1 Introduction
Since the 20th century, many organic synthetic chemists have made a lot of attempts to explore the [4 + 2] cycloaddition reaction. Finally, in 1924, Otto Diels (1876-1954) and his student Kurt Alder (1902-1958) accurately identified the reaction products of cyclopentadiene and quinone as compounds C1 and C2 (Figure 1). In their paper published in 1928, they prospected the importance of this discovery
[1,2][3]. Since then, this breakthrough reaction has been widely used in related fields, and has completely changed people's understanding of cycloaddition chemistry, becoming a major event in the field of organic synthesis. The two chemists (Diels and Alder) were awarded the Nobel Prize in Chemistry in 1950.
Nowadays, the [4 + 2] cycloaddition reaction between conjugated dienes and substituted olefins (dienophiles) is known as the Diels-Alder (D-a) reaction, which can efficiently obtain cyclohexene derivatives. Diels-Alder reactions are indispensable in organic synthesis and can be used to construct six-membered ring systems with high regioselectivity and stereoselectivity
[4⇓⇓⇓⇓⇓⇓⇓⇓~13]. At present, the basic concept of this reaction has been extended to other π systems, such as the use of carbonyl and imine to construct the corresponding heterocyclic system, the so-called hetero-Diels-Alder reaction
[14]. After more than 90 years of development, the understanding of steric and electronic effects has been greatly improved, and more types of reactions have been developed, including reverse D-A reactions, different D-A reactions and corresponding asymmetric reactions
[15,16].
The D-A reaction and its different related reactions play an important role in the total synthesis of natural products and biologically active complex molecules
[17]. For example, the total synthesis of natural products such as tetracyclic indoles, terpenoids, isoquinonucleosides, and even alkaloids
[18⇓⇓~21]. The transition state of the substrate in the D-A reaction is highly ordered and closely resembles the structure of the product. Enzyme-catalyzed [4 + 2] cycloaddition reactions are involved in many aspects of biosynthesis. Enzymes typically catalyze reactions by stabilizing the structure and charge of the transition state components. For most reactions undergoing this mode of catalysis, both the starting substrate and the product are structurally quite different from the transition state. Compared with the starting substrate and product, the transition state structure can be more tightly bound to the enzyme, thus realizing the catalysis of the enzyme on the D-a reaction. Therefore, enzymes designed to stabilize the transition state structure are expected to solve the problems of product inhibition and low conversion rate. In addition, it is also a very effective strategy to introduce torsional strain into the dienophile or diene component to increase the ground-state energy of the substrate and carry out the D-a reaction by reducing the activation energy of the whole reaction. Therefore, Diels-Alder's catalytic research has attracted wide attention of enzyme chemists.
At present, the catalysts of D-a reaction mainly include two categories: (1) natural biological enzymes, such as the protein of hydrolase family discovered by O 'Connor in the study of biosynthesis of vinblastine and related alkaloids, which can catalyze intramolecular [4 + 2] cyclization reaction and control its regioselectivity, thus generating products with different structures
[22,23]; (2) Non-enzymatic catalysts, such as Lewis acids, organic amines, metal-organic frameworks (MOFs) and transition metal (Au, Rh, Ru) catalysts, which have been widely developed and applied in recent years
[24][25][26⇓⇓⇓⇓⇓~32]. Although the specificity and catalytic efficiency of non-enzymatic catalysts are slightly lower than those of natural enzymatic catalysts, their catalytic efficiency can be improved by adding organic ligands, external electric field or light source, noble metal co-catalyst method, flow chemistry and other methods. In addition, efforts have been made to develop universal artificial catalysts with high catalytic activity for a series of substrates with similar structures. Based on the above research background, this paper reviews and summarizes the research and development of D-a reaction catalysts in recent years.
