Asymmetric Diels–Alder Reaction Involving Dynamic Enantioselective

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Asymmetric Diels-Alder Reaction Involving Dynamic Enantioselective Crystallization Naohiro Uemura, Seiya Toyoda, Hiroki Ishikawa, Yasushi Yoshida, Takashi Mino, Yoshio Kasashima, and Masami Sakamoto J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01273 • Publication Date (Web): 28 May 2018 Downloaded from http://pubs.acs.org on May 28, 2018

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The Journal of Organic Chemistry

Asymmetric Diels-Alder Reaction Involving Dynamic Enantioselective Crystallization Naohiro Uemura,† Seiya Toyoda,† Hiroki Ishikawa,† Yasushi Yoshida,† Takashi Mino,† Yoshio Kasashima,‡ and Masami Sakamoto*,† †

Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, and Molecular Chirality Research Center, Yayoi-cho, Inage-ku, Chiba 265-8522, Japan ‡ Education Center, Faculty of Creative Engineering, Chiba Institute of Technology, Shibazono, Narashino, Chiba 275-0023, Japan

achiral conditions O Me O +

reversible Diels-Alder reaction & dynamic stereoselective crystallization in a sealed tube

N Ph

O prochiral materials glass beads solvent

90% ee Me O

80 % yield

O N Ph O

: (+) or (-)-crystalline DA-adduct crystal system) (P212121

ABSRACT: Asymmetric Diels-Alder reaction was achieved under achiral conditions. Reaction of prochiral 2-methylfuran and Nphenylmaleimide in heptane or hexane solution at 80 ºC efficiently gave conglomerate crystal of exo-type DA-adduct selectively, and continuous suspension of the reaction mixture with glass beads promoted attrition-enhanced deracemization leading to optically active exo-adduct in 90% ee ■ INTRODUCTION The Diels-Alder (DA) reaction is one of the most fundamental and illustrious reactions in organic chemistry, providing access to a variety of polycyclic heterocycles.1 Numerous important skeletons have been conveniently constructed by the reaction of various dienes and alkenes.2 Furthermore, this reaction applies to many asymmetric reactions using catalytic asymmetric synthesis3 and chiral auxiliaries,4 leading to optically active cyclic compounds. Naturally, all of these synthetic methodologies require optically active sources such as chiral catalysts or precursors. Recently, asymmetric synthesis involving a reversible reaction and crystal chirality has been developed. Stereoselective crystallization via stereoisomerization from meso to dl-isomers,5 aza-Michael addition reactions,6 photoisomerization followed by ring-closing-opening reactions,7 Strecker-type reactions,8 and reversible photodimerization reactions9 have been reported. These reactions were initiated from prochiral precursors and high optically active crystalline products were conveniently provided under absolutely achiral conditions. These types of reactions all involve dynamic stereoselective crystallization, which is well documented as a total optical resolution method or a crystallization-induced transformation (CIET).10-15 The combination of chiral center generation from

prochiral starting materials followed by CIET makes it possible to design absolute asymmetric synthesis involving many types of organic reactions. Up to now, absolute asymmetric synthesis has been limited to the application of physical chiral forces such as circularly polarized light16 and chiral magnetic fields.17 Of course, Soai’s reaction18 and asymmetric synthesis using the chirality of crystals generated by the crystallization of prochiral materials is also considered to be an absolute asymmetric synthesis.19-20 These processes are of great interest to many scientists in a variety of areas, because absolute asymmetric synthesis could support the hypothesis of the origin of homochirality on the primitive Earth.21 Here, we developed a novel absolute asymmetric Diels-Alder reaction by using prochiral maleimide and furan, which is a well-known reversible reaction.22 Specifically, the reaction of asymmetrical 2-methylfuran and symmetrical N-phenylmaleimide was selected (Scheme 1).23 ■ RESULTS AND DISCUSSION Jarosz et al. reported that their DA reaction gave a mixture of exo- and endo-adducts in a ratio of 1.6:1.0 under high pressure conditions at room temperature.24 Furthermore, the crystal structure of the exo-adduct revealed that the space group was chiral P2 1 2 1 2 1 . We re-analyzed the crystal structure both to eliminate the possibility of a polymorphic crystal system and

