Absolute Asymmetric Synthesis Involving Chiral Symmetry Breaking in Diels–Alder Reaction Absolute Asymmetric Synthesis Involving Chiral Symmetry Breaking in Diels–Alder Reaction

: E ﬃ cient generation and ampliﬁcation of chirality from prochiral substrates in the Diels–Alder reaction (DA reaction) followed by dynamic crystallization were achieved without using an external chiral source. Since the DA reaction of 2-methylfuran and various maleimides proceeds reversibly, an exo -adduct was obtained as the main product as the reaction proceeded. From single crystal X-ray structure analysis, it was found that ﬁve of ten exo -adducts gave conglomerates. When 2-methylfuran and various maleimides with a catalytic amount of TFA were reacted in a sealed tube, the exo -DA adducts were precipitated from the solution, while the reaction mixtures were continuously ground and stirred using glass beads. Deracemization occurred and chiral ampliﬁcation was observed for four of the substrates. Each ﬁnal enantiomeric purity was inﬂuenced by the crystal structure, and when enantiomers were included in the disorder, they reached an enantiomeric purity reﬂecting the ratio of the disorder. The ﬁnal ee value of the 3,5-dimethylphenyl derivative after chiral ampliﬁcation was 98% ee. Abstract: Efficient generation and amplification of chirality from prochiral substrates in the Diels– Alder reaction (DA reaction) followed by dynamic crystallization were achieved without using an external chiral source. Since the DA reaction of 2 ‐ methylfuran and various maleimides proceeds reversibly, an exo ‐ adduct was obtained as the main product as the reaction proceeded. From single crystal X ‐ ray structure analysis, it was found that five of ten exo ‐ adducts gave conglomerates. When 2 ‐ methylfuran and various maleimides with a catalytic amount of TFA were reacted in a sealed tube, the exo ‐ DA adducts were precipitated from the solution, while the reaction mixtures were continuously ground and stirred using glass beads. Deracemization occurred and chiral amplification was observed for four of the substrates. Each final enantiomeric purity was influenced by the crystal structure, and when enantiomers were included in the disorder, they reached an enantiomeric purity reflecting the ratio of the disorder. The final ee value of the 3,5 ‐ dimethylphenyl derivative after chiral amplification was 98% ee.


Introduction
The Diels-Alder (DA) reaction is one of the most important and fundamental organic synthesis reactions, achieving the concerted [4 + 2] cycloaddition of a diene and an alkene [1,2]. Because it can form two C-C single bonds in one step, it is used to create many cyclic compounds including polycyclic compounds (Figure 1) [3−10]. In addition, a number of asymmetric reactions have been reported, since these can theoretically construct four asymmetric centers at once. Excellent catalytic asymmetric synthesis [11−20] and diastereoselective reactions of chiral substrates have also been reported [21−24]. Each of these reactions is an asymmetric induction method using an enantiomerically active catalyst or substrate and constructs a diastereoselective environment in the transition state of the reaction.  In contrast to reactions using chiral sources as starting materials and catalysts, asymmetric synthesis using chirality that occurs naturally when organic compounds crystallize has been reported in recent years ( Figure 2) [25]. In this method, a compound having a chiral center is generated from a prochiral substrate, and a dynamic preferential crystallization accompanied by the racemization of the generated chiral center is performed continuously without using any external asymmetric source. It is possible to obtain a crystal of the product having a high enantiomeric purity. The racemization process of the product includes a reaction that regenerates a prochiral starting material via a reverse reaction or a process via a direct racemization reaction of an asymmetric center.
Symmetry 2020, 12, x FOR PEER REVIEW 2 of 15 In contrast to reactions using chiral sources as starting materials and catalysts, asymmetric synthesis using chirality that occurs naturally when organic compounds crystallize has been reported in recent years ( Figure 2) [25]. In this method, a compound having a chiral center is generated from a prochiral substrate, and a dynamic preferential crystallization accompanied by the racemization of the generated chiral center is performed continuously without using any external asymmetric source. It is possible to obtain a crystal of the product having a high enantiomeric purity. The racemization process of the product includes a reaction that regenerates a prochiral starting material via a reverse reaction or a process via a direct racemization reaction of an asymmetric center. These synthetic reactions are absolute asymmetric syntheses that provide enantiomerically active compounds from prochiral substrates without using an external chiral source; this is a phenomenon that is of wide interest to researchers in many academic fields [26−30]. Successful absolute asymmetric synthesis by fusion of the reaction that forms the chiral center from prochiral starting materials and the subsequent dynamic crystallization process have been reported in several reaction systems. For example, the Mannich-type reaction [31], aldol reaction [32], stereoisomerization of succinimide [25], synthesis of isoindolinone [33], aza-Michael addition [34−36], Strecker reaction [37,38], and a photochemical reaction [39,40] have all been achieved under achiral conditions. In these limited examples, crystals with high ee were obtained from prochiral materials, and this method is expected to be applied to many reaction systems.