2 Natural enzyme catalysis
Natural enzymes in organisms are proteins composed of hundreds of amino acids. Enzymes in nature are often difficult to find and even more difficult to purify. Since the 21st century, enzymes that catalyze D-a reactions in biological metabolic processes have been discovered, such as LovB (scheme 2), phosphate synthase, riboflavin synthase
[33,34][35][36]. The stereochemical results of the relevant reactions indicate that the formation of the product can be directed by the enzyme in each case, but these enzymes usually exhibit more than one catalytic activity and, therefore, their specific effect on the cycloaddition reaction cannot be determined. In 2017, Liu Hongwen and others reviewed several natural enzymes that can independently catalyze D-A reactions, such as Sol5, VstJ, AbyU and so on
[37]. On this basis, this part will focus on several classical monofunctional or multifunctional natural enzymes of D-a reaction, as well as several natural enzymes discovered in the latest research, and compare the performance of natural enzymes from the effect of intramolecular or intermolecular D-a reaction.
2.1 Enzyme-catalyzed intramolecular D-a reaction
In 2011, Kim et al. Found the first natural enzyme that can be used alone to catalyze D-a reaction in vitro
[38]. In the total synthesis of spinosad, the 4, 7, 11 and 12 sites of C4 molecule provide the dienophile and conjugated diene structure required by D-a reaction, respectively (Figure 3). The SpnF enzyme is a small protein with significant sequence similarity to known O-methyltransferases. It was found that SpnM-catalyzed dehydration of C3 to C4, followed by SpnF-catalyzed cyclization of C4 to C5. Then, the hydroxyl group of the obtained tricyclic lactone C5 molecule is modified with a rhamnosyl group by SpnG enzyme. Finally, SpnL catalyzes the cross-coupling between olefin carbon atoms to obtain a tetracyclic core structure, thereby realizing two steps of the spinosad A reaction. Compared with the addition of SpnF in different reaction steps, it was found that SpnF could only specifically catalyze the C4 to C5 stages, and the kinetic analysis showed that SpnF specifically accelerated the formation of the ring, and the reaction rate was increased by about 500 times.
The discovery of SpnF provides a unique research idea for the enzyme-catalyzed [4 + 2] cycloaddition reaction and other Diels-Alder enzymes in nature. With the further study on the total synthesis of biomolecules, A series of monofunctional and multifunctional D-a enzymes have been found. Tian et al. reported PyrE3 and PyrI4 native enzymes that catalyze the D-A reaction in the biosynthesis of pyrrolomycin
[39]. As shown in Figure 4, it is found that both of them can only catalyze one step of the synthetic pathway. Starting from an intermediate containing two pairs of 1,3 diene and alkene groups, the cyclases PyrE3 and PyrI4 catalyze the formation of two cyclohexene rings in the dialkyldecalin system as well as the tetraester spiro-conjugated structure (C8, C9), respectively. Their analysis of the corresponding tetraester helical structure synthesis pathway confirmed that the homologs (ChIE3, ChIL) are functionally interchangeable, establishing the broad spectrum of these findings. At the same time, they speculated that this natural coevolution of protein and chemical structure may be inherent in enzymatic [4 + 2] cycloaddition reactions, and that many [4 + 2] cyclases with different structures but the same function are produced in biotransformation systems, which can be used to biosynthesize a variety of cyclohexene-containing natural products.
In studying the biosynthesis of vinblastine and its related alkaloids, Caputi et al. Found that proteins of a family of hydrolases can catalyze intramolecular [4 + 2] cyclization reactions and control regioselectivity to produce products of different structures
[40]. Molecules C11 and C12 were proved to be enzymatically formed by reductase (DPAS) and vinblastine synthase (CS) or vinblastine synthase (TS) in Catharanthus roseus to synthesize intermediate enamines (Scheme 5). In addition, the cyclases DPAS and CorS form C13 with the precursor molecule C10, which is structurally similar to the molecule C11 but has an opposite configuration as well as a lower oxidation state. These three cyclases have high amino acid identity, but their products are different, which provides a basis for exploring the selectivity of cycloaddition products.