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The Journal of Organic Chemistry to determine the crystal system of the endo-adduct. When a homogeneous toluene solution of N-phenylmaleimide 2 and 2methylfuran 1 (1.5 eq) was left standing overnight, a colorless solid of the exo-adduct was obtained. The filtered exo-3 and endo-4 isolated from the mother liquor were analyzed by Xray crystallography. The exo-3 was indeed obtained as a conglomerate of the P2 1 2 1 2 1 space group and the absolute configuration of (+)-exo-3 was determined as (3aR,4S,7R,7aS) (Figure 1),25 whereas the space group of endo-4 was racemic Pbca (Figure 2).26 O

Me O

+

N

Diels-Alder reaction Ph

Me

Me

O

dynamic stereoselective crystallization by the property of conglomerate crystals is promoted, deracemization will occur and optically active crystals should be obtained. in solution

1

+

2

∆

Me (R)

N

∆

apparent racemization

O (S)

O

O

O

N

Ph

+

O

N

(S)

Ph

1

2

O

exo-3

(S)

(R)

Ph

Ph

O

N (S)

O

O

(+)-3 O

Me

O

(R)

(R)

(-)-3

O

deracemization with crystallization

endo-4

Scheme 1. Diels-Alder reaction of N-phenylmaleimide and 2methylfuran.

conglomerate crystal

(+)-3

or

(-)-

3

Scheme 2. Absolute Asymmetric synthesis by Diels-Alder reaction involving dynamic stereoselective crystallization.

Figure 1. Perspective view of exo-(+)-3. Ellipsoids were drawn in 50% probability.

While the DA reaction generally proceeds endo-selectively, the exo-adduct is more thermodynamically stable. We monitored the reaction course by NMR spectroscopy. Figure 3 shows the reaction course in which 0.02 M of N-phenylmaleimide and 10.0 eq of 2-methylfuran was reacted at 60 ºC in CDCl 3 . At the early stage of the reaction, both exo- and endoadducts formed equally, but after half an hour the endo-adduct gradually decreased, and the ratio of exo to endo reached 8:1 after 6 h. When the reaction was performed on a preparative scale and concentration, the crystalline exo-adduct precipitated and was removed from the reaction system. Finally, the products converged to the exo-adduct, which was isolated in 90% yield accompanied by a trace amount of endo-adduct. These results indicated that the conglomerate crystal of the exo-adduct was formed stereoselectively in this DA reaction system. 100 80 yield [%]

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Figure 2. Perspective view of endo-4. Ellipsoids were drawn in 50% probability.

60 40 20 0 0

The DA reaction is well-known to be a concerted electro-cycloaddition reaction and to involve a reversible process. We applied this reaction system to the asymmetric synthesis involving dynamic stereoselective crystallization as shown in Scheme 2. The primary DA reaction provides asymmetric chiral materials from prochiral starting substrates and the racemization of (±)-3 might be promoted by a reversible process. If

1

2

3 time [h]

4

5

6

Figure 3. Time-dependent reaction course as monitored by 1H NMR spectroscopy. N-Phenylmaleimide (0.02 M) and 2methyfuran (0.1 M) were reacted in CDCl 3 at 60 ºC. Blue triangles = unreacted 2; red squares = exo-3; green diamonds = endo-4.