We recently reported the asymmetric Diels-Alder reaction of prochiral starting materials leading to a conglomerate crystal of the adduct in enantiomerically active form [41]. When 2-methylfuran and N-phenylmaleimide were reacted with a small amount of solvent and a catalytic amount of trifluoroacetic acid in a sealed tube at 80 °C, the racemic exo-adduct quickly precipitated. Subsequently, the continuous suspension of the reaction mixture with glass beads promoted the chiral amplification to 90% ee by attrition-enhanced deracemization ( Figure 3). In this phenomenon, a racemic product having a chiral center is first formed by a DA reaction from a prochiral substance, followed by preferential crystallization of conglomerate crystals. In the mother liquor, by returning to the prochiral substrate by the reverse reaction (retro-DA reaction), the racemic condition is always maintained, preventing the excessive formation of the enantiomer. These synthetic reactions are absolute asymmetric syntheses that provide enantiomerically active compounds from prochiral substrates without using an external chiral source; this is a phenomenon that is of wide interest to researchers in many academic fields [26][27][28][29][30]. Successful absolute asymmetric synthesis by fusion of the reaction that forms the chiral center from prochiral starting materials and the subsequent dynamic crystallization process have been reported in several reaction systems. For example, the Mannich-type reaction [31], aldol reaction [32], stereoisomerization of succinimide [25], synthesis of isoindolinone [33], aza-Michael addition [34][35][36], Strecker reaction [37,38], and a photochemical reaction [39,40] have all been achieved under achiral conditions. In these limited examples, crystals with high ee were obtained from prochiral materials, and this method is expected to be applied to many reaction systems.
We recently reported the asymmetric Diels-Alder reaction of prochiral starting materials leading to a conglomerate crystal of the adduct in enantiomerically active form [41]. When 2-methylfuran and N-phenylmaleimide were reacted with a small amount of solvent and a catalytic amount of trifluoroacetic acid in a sealed tube at 80 • C, the racemic exo-adduct quickly precipitated. Subsequently, the continuous suspension of the reaction mixture with glass beads promoted the chiral amplification to 90% ee by attrition-enhanced deracemization ( Figure 3). In this phenomenon, a racemic product having a chiral center is first formed by a DA reaction from a prochiral substance, followed by preferential crystallization of conglomerate crystals. In the mother liquor, by returning to the prochiral substrate by the reverse reaction (retro-DA reaction), the racemic condition is always maintained, preventing the excessive formation of the enantiomer.
In this asymmetric amplification by dynamic crystallization, attrition-enhanced deracemization was quite effective in promoting Viedam ripening by continuous grinding of the crystals using glass beads, and finally, the enantiomer crystals converged to high enantiomeric purity [42]. This technique was followed in the deracemization reaction from a racemic mixture of NaClO 3 and has recently been applied to deracemization of conglomerate crystals of organic compounds such as amino acids and pharmaceutical and agricultural chemical intermediates [43][44][45][46][47][48][49][50][51][52][53][54]. A key feature of this technique is that it can be applied to deracemization in a system with a relatively low racemization rate, as compared with the method of promoting crystallization using a solvent evaporation method or a temperature gradient [55][56][57][58]. In this asymmetric amplification by dynamic crystallization, attrition-enhanced deracemization was quite effective in promoting Viedam ripening by continuous grinding of the crystals using glass beads, and finally, the enantiomer crystals converged to high enantiomeric purity [42]. This technique was followed in the deracemization reaction from a racemic mixture of NaClO3 and has recently been applied to deracemization of conglomerate crystals of organic compounds such as amino acids and pharmaceutical and agricultural chemical intermediates [43−54]. A key feature of this technique is that it can be applied to deracemization in a system with a relatively low racemization rate, as compared with the method of promoting crystallization using a solvent evaporation method or a temperature gradient [55−58].