In addition to the discovery of D-a enzymes in the biosynthetic macromolecular pathway, there are also key cycloaddition reactions in the synthesis of small molecular products with decalin structure. Tan et al. reported a series of native enzymes that catalyze the intramolecular D-A reaction (IMDA) during the formation of the decalin structure
[41]. They proposed a "carboxylation inactivation" strategy for the construction of antifungal agents in this biosynthetic pathway. The results show that the oxidoreductase activity can influence the course of the biosynthetic pathway of the D-A reaction (Scheme 6). The oxidation of the dienolate of molecule C14 to the dienol carboxylate C15 can significantly increase the protective barrier of the D-A reaction while effectively inhibiting the nonenzymatic reaction. The stereospecific PvhB activity was used to obtain the desired cis-decalin product. The discovery of PvhB further illustrates the functional diversity of lipocalcal-like D-a enzymes in fungi.
Biological macromolecular enzymes have structural diversity and functional group diversity, and the same natural enzyme can catalyze different types of reactions because of its multiple active sites. In 2017, Ohashi et al. discovered an S-adenosylmethionine-dependent multifunctional enzyme LepI in the study of biosynthesis of secondary metabolites of fungi, which can catalyze both D-A reaction and retro-Claisen rearrangement reaction
[42]. Compound C16 of Scheme 7 is an intermediate in the synthesis pathway, which can spontaneously dehydrate to form C17 and C19 in the absence of enzyme LepI, and further can spontaneously undergo intramolecular D-a reaction (IMDA) or hetero-D-a reaction (HDA). For example, under spontaneous conditions, the molecule C17 can undergo either an intramolecular D-a reaction to form the compound C18 or a hetero-D-a reaction to form the molecule C20. Under the catalysis of enzyme LepI, the compound C16 is specifically dehydrated to form C17,
Furthermore, the hetero-D-a reaction occurs to form the single product C20, which confirms that LepI is an enzyme that can catalyze the intramolecular hetero-D-a reaction. Further studies have shown that LepI can also convert C18 to C20, which is a retro-Claisen rearrangement reaction, and this is the first report of a natural enzyme that can catalyze retro-Claisen rearrangement.
2.2 Enzyme-catalyzed intermolecular D-a reaction
At present, although the enzymes that catalyze intramolecular D-a reactions have been studied to some extent, the enzymes that can catalyze intermolecular D-a reactions are very limited, only Macrophomate synthetase and riboflavin synthetase, as well as the newly discovered EupfF enzyme that catalyzes intermolecular oxa-D-a reactions by Hu Youcai of the Institute of Medicine
[43][44,45][46]. They found that the native enzyme EupfF, which catalyzes the intermolecular oxa-D-a reaction between C22 and C23, also catalyzes the oxidation of hydroxyl groups (Figure 8). These enzymes are all multifunctional Diels-Alder enzymes. With the further study of the reaction mechanism, it is found that some enzymes do not construct C-C bonds in natural products through the D-a reaction mechanism catalyzed cooperatively. Macrophomate synthetase is not an intermolecular D-a reaction enzyme, but an aldolase, which catalyzes the formation of two C-C bonds by stepwise Michael addition and aldol reaction
[47,48].
It has been more than 90 years since the initial discovery of D-a reaction, and there has been no "real" monofunctional Diels-Alder enzyme catalyzing D-a reaction between molecules in nature. Until 2020, Lei Xiaoguang and others at Peking University discovered the first truly monofunctional intermolecular Diels-Alder enzyme
[49]. They proposed a novel biosynthetic intermediate-based probe molecule, which first used molecules C24 and C25 as substrates to separate active targeting proteins, and then successfully enriched BBE-like protein family proteins in mulberry callus.The expression levels of MaMo and MaDA were the highest, and MaDA was proved to be the first monofunctional enzyme catalyzing intermolecular [4 + 2] cyclization reaction by controlling the experimental conditions (Figure 9). Subsequently, it was also confirmed that MaDA had good substrate compatibility with dienophiles and dienes, and the conversion rate of molecules C26 and C27 could reach more than 80%. This enzymatic synthesis shows high efficiency and stereochemical specificity, which is difficult to achieve by ordinary chemical methods, reflects the advantages and characteristics of MaDA in biocatalysis, and opens up a new research direction for the development of enzymatic synthesis methods to efficiently prepare functional organic molecules with diverse structures.