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Another important requirement to apply this asymmetric DA reaction using dynamic stereoselective crystallization is the rate of the reverse reaction under the same conditions. The reverse reaction without catalyst was quite slow, thus, we sought out the best catalyst for activating the reverse reaction using various catalysts such as Zn(OAc) 2 , TfOH, TsOH, HCl, AcOH, (TfO) 3 Yb, (TfO) 3 Eu, p-CF 3 C 6 H 4 B(OH) 2 , (iPrO) 2 TiCl 2 , TMSNTf 2 , TMSOTf, and trifluoroacetic acid (TFA). When TMSNTf 2 or TMSOTf was used to activate the reverse reaction, 3-methyl-N-phenylphthalimide was obtained quantitatively by C-O bond cleavage followed by aromatization. Other Lewis acids and Brönsted acids were not effective for the reverse DA reaction. Of these catalysts, TFA was the best for accelerating the reversible DA reaction. Figure 4 shows the time course of the retro-DA reaction in which a 0.02 M CDCl 3 solution of the exo-adduct was heated at 60 ºC with or without TFA (0.2 eq). Additionally, it was confirmed that TFA did not promote other side reactions.

The attrition of crystals using glass beads was quite effective for deracemization, since deracemization was not observed under suspension without glass beads even after 30 days. Furthermore, the induction period could be reduced by the use of TFA as an acid catalyst (lines 2–4). TFA accelerated not only the DA cycloaddition reaction but also the retro-DA reaction without promoting other side reactions. As the amount of TFA increased, there was a tendency toward both a reduction in the induction period and an acceleration in the deracemization, with deracemization starting at the fourth day leading to 90% ee after 11 days (line 4).

(a) 100

ratio [%]

80 60 40 20 0 0

1

2

3 time [h]

0

1

2

3 time [h]

4

5

6

Figure 5. Asymmetric Diels-Alder reaction followed by attritionenhanced deracemization using glass beads applied to achiral Nphenylmaleimide (100 mg, 0.578 mmol) and 2-methylfuran (710 mg, 8.67 mmol) in hexane or heptane (1.00 mL) at 80 ºC with or without TFA (0 – 1.0 eq).

(b) 100 80 60 ratio [%]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

40 20 0 4

5

6

Figure 4. Time-dependent course of retro-Diels-Alder reaction. The reaction was applied to the exo-adduct (0.02 M) in CDCl 3 solution at 60 ºC. Red squares = exo-3; black circles = 2-methylfuran 1; blue triangles = 2. (a) without TFA, (b) in the presence of TFA (0.2 eq).

Next, we examined the asymmetric DA reaction involving dynamic enantioselective crystallization. When a heptane solution of N-phenylmaleimide, 2-methylfuran (15.0 eq) and TFA (0 – 1.0 eq) was stirred in the presence of glass beads (Φ = 0.2 mm) at 80 ºC in a sealed tube, the crystalline exo-adduct appeared quickly. The solution was kept in suspension by stirring for several days at the same temperature, and the change in ee value of exo-3 by attrition-enhanced deracemization was monitored by HPLC using a chiral column, CIRALPAK IA (Daicel Ind.). When we stirred achiral N-phenylmaleimide and 2-methylfuran without TFA in a heptane solution, the induction period until deracemization started was several days. Deracemization began gradually after 15 days, but once initiated, the ee value sharply increased up to 90% ee as shown in Figure 5, line 1.

When using hexane instead of heptane, deracemization proceeded much faster (lines 5-8). Deracemization started after ten days and reached 86% ee after 19 days without TFA (line 5). TFA influenced both the reduction of induction and deracemization periods, affording a 86% ee of exo-3 after only five days by the use of 1.0 eq of TFA (line 8). However, the maximum ee value of the solid obtained from the reaction in hexane was slightly lower than that in heptane (86% vs. 90%). The solubility of the DA adduct may play an important role in the deracemization with its repeated dissolution and crystallization processes. Hexane had a slightly higher solubility for the DA adduct than heptane at 80 ºC in a sealed tube, resulting in the shorter deracemization time and lower ee value of the solid. Chemical yields of the solid in both solvents were 80% after cooling to room temperature. The optical purity of the solid formed by attrition-enhanced deracemization at 80 ºC may be much higher than 90% ee. The reaction vessel, a sealed tube, was cooled to room temperature before it was opened, because the boiling point of 2-methylfuran was 63 ºC. Cooling the reaction mixture introduced crystallization of the racemic DA adduct dissolved in the mother liquor, thus lowering the ee value of the crystals and explaining the capped ee values. However, a chance of a co-crystal or other factor could not be excluded.