The bottleneck of deracemization by the dynamic crystallization method is whether or not the target substrate crystallizes as a stable conglomerate. The occurrence of racemic mixtures crystallizing as a conglomerate is approximately 5-10% [59−62]. However, some substrates form conglomerates or chiral crystals at a very high rate due to the effects of molecular shapes and intermolecular interactions. We succeeded in the asymmetric DA reaction utilizing the fact that the DA adduct of 2-methylfuran and N-phenylmaleimide was a conglomerate [41]. However, to investigate the generality of this methodology, we synthesized and analyzed a variety of DA adducts with various substituents on the nitrogen atom ( Figure 4).
Analysis of the crystal structures of the adducts revealed that they exhibited a very high probability of affording conglomerates. For these substrates, we achieved an asymmetric DA reaction without using an external chiral source and clarified the relationship between the crystal structure and the enantiomeric purity of the products.

Results and Discussion
In order to investigate the effect of the substituent on the nitrogen atom of the DA adduct on the The bottleneck of deracemization by the dynamic crystallization method is whether or not the target substrate crystallizes as a stable conglomerate. The occurrence of racemic mixtures crystallizing as a conglomerate is approximately 5-10% [59][60][61][62]. However, some substrates form conglomerates or chiral crystals at a very high rate due to the effects of molecular shapes and intermolecular interactions. We succeeded in the asymmetric DA reaction utilizing the fact that the DA adduct of 2-methylfuran and N-phenylmaleimide was a conglomerate [41]. However, to investigate the generality of this methodology, we synthesized and analyzed a variety of DA adducts with various substituents on the nitrogen atom ( Figure 4). In this asymmetric amplification by dynamic crystallization, attrition-enhanced deracemization was quite effective in promoting Viedam ripening by continuous grinding of the crystals using glass beads, and finally, the enantiomer crystals converged to high enantiomeric purity [42]. This technique was followed in the deracemization reaction from a racemic mixture of NaClO3 and has recently been applied to deracemization of conglomerate crystals of organic compounds such as amino acids and pharmaceutical and agricultural chemical intermediates [43−54]. A key feature of this technique is that it can be applied to deracemization in a system with a relatively low racemization rate, as compared with the method of promoting crystallization using a solvent evaporation method or a temperature gradient [55−58].
The bottleneck of deracemization by the dynamic crystallization method is whether or not the target substrate crystallizes as a stable conglomerate. The occurrence of racemic mixtures crystallizing as a conglomerate is approximately 5-10% [59−62]. However, some substrates form conglomerates or chiral crystals at a very high rate due to the effects of molecular shapes and intermolecular interactions. We succeeded in the asymmetric DA reaction utilizing the fact that the DA adduct of 2-methylfuran and N-phenylmaleimide was a conglomerate [41]. However, to investigate the generality of this methodology, we synthesized and analyzed a variety of DA adducts with various substituents on the nitrogen atom ( Figure 4).
Analysis of the crystal structures of the adducts revealed that they exhibited a very high probability of affording conglomerates. For these substrates, we achieved an asymmetric DA reaction without using an external chiral source and clarified the relationship between the crystal structure and the enantiomeric purity of the products.

Results and Discussion
In order to investigate the effect of the substituent on the nitrogen atom of the DA adduct on the crystal structure and the enantiomeric purity of the crystal in dynamic crystallization, the adducts exo-3b-j were synthesized by changing the substituent as shown in Table 1. Analysis of the crystal structures of the adducts revealed that they exhibited a very high probability of affording conglomerates. For these substrates, we achieved an asymmetric DA reaction without using an external chiral source and clarified the relationship between the crystal structure and the enantiomeric purity of the products.

Results and Discussion
In order to investigate the effect of the substituent on the nitrogen atom of the DA adduct on the crystal structure and the enantiomeric purity of the crystal in dynamic crystallization, the adducts exo-3b-j were synthesized by changing the substituent as shown in Table 1. In the DA reaction between 2-methylfuran 1 and maleimides 2b-j, the formation of endo-isomers was confirmed at the beginning of the reaction as in the case of the reaction with 2a [41]. When the reaction time was extended, the products predominantly converged to exo-isomers, because the crystalline exo-adducts were excluded from the reaction system in solution. Therefore, the crystals of the exo-adducts were analyzed by single crystal X-ray structure analysis. When the racemate of each exo-isomer was recrystallized, single crystals suitable for crystal structure analysis were obtained for exo-3b-g. The crystal space groups of these seven types of crystals are shown in Table 1. All of them had 2 1 helices in the crystal lattices. The space group of 3a-3c and 3e was the orthorhombic P2 1 2 1 2 1 , and 3d and 3f-g were in the monoclinic space group. Surprisingly, five of the ten synthesized substrates, 3a-3e, formed conglomerates of a chiral crystal space group.