3 Non-enzymatic catalysis
3.1 Acid-catalyzed D-a reaction
3.1.1 Lewis acid
Lewis acid is also called electrophile. In the process of electron transfer in the cycloaddition reaction, the positive charge of the cation center can accelerate the transfer rate of the electron pair, thus catalyzing the reaction. To date, researchers have discovered various Lewis acids, ranging from simple Lewis acid halides (ZnCl
2, BF
3, SnCl
4, or AlCl
3) to chiral boron cations and ionic liquids, which have been successfully applied in the catalysis of D-A reactions
[50][51][52⇓~54].
In 2017, Matuszek et al. Reported the alkene-ester cycloaddition reaction of cyclopentadiene and ethyl acrylate using ionic liquids based on tridentate boron cations as Lewis acidic catalysts
[55]. As shown in fig. 10, the boron cation is a three-coordinate, strong Lewis acid species in which the acidity of the free p orbital of the boron is enhanced by a positive charge. A small amount of ionic liquid is dissolved in the reactant mixture, thereby avoiding the influence of the "solvent effect".
At very low catalyst concentrations (0.10 mol/mol), a good correlation between the intensity of Lewis acidity (AN value) and dienophile conversion was observed (Figure 1). When the catalyst loading was increased to 0. 20-0. 50 mol/mol, complete conversion was achieved within 5 min at 0 ℃, and the selectivity of endo: exo (endo/exo addition product) was always high, which was not affected by the AN value of the catalyst or the type of loading. Boron ionic liquids are active for a wide range of substrates, and they have been used as homogeneous Lewis acid catalysts for a variety of reactions, including boration, in aprotic organic solvents.
In 2020, Choi et al. Found that the intermolecular D-A reaction of 2-bromo-diene and N-phthalimidene could be catalyzed by simple titanium cation Lewis acid
[56]. By comparing the universality of the substrate, they found that the bromo substituent of the molecule C28 can be used as both a cycloaddition inducing group and a cross-coupling nuclear reagent, compared with previous studies.The additional steps required for the commonly used silyl enol ether and enol sulfonate are omitted, and the regioselectivity and stereoselectivity of the olefin are well controlled throughout the reaction (Scheme 11). As shown in Table 1, the titanium cation Lewis acid has a higher conversion rate compared to the common boron cation acid catalysis, and the product is a diastereomer with high purity.
3.1.2 Bronsted acid
The proton theory, proposed by Brønsted and Lowry in 1923, holds that any substance that gives a proton (H+) is an acid and any substance that accepts a proton (H+) is a base. The acid-base proton theory expands the meaning of acid and base and the scope of acid-base reaction.
In 2015, Min et al. Uniquely used chiral Bronsted acids to study cycloaddition reactions
[57]. The imine ions derived from 5-bromoindole and cinnamoxybenzaldehyde or other secondary aniline-type amines are devoid of acidic N-H protons, thus greatly reducing the possibility of forming a hydrogen-bonded stable ion pair with the catalyst anion, and this interaction plays an important role in the enantioselectivity of the product (Scheme 12). By comparison, it was found that the strong acid TFA, which can widely promote the apparent cycloaddition reaction of aryl imines and alkenes, had little activity for this reaction, while the Bronsted acid C29 could selectively catalyze the [4 + 2] cycloaddition reaction at a low content (0.025 mol/L), with high catalytic activity and enantioselectivity (Table 2). Interestingly, the most widely used chiral phosphoric acid catalyst (S) -TRIP (C30) has similar enantioselectivity for this reaction, but its activity is significantly lower than that of molecule C29. Bronsted acid molecules based on acid-base proton theory get rid of the limitation that acid-base must occur in water, which provides a new reference for the development of acid-base catalysts.
The definition of Bronsted acid covers a wide range, and there have been more mature studies in the catalysis of D-a reaction. In terms of multi-substrate screening methods, catalysts have not previously been found to be well suited because of the kinetic competition between substrate and product, which can complicate the analysis. In 2019, Kim et al. Identified an efficient and stereoselective imidazole diphosphate organocatalyst for the scalable D-A reaction of cyclopentadiene with different classes of vinylidene and unsaturated aldehydes by using the method of multi-substrate screening
[58].
