 dr (Scheme 25). Scheme 25. Asymmetric IEDDA Reaction of Cyclic Ketones with Enones Catalyzed by Combination of Y(OTf)3 with 193

active non-natural α-amino acid derivatives 190 with high yields and excellent enantioselectivity (>99% ee) after rapid ringopening methanolysis of the resulting 1,4-benzoxazinone intermediates 189.

In view of the above success, employing the similar bifunctional activated strategy, Wang et al.147 reported a highly chemo- and enantioselective IEDDA reaction of cyclic ketones 191 with γ,β-unsaturated α-ketoesters 29 catalyzed by primary amine-based enamine/metal Lewis acid catalyst system. Although the combination of enamine catalysis with Cu(I),148 Ag(I),149 Pd(0),150 Pd(II),151 and Au(I)152 has shown many advantages for asymmetric organic transformations and several catalytic asymmetric reactions have been well documented, Xu and Wang showed that the metal Lewis acid−organic base cooperative catalytic system was efficient for this asymmetric [4 +2] transformation,153 in which a catalytic amount of enamine formed in situ served as a nucleophile and the metal Lewis acid activated the electrophile. The authors suggested that the base and the metal Lewis acid were brought into close proximity in one molecule without interacting with each other because the primary amine was tethered to a chelating ligand, which could act as a “trap” for the incoming metal (Figure 13). This in fact was a key for the success of the reaction. To explore the possibility of the proposed [4 + 2] cyclization process, a range of Lewis acids such as Cu(SbF6)2, Sc(OTf)3, Eu(fod)3, Y(OTf)3, Yb(OTf)3, and La(OTf)3 were tested. Among them, Y(OTf)3 was selected as the most efficient metal because

One possible reaction mechanism could involve a bifunctional activated mode by the metal Lewis acid−base cooperative catalysis. The metal could strongly activate enone 29 through chelation, and an enamine could be formed in situ by the interaction between the primary amine and ketone. The activated enone reacted with the enamine, leading to the formation of cyclic aminal C, which was hydrolyzed to regenerate the hexahydrochromene 192, thus completing the catalytic cycle (Scheme 26). Scheme 26. Proposed Mechanism for Metal Lewis Acid− Base-Catalyzed IEDDA Reaction

Figure 13. Cooperative catalytic system of primary amine and metal Lewis acid. Y


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5.2. Bifunctional H-Bond-Directing Aminocatalysis

LUMO-activated by the two thiourea hydrogen atoms through weak hydrogen bonds, while the cyclic keto−enolate salt could be HOMO-activated by the simultaneous formation of ketiminium cation and protonation (Brønsted acid not only involves in the formation of ketiminium intermediates, but also promotes the protonation of enolate salt). As a result of the main stereochemical control of 1,2-diaminocyclohexane moiety and steric hindrance from the dehydroabietic amine moiety of the thiourea,169 high Re-face and endo-selectivity could be enforced to give the desired chiral product. The products were then converted into chiral spirolactam 197, which is found in some bioactive compounds.170

Hydrogen bonding is involved in a variety of biochemical processes in living organisms. It sustains the stability and functionality of many biomolecules, from nucleic acids to proteins and all of the way to supermolecular assemblies such as ribosomes.154 Many remarkable and vital properties of life are attributed to this unique, mysterious “glue”. From the aspect of chemistry, hydrogen bonding decreases the electron density of electrophiles and thus activates these species toward nucleophilic attack.155 This principle is widely employed by many biocatalysts, such as enzymes and ribozymes, for acceleration of a wide range of biochemical processes.156 It is well recognized that ureas and thioureas can act as catalysts by activating electrophiles through hydrogen bonding,157 and, to date, their applications have been extended to a wide range of useful organic transformations by our group as well as other groups,158 involving nucleophilic addition,159 Baylis−-Hillman reactions,160 Friedel−Crafts alkylation,161 acetalization,162 epoxide opening,163 acyl-Strecker reaction,164 Diels−Alder reaction,165 as well as other useful organic processes.166 In 2003, Takemoto and co-workers167 reported the first aminethiourea-based bifunctional catalyst, which was capable of the efficient promotion of the addition of malonate esters to βnitrostyrenes with excellent enantioselectivity. Since then, bifunctional catalytic asymmetric catalysis using chiral (thio)ureas has shown many advantages in a range of catalytic asymmetric reactions. Nevertheless, the catalytic version of the asymmetric IEDDA reaction only first appeared in 2012 when Wang et al. 168 reported the first example of highly enantioselective bifunctional catalytic IEDDA reaction of cyclic keto/enolate salts 194 with N-tosyl-2-methylenebut-3-enoates 195 using a chiral amine-thiourea 198 (eq 57). The reaction led to the diversely structured spirohemiaminals 196 in high to excellent yields (84−96%), enantioselectivities (88→99% ee), and excellent diastereoselectivity (>20:1 dr).