In all cases, interactions such as CH-π, C=O-HC and O-HC with relatively small energies were present, which controlled the molecular arrangement (Figures S1-S8). These molecules had nearly spherical shapes and were closely packed in the crystal. Even when alcohol or benzene-based solvents were used, solvent molecules were not incorporated into the crystals.
For 3h-j, single crystals suitable for X-ray crystallography could not be obtained, thus the detailed molecular arrangements were unknown. However, the second harmonic generation (SHG) of these crystals was inactive by irradiation with 1064 nm light from an Nd-YAG pulsed laser, indicating that they might be racemic crystals [63,64]. However, if the emission of the SHG is weak, the possibility of a conglomerate may have been overlooked.
For asymmetric synthesis by the proposed method, the product crystals must be conglomerates. For the four new substrates 3b-3e determined to be in a chiral crystal space group from the above crystal structure analysis, we investigated the absolute asymmetric DA reaction via asymmetric amplification by crystallization.
Another requisite for chiral amplification by dynamic crystallization is rapid racemization under crystallization conditions. Adducts 3 have four chiral centers determined uniquely in the one-step concerted reaction and these cannot directly racemize. However, apparent racemization occurs due to the equilibrium reaction with a reverse DA reaction to regenerate achiral furan and maleimide [65] ( Figure 5).
Utilizing this reversible DA reaction, a deracemization reaction by dynamic crystallization was developed. Many dynamic crystallization methods require rapid racemization under crystallization conditions. However, attrition-enhanced deracemization, which is a method based on crystal grinding, has been reported in many successful cases even in systems with a low racemization rate compared to dynamic preferential crystallization methods using a temperature gradient or solvent evaporation [55][56][57][58]. However, fast deracemization under the racemization conditions suppresses side reactions, and crystals with high enantiomeric purity can be obtained efficiently. In the case of the asymmetric synthesis of exo-3a, we already found out that trifluoroacetic acid (TFA) was the best catalyst for both of the forward and reverse reactions. NMR spectroscopy was used to follow the reversible reaction at 60 °C in deuterated chloroform. Even when the substituents were changed, the catalytic activity of TFA was effective, and the reaction rate was improved in both the DA and retro-DA reversible reactions without side reactions. Table 2 shows the half-life of each substrate. For 1a, as reported in a previous paper, the addition reaction of maleimide reached 50% in about 1 hour (Table 2), and an endo-adduct was formed at the initial stage of the reaction, which eventually converged to an exo-adduct over time [41]. In other cases, almost the same courses in the reactions were observed ( Figure S9−S11). The change with time, in these cases, is a reaction in a homogeneous system, but the actual reaction is performed at a higher concentration, where the highly crystalline exo-adduct is crystallized and removed from the reaction system. The reaction in the NMR tube was also examined for the reverse reaction. The degradation of exo-3 at low concentration (0.05 M) in deuterated chloroform at 60 °C was followed. Maleimide 2 and methylfuran 1 were quantitatively regenerated in all cases. In order to perform highly efficient deracemization, it was necessary to accelerate both the forward and reverse reactions. Specifically, it was necessary to search for a catalyst that greatly accelerated the reverse reaction. In the case of the asymmetric synthesis of exo-3a, we already found out that trifluoroacetic acid (TFA) was the best catalyst for both of the forward and reverse reactions. NMR spectroscopy was used to follow the reversible reaction at 60 • C in deuterated chloroform. Even when the substituents were changed, the catalytic activity of TFA was effective, and the reaction rate was improved in both the DA and retro-DA reversible reactions without side reactions. Table 2 shows the half-life of each substrate. For 1a, as reported in a previous paper, the addition reaction of maleimide reached 50% in about 1 h (Table 2), and an endo-adduct was formed at the initial stage of the reaction, which eventually converged to an exo-adduct over time [41]. In other cases, almost the same courses in the reactions were observed (Figures S9-S11). The change with time, in these cases, is a reaction in a homogeneous system, but the actual reaction is performed at a higher concentration, where the highly crystalline exo-adduct is crystallized and removed from the reaction system. The reaction in the NMR tube was also examined for the reverse reaction. The degradation of exo-3 at low concentration (0.05 M) in deuterated chloroform at 60 • C was followed. Maleimide 2 and methylfuran 1 were quantitatively regenerated in all cases. In order to perform highly efficient deracemization, it was necessary to accelerate both the forward and reverse reactions. Specifically, it was necessary to search for a catalyst that greatly accelerated the reverse reaction.