As shown in Fig. 13, IDPI is Bronsted acid molecule, which has high catalytic activity and stereoselectivity for the asymmetric D-A reaction between unsaturated aldehydes with diverse structures and cyclopentadiene, and the yield of some highly enantioselective products (C31 ~ C34) reaches more than 92%, which provides reference for the development of other broad-spectrum catalysts.
3.2 Amine catalyzed D-a reaction
The amine nitrogen has a lone pair of electrons and can be used as a nucleophile to participate in organic reactions. Evidence has been provided that enamine intermediates formed in situ between amine catalysts and enolizable aliphatic aldehydes can act as electron-rich dienophiles in partial D-A reactions that are often highly chemoselective, regioselective, and stereoselective
[59].
Melchiorre et al. Have made important progress in the development of trienamine catalysts
[60]. They found that trienamine precursors could be formed with α, β-unsaturated aldehydes using organic amines, overcoming the high energy barrier effect of the dearomatization reaction. Subsequently, the precursor was subjected to highly stereoselective D-A reaction with nitroalkenes (Figure 14), resulting in the synthesis of chiral indole derivatives with complex structures, showing high selectivity.
In 2020, Charles et al. Developed a novel 3,5-bis (trifluoromethyl) phenyl variant secondary amine catalyst molecule and applied it to the D-a reaction of pyrones with α, β-unsaturated aldehydes
[61]. Most reactions involving unsaturated aldehydes usually require a catalyst loading of about 20 mol/mol to maintain high product selectivity, while the new secondary amine catalyst requires only 5 mol/mol to increase the yield of some products to more than 90% (Scheme 15). The discovery of low loading amine molecular catalyst has important reference significance for the development of organic amine catalyst for this kind of reaction.
3.3 D-a Reaction Based on Transition Metal Catalysis
3.3.1 Complexes of transition metal with ligand
Transition metals have d orbital electrons or empty d orbitals, which can provide empty orbitals as electrophiles or lone pair electrons as nucleophiles in chemical reactions to form intermediate products and reduce the activation energy of the reaction, thus promoting the reaction. The D-a reaction catalyzed by transition metal is usually catalyzed by the complex formed by transition metal and ligand.Uch as Pd(PPh)
2Cl
2, Pd(PPh
3)
4, Rh(PPh
3)
3Cl, Ni(CO)
4,H
2PtCl
6, HCo(CO)
4 and the like can be used as specific catalysts
[62⇓~64].
In 2016, McGee et al. developed a new approach to form angular carbocyclic products through gold (I) -catalyzed dehydrogenation D-A reaction, and screened six different chiral ligands (C35-C40) for the intramolecular [4 + 2] cycloaddition reaction of enol ethers in the total synthesis reaction of (±) Magellan base (Figure 16)
[65]. As shown in Table 3, each reaction product has only one enantiomer under the synergistic catalysis of six ligand molecules. The catalytic system has excellent diastereoselectivity and high yield, and is 7 steps shorter than the traditional total synthesis method.
In 2018, Liu et al. Realized different cross-couplings in Mn (I) -catalyzed C-H activation of indoles and C-C coupling of enynes
[66]. In the presence of the Zn(OAc)
2/PivOH additive, the reaction proceeds through a series of C--H olefination, intramolecular D-a, and elimination aromatization (Scheme 17A) to yield the fused phenol (C41) as the major product. In the process of the intramolecular D-a reaction, the olefination reaction is firstly carried out, and then the alcohol group is eliminated, so that the fused six-membered ring is generated. In previous studies, they relied on the polarizable nature of the M — C bond (high-valent M (III) — C bond (M = Co, Rh, and Ir)), the nucleophilic carbon atom and the Lewis acid are integrated in the same system, and their effective interaction with the coupling agent can easily form a cycloadduct (Scheme 17b)
[67⇓⇓~70]. In contrast, the Mn-catalyzed C-H activation of indoles and the functionalization of acetylenic cyclohexanediones follow different selectivities due to the high nucleophilicity and unique reactivity of organomanganese complexes, and their selectivities remain complementary to those of Rh and Co catalytic systems. Due to the structural diversity and controlled synthesis of indole derivatives, these cascaded cyclic systems will find more applications in the synthesis of diverse complex molecules.