While the HOMO-raising activation by the condensation of aldehydes with amines via in situ enamine-based strategy has been made possible, this catalytic system is not suitable for the activation of much less reactive ketones. On the basis of the above bifunctional catalytic strategy, Wang’ group further discovered that the chiral amine-thiourea 202 could also serve as efficient bifunctional promoter in the catalytic asymmetric IEDDA reaction of enones 29 with cyclic ketones 199 (eq 58).171 The results showed that various substituted enones including those bearing electron-withdrawing and electrondonating substituents at different positions on the aromatic ring and heterocyclic groups could be well tolerated, giving bicyclic hemiketals 200 with excellent enantioselectivities (up to 97% ee) and good diastereoselectivities (up to 10:1 dr). One of the chiral bicyclic products could be converted smoothly into the 10-membered lactone 201 in 61% yield through a retro-Henrytype cleavage, performed by treatment of 200 with the catalytic amounts of nBu4NF in a single step. This representative example demonstrates the inherent synthetic potential of this kind of bicyclic hemiketals. Moreover, it provides an alternative asymmetric access to enantioenriched macrolides.172 One possible bifunctional catalytic mechanism could involve a HOMOdienophiles and LUMOdienes activated mode to account for the observed results, featuring an endo-selective mode of reaction (Scheme 27). The Lewis acid (the thiourea hydrogen atoms of the catalyst) LUMOdienes-lowering activated enones would be expected to undergo nucleophilic attack by the Lewis base HOMOdienophiles-controlling activated cyclic ketones by deprotonation at its a-carbon atom (enolization) to lead to the generation of bicyclic hemiketals. All possible conformers of the initially found transition state structures for the cycloaddition reaction based on the observed newly formed chiral centers in the product by DFT calculations were proposed (Figure 14). The DFT calculation revealed that the 4-fluoro-substituted phenyl ring on enone points toward the hydrophobic center when transition state structures form Xa. Otherwise in the way of Xb, this 4-fluoro-substituted

This approach features a dual control of HOMOdienophiles and LUMOdienes activated pathway. A possible model was proposed to explain the stereochemistry of the IEDDA reaction employing a bifunctional in situ generation-activation strategy (eq 57). The N-tosyl-2-methylenebut-3-enoate is fixed and Z


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the corresponding dihydropyran derivatives 204 with 42−82% yields in moderate to high enantioselectivities (75−93% ee).

Scheme 27. Catalytic Cycle and Reaction Transition State

6. SUMMARY AND PERSPECTIVE Catalytic asymmetric inverse-electron-demand Diels−Alder [4 + 2] cycloadditions have been shown to be highly efficient and selective reactions. Utilizing them, various highly useful organic chiral building blocks, such as six-membered rings, can be achieved with excellent stereoselectivities from readily available starting materials. In this Review, some elegant applications of asymmetric IEDDA reactions in organic synthesis have been discussed. Many novel catalysts such as metal complexes as well as organic molecules, which have been custom designed and synthesized to perform asymmetric IEDDA reactions with high efficiency, are presented. Although considerable progress has been achieved, catalytic asymmetric IEDDA reaction is still in the early stages of development as compared to what has been achieved in asymmetric catalysis. Currently, only a limited number of metals and chiral catalysts have been successfully used, and only a few catalyst systems have been optimized regarding catalytic activity and selectivity. As compared to other classic reactions, it presents more difficulties due to the governing strict principle of generation of IEDDA reaction including the suitable matching of diene with dienophile in accordance with the electronic orbital theory. Indeed, one of the long-standing limitations for the progress of asymmetric IEDDA reaction is the lack of appropriate and effective dienes or dienophiles. Last, but not least, the number of useful protocols already adopted for catalytic asymmetric IEDDA reaction remains insufficient. All of these are challenges that remain to be explored. It is to be expected, however, that with a greater understanding of these valuable transformations, new catalysts as well as new catalytic asymmetric strategies will be developed, the scope of the dienes or dienophiles will be further expanded, and eventually these reactions will be more widely applied in organic synthesis.

Figure 14. Plausible reaction models for asymmetric IEDDA reaction.

phenyl ring points away from the hydrophobic center and undergoes a steric repulsion with the nitro group oxygen. Thus, the Xa is more favorably formed than Xb to preferentially give the (4R, 4′R, 8′S) bicyclic product. In addition, Jørgensen and co-workers recently described a chiral squaramide-containing aminocatalyst 205, which could serve as an efficient bifunctional promoter for asymmetric IEDDA reaction involving α,β-unsaturated aldehyde 203 and β,γ-unsaturated α-keto esters 29 (eq 59).173 In this work, Jørgensen et al. also showed the double HOMOdienophile/ LUMOdiene-activated asymmetric process, in which the α,βunsaturated aldehyde 203 could be effectively HOMOactivated by generation of a highly reactive dienamine intermediate, alongside heterodiene 29 that was LUMOactivated by the squaramide moiety of the catalyst through H-bonding interactions with its α-ketoester functionality. The authors also postulated that the π-stacking interactions between the aromatic moieties of heterodiene 29 and the dienamine specie could play an important role in the stabilization of the transition state. In general, the reaction proceeded efficiently for various aldehydes and unsaturated α-keto esters, affording

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. AA


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Notes

and Technology of China (2012ZX09504-001-003), and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT: IRT1137). We also thank Dr. Jia Liu at The Scripps Research Institute for proofreading the manuscript.