When various maleimides 2a-d were reacted with 2-methylfuran in the presence of TFA, the DA reaction was accelerated about 4 times for most substrates. Regarding the reverse reaction, it was found that when exo-3a-d were reacted with TFA in the same concentration of 0.03 M, the reaction was accelerated by 1.5 to 2 times compared to the reaction without TFA ( Table 2, Figures S9-S11). Table 2 shows the results at 60 • C, but the actual reaction can be run at 80 • C, whereupon the rate is expected to be several times faster, and a sufficient reversible reaction rate is ensured.
Once the formation of conglomerates and the progress of racemization were confirmed, the asymmetric synthesis involving the dynamic crystallization process was examined. In a sealed tube, N-arylmaleimide 2 (100 mg), 2-methylfuran 1 (15.0 equiv), TFA (0-1.0 equiv) as the catalyst, heptane (1.0 mL) as a solvent, and glass beads (2 mmΦ, 250 mg) were added to crush the crystals and the mixture was stirred at 80 • C for several days. The DA reaction proceeded immediately after the start of the reaction, and within a few minutes, crystals of the adducts precipitated and the reaction solution was suspended. After that, deracemization occurred by continuously stirring the obtained suspension. The change in ee value of exo-3 by deracemization was monitored by HPLC using a CHIRALPAK IA (Daicel Ind.) column.
In our previous paper, when 0.5 equiv of TFA was used, the enantiomeric purity started to increase after six days from the start of the reaction and reached 90% ee after 14 days ( Figure 6) [41]. Thereafter, the suspension was filtered to isolate the crystals, and exo-3a was obtained with a yield of 80% and 90% ee. The plot of enantiomeric purity versus time showed a non-linear curve. This sigmoid-like increase in enantiomeric purity is typical for Viedma ripening, and the population balance model [66,67] and existing formulas were extended in view of the effects of Ostwald ripening and autocatalytic enantioselective crystal growth. Theoretical analysis by fitting [68,69] has also been performed. On the other hand, when no glass beads were used, deracemization did not occur.   When 2b was used, crystals of DA adduct were precipitated immediately after the reaction, and the continuous stirring while suspending the solids led to an increase in the enantiomeric purity of exo-3b from the 7th day, reaching 40% ee after 15 days. However, no further asymmetric amplification occurred. This is attributable to the crystal structure of exo-3b. Disordered packing was indicated by single-crystal structure analysis, and the ratio of the enantiomers was 73:27, a result that exactly reflected the ee value of the converged enantiomorphic crystals.
In the case of 2c, the crystallinity of the produced exo-3c was also good, and a stable suspension by glass beads and the stir bar was obtained. The ee value of exo-3c increased after 3 days and reached 98% after 9 days, achieving the most efficient asymmetric amplification among all the substrates.
When 2d was used, immediately after the reaction, crystals were precipitated, a suspension was obtained, and asymmetric amplification started 4 days later. Eight days later, the ee reached 49%, after which further amplification did not occur. The reason for this limitation is that, similar to the case of exo-3b, due to the crystal packing of exo-3d, the enantiomer contained in the single crystal is Based on the results of the asymmetric reaction of 2a to exo-3a, asymmetric DA reactions for 2b-2e with 1 were also examined leading to conglomerates exo-3b-3e. As in the case of the reaction of 2a, 2-methylfuran 1, various N-arylmaleimides 2b-2e, 0.5 equiv of TFA as a catalyst for promoting racemization, heptane as a solvent, and glass beads for grinding the precipitated solids were stirred in a sealed tube at 80 • C for several days while tracking the change of the ee value of the solid exo-3 (Table 3 and Figure 6). Table 3. Asymmetric DA reaction of 3a-d [a] .
[c] Yields of crystalline 3 after filtration. [ When 2b was used, crystals of DA adduct were precipitated immediately after the reaction, and the continuous stirring while suspending the solids led to an increase in the enantiomeric purity of exo-3b from the 7th day, reaching 40% ee after 15 days. However, no further asymmetric amplification occurred. This is attributable to the crystal structure of exo-3b. Disordered packing was indicated by single-crystal structure analysis, and the ratio of the enantiomers was 73:27, a result that exactly reflected the ee value of the converged enantiomorphic crystals.