3.3.2 Metal-organic framework (MOF)
MOF materials based on transition metals are a new type of porous crystalline materials, which are formed by metal ions or metal clusters and multidentate organic ligands through coordination bonds. In 2019, Zhao et al. successfully constructed MOF materials based on corrole for the first time, and studied the application of iron-core corrole MOF materials in heterogeneous catalytic D-A reactions
[71].
As shown in Figure 2, the MOF material is based on the geometric configuration of the corrole monomer, and metal zirconium and hafnium clusters are selected as the secondary structural units for constructing the MOF. Since the zirconium cluster has a variety of topological structures, it can be connected with a variety of polydentate carboxylic acid ligands to form MOF materials with different numbers of units. Subsequently, iron cations were introduced into the MOF material to form stable complexes, and the D-a reaction of aldehydes and 1,3-butadienes was carried out. The results show that the iron cation-MOF material has catalytic ability for multiple substrates, and has higher product yield compared with other complex catalysts of iron cation (Figure 18).
3.3.3 Transition metal complex photosensitizer
Transition metal-based catalyst composites come in a variety of forms, among which the combination of the light-induced method and the transition metal can establish an advantageous catalytic system (Scheme 19)
[72].
In 2019, Ma et al. Found the [4 + 2] cycloaddition reaction of dearomatization promoted by energy transfer of pyridine
[73]. The ground-state alkene is first promoted to the corresponding triplet excited state, and the metal iridium-based photocatalyst performs efficient dearomatic cycloaddition of the high-energy intermediate to produce the isoquinoline nucleoside analog (Scheme 20). Upon irradiation with LED blue light in the presence of a heterogeneous photocatalyst [Ir-F] @ polymer (1.5 mol/mol), N-cinnamoylpyridinecarboxamide C43 was completely converted to the dearomatic [4 + 2] cycloaddition product C44 in 99% yield. At the same time, no [2 + 2] or [3 + 2] cycloaddition products were detected in the system, showing the perfect regioselectivity of the catalyst. In addition, the reaction showed high tolerance to reaction conditions, and the yield was not reduced in different solvents or by reducing the catalyst loading (0.75 mol/mol). The energy transfer process is realized by a recyclable polymer-immobilized iridium-based photocatalyst, and this work demonstrates the contribution of visible-light catalysis to the realization of challenging thermo-organic transformations.
3.4 Photocatalytic D-a reaction
Photoinduced organic synthesis plays a special role in organic synthesis, especially in the synthesis of some common structures, which can greatly shorten the steps of traditional synthetic chemistry. Photocatalysis has the characteristics of mild reaction conditions, which avoids the shortcomings of side reactions caused by harsh reaction conditions in traditional organic synthesis, and can solve the environmental and energy problems brought by the synthesis process to a certain extent.
In 2019, Houck et al. introduced photostable dynamic materials and used the photoinduced D-A reaction between triazolinedione (TAD) and naphthalene ring as the dynamic covalent crosslinking platform to form green-induced covalent crosslinking polymer materials, and the crosslinked materials collapsed spontaneously in the dark at room temperature
[74]. The universality comparison of naphthalene rings with different substituents and different substitution sites shows that different substituents or substitution sites will greatly affect the addition of TAD (scheme 21,C
A represents substituted aromatic rings,C
B represents a cycloaddition on an unsubstituted aromatic ring), the product is more likely to form a substituted aromatic ring adduct when the substituent is a methylene group and is located at point 2, and the product is more likely to form an unsubstituted aromatic ring adduct when the substituent is an ester group and is located at point 2. This was followed by a comparison of the ring reduction rates at points 1 and 2, which revealed that the addition of TAD to the unsubstituted naphthalene ring would lead to a faster dissociation of the corresponding cycloadduct. The decrease in individual regioisomer content over time suggests that the pathway to accelerate spontaneous ring dissociation in the dark requires only a change in the electronic environment of the naphthalene from a methylene substitution to an electron-withdrawing ester group. The introduction of dynamic covalent crosslinking into the application field of photoorientation provides a reference for green and mild control of polymer materials.