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We were unable to control the handedness of the chirality in the spontaneous crystallization; solids of both types of handedness were obtained in each experiment in almost the same ratio. Primary nucleation gave one small crystal of one enantiomer (conglomerate behavior), followed by rapid propagation due to secondary nucleation of the enantiomer. However, we were able to control the handedness by a seeding method, in which a small amount of crystals was added during the induction period. Furthermore, when we started the attrition-enhanced deracemization from a DA adduct with low ee (5% ee) in heptane with TFA (0.1 eq) at 80 ºC, deracemization started immediately and the same handedness of the enantiomer as the slightly major stereoisomer could be obtain in 90% ee after 8 days. The use of hexane as the solvent shortened the time for deracemization. We could achieve deracemization up to 86% ee from 5% ee of the starting enantiomer after only 4 days under the same conditions. ■ CONCLUSIONS The first example of asymmetric DA reaction was developed involving stereoselective dynamic crystallization via a reversible process. This second order asymmetric reaction process can be applied to many types of reversible reactions or reactions combined with a racemization process for conglomerate crystals. ■ EXPERIMENTAL SECTION General Information. NMR spectra were recorded in CDCl 3 solutions on a Bruker 300 spectrometer operating at 300 and 75 MHz, respectively, for 1H- and 13C-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 PU1580 pump, DG-1580-53, LG-2080-02, MD-2015, UV-2075 and CD-2095 detector). X-ray single crystallographic analysis was conducted using a SMART APEX II (Bruker AXS) and APEX II ULTRA (Bruker AXS). Commercially available N-phenylmaleimide and 2-methylfuran were used without further purification. Reaction conditions for asymmetric DA reaction involving dynamic crystallization: In a sealed tube (L = 200 mm, Φ = 25 mm), N-phenylmaleimide (100 mg, 0.578 mmol), 2-methylfuran (710 mg, 8.67 mmol), TFA (0 – 1.0 eq), and hexane or heptane (1.0 mL) were stirred with or without glass beads (250 mg) using a stir bar at 80 ºC. The crystalline exo-adduct 3 appeared after few minutes, and the solution was kept in suspension by stirring at 600 rpm for several days at the same temperature. The change of ee value of crystalline 3 was monitored by HPLC using a chiral column, CHIRALPAK IA (Daicel Ind.); eluent: n-Hexane/EtOH = 80/20 (v/v). Finally, crystalline exo-3 was obtained in 80% (118 mg, 0.46 mmol) chemical yield by filtration. The structures of both exo-3 and endo-4 were confirmed by comparison with the reported spectral data.24 (2aS*,1R*,7S*,6aR*)-1-Methyl-4-phenyl-10-oxa-4-azatricyclo[5.2.1.0 2,6 ]dec-8-ene-3,5-dione (exo-3): Colorless prism, Mp: 144-146 °C; 1H NMR: δ 1.79 (s, 3 H, CH 3 ), 2.86 (d, J=6.5 Hz, 1 H, 2-H), 3.12 (d, 1 H, J = 6.5 Hz, 6-H), 5.30 (d, J=1.8 Hz, 1 H, 7-H), 6.37 (d, J = 5.6 Hz, 1 H, 9-H), 6.56 (dd, J = 1.8 and 5.6 Hz, 1 H, 8-H); 13C{1H} NMR: δ 15.7 (CH 3 ), 49.5, 50.6 (C-2, C-6), 81.1