In the case of 2c, the crystallinity of the produced exo-3c was also good, and a stable suspension by glass beads and the stir bar was obtained. The ee value of exo-3c increased after 3 days and reached 98% after 9 days, achieving the most efficient asymmetric amplification among all the substrates.
When 2d was used, immediately after the reaction, crystals were precipitated, a suspension was obtained, and asymmetric amplification started 4 days later. Eight days later, the ee reached 49%, after which further amplification did not occur. The reason for this limitation is that, similar to the case of exo-3b, due to the crystal packing of exo-3d, the enantiomer contained in the single crystal is disordered in a ratio of 74:24, which exactly reflected the maximum ee value of exo-3d.
The asymmetric synthesis of exo-3e using maleimide 2e was also examined, but exo-3e was obtained as a racemate without asymmetric amplification. The powdered X-ray crystal structure analysis of the obtained solid was different from the analysis pattern simulated from the conglomerate crystal P2 1 2 1 2 1 (Figure 7). Conglomerate crystals of exo-3e gradually changed to a racemic crystal system during suspension with glass beads. The crystal does not contain a crystallization solvent and it showed a polymorphism with a phase transition.  It was unable to control the handedness of the crystals obtained after the DA reaction; solids of both types of handedness were obtained in approximately the same number of times for every ten experiments. However, we were able to control the handedness by starting the attrition-enhanced deracemization from a DA adduct with low ee (5% ee). The deracemization started immediately and the same handedness of the enantiomer as the slightly excess stereoisomer could be efficiently obtained. It was unable to control the handedness of the crystals obtained after the DA reaction; solids of both types of handedness were obtained in approximately the same number of times for every ten experiments. However, we were able to control the handedness by starting the attrition-enhanced deracemization from a DA adduct with low ee (5% ee). The deracemization started immediately and the same handedness of the enantiomer as the slightly excess stereoisomer could be efficiently obtained.

Conclusions
Asymmetric DA reactions from prochiral starting materials involving dynamic preferential crystallization were achieved under achiral conditions. Since the DA reaction of 2-methylfuran and various maleimide derivatives proceeded reversibly, exo-adducts were obtained as major products as the reaction proceeded. Nine exo-adducts were newly synthesized by the DA reaction using maleimides with various substituents on the nitrogen atom. Single crystal X-ray structure analysis revealed that four derivatives gave conglomerates.
When 2-methylfuran and each maleimide in the presence of a catalytic amount of TFA were reacted in a sealed tube, DA adducts precipitated as crystals. The mixture was continuously ground and stirred using glass beads. Deracemization of exo-type DA adducts occurred and asymmetric amplification was observed for four substrates. Each final enantiomeric purity was greatly influenced by the crystal structure, and when enantiomers were included in the disorder, they reached an enantiomeric purity reflecting the ratio. In addition, it was found that the chirality of the 3,5-dimethylphenyl derivative was deracemized to 98% ee. We have developed an absolute asymmetric DA reaction that can obtain enantiomerically active DA adducts without using an external asymmetric source.

Experimental
General Information. NMR spectra were recorded in CDCl 3 solutions on a Bruker DPX 300 and DPX 400 spectrometers for 1 H-and 13 C-NMR. Chemical shifts are reported in parts per million (ppm) relative to TMS as an internal standard. IR spectra were recorded on a JASCO FT/IR-230 spectrometer. HPLC analyses were performed on a JASCO HPLC system (JASCO PU-1580 pump, DG-1580-53, LG-2080-02, MD-2015, UV-2075 and CD-2095 detector). Single crystal X-ray structure analysis was conducted using a SMART APEX II (Bruker AXS) and APEX II ULTRA (Bruker AXS). Powder X-ray crystallographic analysis was performed using D8 ADVANCE (BRUKER AXS). Commercially available N-phenylmaleimide and 2-methylfuran were used without further purification. Other maleimides 2b-j were provided according to the reported procedure [70,71]. (Figures S18-S35) Synthesis of Exo-3a-j.
The corresponding maleimides 2 (1.0 g) and 2-methylfuran 1 (15 equiv) were added to 10 mL of hexane, and the mixture was stirred at 60 • C for 24 h. Thereafter, the solvent and extra amount of methylfuran were removed under reduced pressure, and the crude crystalline products were recrystallized from chloroform/hexane to isolate exo-3. The structures of known adducts 3a were determined by comparing their spectral data to literature values. The adducts, 3e-g, and 3j are commercially available; however, these materials were easily obtained by the above method.

Conflicts of Interest:
The authors declare no conflict of interest.