In 2020, Feist et al. Discovered a way to use electron-deficient alkynes as dienophiles to form 1,4-dihydro-1-naphthalene
[75]. The cycloaddition intermediate naphthol does not absorb in the excitation wavelength range corresponding to o-MBA (o-methylbenzaldehyde, C49). After the completion of the photoinduced cycloaddition reaction at 385 nm, the fluorophilic naphthalene can be rapidly generated by adding a catalytic amount of acid (Scheme 22). The results showed that the photoreaction was not interfered by the competitive absorption of the substrate, and it was easy to follow the reaction through the fluorescence spectrum because of the controllability of the fluorophore.
3.5 Electrocatalytic D-a reaction
Electrocatalysis is generally considered to control the reaction rate by applying a potential gradient, and its ability is unique to redox systems. However, a theoretical study by Aragon Aragonès et al. In 2016 showed that the directional electric field can affect the results of a series of chemical reactions, regardless of whether the redox system is involved
[76]. Inspired by the theoretical prediction of Shaik et al., the barrier height of some D-a reactions can be greatly reduced in the presence of an appropriate directional electric field
[77]. They used a furan derivative immobilized on a substrate as a conjugated diene and a rigid terminal double bond as a nonpolar dienophile (NB). When assembled on a flat gold surface, the presence of a methylenethiol group maintained the definite orientation of the terminal double bond (dienophile). When the diene molecules in the system are close together, the rigidity of the NB helps to position and align the dienophile with respect to the direction of the electric field (fig. 23). Based on single-molecule conductance measurements with a scanning tunneling microscope (STM), the results show that the frequency of single-molecule junction formation during the reaction increases by a factor of 5 when the electric field is present and aligned to facilitate electron flow from the dienophile to the diene. That is to say, when the applied electric field can make these small charges arrange in an electrostatic stable way, the resonance degree of the system increases, which leads to the overall stable existence of molecules or transition States.
Most electrocatalytically activated D-a reactions are processes in which the reaction system is immobilized on the micelle or gel to accelerate the charge transfer at the electrode or electrolyte interface. Hydrophobic hydroquinone can hardly be oxidized in the micellar system when the reaction system is immobilized in silica gel. However, when Ce
2(SO
4)
3(0.02 equivalent) was added to the electrolytic system, the selective oxidation of hydroquinone occurred in the subsequent diene cycloaddition reaction
[78]. Cerium (IV) ions are sufficiently generated on the electrode so that the oxidation of the hydrophobic hydroquinone should occur at the interface of the SDS micelles (fig. 24). The hydrophobic environment provided by cerium oxide in SDS micelles enables benzoquinone to form the corresponding cycloadducts in high yields.
Many formally covalent species can be stabilized by smaller charge-separated resonance contributors. When the applied electric field is aligned in an electrostatically stable manner, it may result in overall stabilization of the molecule or transition state. This ability to manipulate chemical reactions using electric fields provides a theoretical reference for changing the methods of heterogeneous catalysis.
4 Conclusion and prospect
In recent years, the catalysis of D-a reaction has been developed rapidly. A series of natural biological enzymes (SpnF, LepI, MaDA) and non-enzymatic catalysts (Lewis acid, Bronsted acid, transition metal, external electric field, etc.) Have been used to catalyze D-a reaction, and good results have been achieved. In the aspect of enzyme catalyzed D-a reaction, macromolecular protein natural enzymes have high specificity and show great potential in the synthesis of complex products. Non-enzymatic catalysts are mostly Lewis acids, transition metal-ligand complexes and so on, which have a wide range of applications. However, the catalytic efficiency and stereoregioselectivity of D-a still need to be further improved. Different types of D-a reactions have different requirements for the ground state energy of the substrate electron, and the direction of electron transfer can not be completely controlled at present. Therefore, exploring new natural enzymes, developing new non-enzymatic catalysts, improving the conversion rate of catalysts, realizing the recycling of catalysts, broadening the scope of substrates, improving the stereoselectivity of products and industrial synthesis of important target molecules are still many challenges in the development of D-a reaction catalysts.
National Natural Science Foundation of China(21807083)
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