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(C-7), 88.5 (C-1), 126.5, 128.6, 129.0, 131.7, 137.0, 140.7, 174.0, 175.2. (2aS*,1S*,7R*,6aR*)-1-Methyl-4-phenyl-10-oxa-4-azatricyclo[5.2.1.0 2,6 ]dec-8-ene-3,5-dione (endo-4): Colorless prism, Mp: 115-116 °C; 1H NMR: δ 1.88, (s, 3 H, CH 3 ), 3.27 (d, J = 7.7 Hz, 1 H, 2-H), 3.81 (dd, J = 5.5 and 7.7 Hz, 1 H, 6-H), 5.43 (dd, J = 1.6 and 5.5 Hz, 1 H, 7-H), 6.38 (d, J = 5.7 Hz, 1 H, 9-H), 6.54 (dd, J = 1.6 and 5.7 Hz, 1 H, 8-H); 13C{1H} NMR: δ 18.4, 48.5, 50.5, 79.4, 88.9, 126.3, 128.7, 129.1, 131.4, 135.1, 137.7, 174.0, 174.1. Single crystal X-ray crystallographic analysis of (2aS,1R,7S,6aR)-1-methyl-4-phenyl-10-oxa-4-azatricyclo[5.2.1.0 2,6 ]dec-8-ene- 3,5-dione (exo-(+)-3). Colorless prism (0.20 x 0.10 x 0.10 mm3), orthorhombic space group P2 1 2 1 2 1 , a = 6.7516(3) Å, b = 11.9488(5) Å, c = 15.6306(7) Å, V = 1260.98(10) Å3, Z = 4, λ (CuKα) = 1.54178 Å, ρ = 1.345 g/cm3, µ (CuKα) = 0.775 cm, 24869 reflections measured (T = 173 K, 4.658° < θ < 68.227°) , nb of independent data collected: 2303, nb of independent data used for refinement: 2302 in the final least-squares refinement cycles on F2, the model converged at R 1 = 0.0463, wR 2 = 0.1263 [I > 2s(I)], R 1 = 0.0464, wR 2 = 0.1263 (all data), and GOF = 1.114, H-atom parameters constrained, absolute Flack parameter = 0.09(3). (CCDC 1827990). Single crystal X-ray crystallographic analysis of (2aS*,1S*,7R*,6aR*)-1-methyl-4-phenyl-10-oxa-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (endo-4). Colorless prism (0.20 x 0.20 x 0.10 mm3), orthorhombic space group Pbca, a = 12.7547(17) Å, b = 11.3387(15) Å, c = 16.800(2) Å, V = 2429.6(6) Å3, Z = 8, λ (MoKα) = 0.71073 Å, ρ = 1.396 g/cm3, µ (MoKα) = 0.098 cm, 13062 reflections measured (T = 173 K, 2.4246° < θ < 20.9203°) , nb of independent data collected: 2758, nb of independent data used for refinement: 1797 in the final least-squares refinement cycles on F2, the model converged at R 1 = 0.0450, wR 2 = 0.1001 [I > 2s(I)], R 1 = 0.0800, wR 2 = 0.1121 (all data), and GOF = 0.968, H-atom parameters constrained. (CCDC 1827991). ■ ASSOCIATED CONTENT * Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI……. X-ray crystallographic analysis, HPLC analysis and spectroscopic data for synthesized compounds (PDF). ■ AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. ORCID Yasushi Yoshida: 0000-0002-3498-3696 Takashi Mino: 0000-0003-1588-1202 Masami Sakamoto: 0000-0001-9489-2641 NOTES The authors declare no competing financial interest. ■ACKNOWLEDGMENT This work was supported by Grants-in-Aid for Scientific Research (Nos. 25288017, 26410124 and 16H04144) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of the Japanese Government. Mr. Uemura acknowledges financial