The authors declare no competing financial interest. Biographies

ABBREVIATIONS Ac acetyl AcOH acetic acid Binol binaphthol Bn benzyl Bu butyl i-Bu isobutyl BzOH benzoic acid DCE 1,2-dichloroethane de diastereomeric excess DEA N,N-diethylacetamide dr diastereomeric ratio ee enantiomeric excess EDG electron-donating groups Et ethyl EWG electron-withdrawing groups HOMO highest occupied molecular orbital LUMO lowest unoccupied molecular orbital Me methyl MeCN acetonitrile MeOH methanol MTBE methyl tert-butyl ether OFBA o-fluorobenzoic acid OTf trifluoromethanesulfonyl i-Pr isopropyl Ph phenyl TBS tert-butyldimethylsilyl TES triethylsilyl TMS trimethylsilyl Ts toluenesulfonyl THF tetrahydrofuran

Xianxing Jiang was born in 1981. He received his Ph.D. degree in organic chemistry from Lanzhou University in 2011 under the direction of Professor Rui Wang. He then joined the research group of Professor Rui Wang at the same university, where he has been involved in the studies of new strategies for asymmetric inverseelectron-demand Diels−Alder reaction and its application in the synthesis of natural products. He is currently an Assistant Professor at Institute of Drug Design and Synthesis. His research interests lie in the area of asymmetric catalysis, natural product synthesis, and pharmaceutical chemistry.

REFERENCES (1) (a) Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099. (b) Hayashi, Y. In Cycloaddition Reactions in Organic Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH: New York, 2002; p 5. (c) Behforouz, M.; Ahmadian, M. Tetrahedron 2000, 56, 5259. (d) Ooi, T.; Maruoka, K. In Comprehensive Asymmetric Catalysis I-III; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999; Vol. 3, pp 1237−1254. (e) Tietze, L. F.; Kettschau, G. In Topics in Current Chemistry; Metz, P., Ed.; Springer: New York, 1997; Vol. 189, pp 1−120. (f) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137. (g) Cativiela, C.; García, J. I.; Mayoral, J. A.; Salvatella, L. Chem. Soc. Rev. 1996, 25, 209. (h) Whiting, A. In Advanced Asymmetric Synthesis; Stephensen, G. R., Ed.; Kluwer Academic Publishers: Norwell, MA, 1996; pp 126−145. (i) Roush, W. R. Intramolecular Diels-Alder Reactions. In Comprehensive Organic Synthesis; Paquette, L. A., Ed.; Pergamon: New York, 1991; Vol. 5, pp 513−550. (j) Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Tetrahedron Organic Chemistry Series; Pergamon Press: Elmford, NY, 1990; Vol. 8. (k) Taschner, M. J. In Organic Synthesis: Theory and Applications; Hudlicky, T., Ed.; JAI: Greenwich, CT, 1989; Vol. 1, pp 1−101. (l) Boger, D. L. Tetrahedron 1983, 39, 2869. (2) Diels, O.; Alder, K. Liebigs Ann. Chem. 1928, 460, 98. (3) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (b) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650. (4) (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668. (b) Daly, J. W.; Spande, T. F. In Alkaloids: Chemical and Biological

Rui Wang was born in 1963. He received his Ph.D. degree in organic chemistry and medicinal chemistry in 1988 from Sino-Japan joint Ph.D. program of Lanzhou University and Kyoto University, Japan. He then worked as a postdoctoral fellow at Lanzhou University and the University of Kansas, from 1989 to 1993. He was appointed as a professor at Lanzhou University in 1994 and named the Cheung Kong Professor of Peptide Pharmaceutical Sciences in 2004. He obtained the National Outstanding Youth Fund (2005−2008). So far he has published more than 260 SCI academic peer review papers and received the Thomson Reuters Research Fronts Award in 2008 and the State Natural Science Award of China in 2009. He works in the fields of asymmetric catalysis, peptides chemistry, biology, and pharmaceutical sciences.

ACKNOWLEDGMENTS We are grateful for the grants from the National Natural Science Foundation of China (nos. 20932003, 21272102, 21202072, and 91213302), the Key National S&T Program “Major New Drug Development” of the Ministry of Science AB


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