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The Journal of Organic Chemistry support from Frontier Science Program of Graduate School of Science and Engineering, Chiba University. ■REFERENCES (1) (a) Diels, O.; Alder, K. Synthesen in der Hydroaromatischen Reihe, Justus Liebigs Ann. Chem. 1928, 460, 98–122; (b) Diels, O.; Alder, K. Synthesen in der Hydroaromatischen Reihe, IV. Mitteilung: Über die Anlagerung von Maleinsäure-anhydrid an Arylierte Diene, Triene und Fulvene, Ber. Dtsch. Chem. Ges. 1929, 62, 2081–2087. (2) For recent reviews on the application of DA reactions in total synthesis see: (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. The Diels-Alder Reaction in Total Synthesis, Angew. Chem. Int. Ed., 2002, 41, 1668– 1698; (b) Takao, K.-I.; Munakata, R.; Tadano, K. Recent advances in natural product synthesis by using intramolecular Diels-Alder reactions, Chem. Rev. 2005, 105, 4779–4807. (3) Examples for asymmetric DA reaction using chiral auxiliaries: (a) Walborsky, H.; Barash, L.; Davis, T. Communications- Partial Asymmetric Syntheses: The Diels-Alder Reaction, J. Org. Chem. 1961, 26, 4778–4779; (b) Evans, D. A.; Chapman, K. T.; Bisaha, J. Asymmetric Diels-Alder Cycloaddition Reactions with Chiral α,β-Unsaturated N-Acyloxazolidinones, J. Am. Chem. Soc. 1988, 110, 1238–1256. (4) Examples for catalytic asymmetric synthesis: (a) Corey, E. J.; Shibata, T.; Lee, T. W. Asymmetric Diels-Alder Reactions Catalyzed by a Triflic Acid Activated Chiral Oxazaborolidine, J. Am. Chem. Soc. 2002, 124, 3808–3809; (b) Choy, W.; Reed, L. A.; Masamune, S. Asymmetric Diels-Alder Reaction: Design of Chiral Dienophiles, J. Org. Chem. 1983, 48, 1137– 1139; (c) Oppolzer, W. Asymmetric Diels-Alder and Ene Reactions in Organic Synthesis. New Synthetic Methods (48), Angew. Chem., Int. Ed. Engl. 1984, 23, 876–889; (d) Kagan, H. B.; Riant, O. Catalytic Asymmetric Diels-Alder Reactions, Chem. Rev. 1992, 92, 1007–1019; (e) Mehta, G.; Uma, R. Stereoelectronic Control in Diels−Alder Reaction of Dissymmetric 1,3-Dienes, Acc. Chem. Res. 2000, 33, 278–286; (f) Wilson, R. M.; Jen, W. S.; MacMillan, D. W. C. Enantioselective Organocatalytic Intramolecular Diels−Alder Reactions. The Asymmetric Synthesis of Solanapyrone D, J. Am. Chem. Soc. 2005, 127, 11616–11617. (5) Hachiya, S.; Kasashima, Y.; Yagishita, F.; Mino, T.; Masu, H.; Sakamoto, M. Asymmetric Transformation by Dynamic Crystallization of Achiral Succinimides, Chem. Commun. 2013, 49, 4776–4778. (6) (a) Steendam, R, R. E.; Verkade, J. M. M.; van Benthem, T. J. B.; Meekes H.; van Enckevort, W. J. P.; Raap, J.; Rutjes, F. P. J. T.; Vlieg, E. Emergence of Single-molecular Chirality from Achiral Reactants, Nature Commun., 2014, 5, 5543; (b) Kaji, Y.; Uemura, N.; Kasashima, Y.; Ishikawa, H.; Yoshida, Y.; Mino, T.; Sakamoto, M. Asymmetric Synthesis of an Amino Acid Derivative from Achiral Aroyl Acrylamide by Reversible Michael Addition and Preferential Crystallization, Chem. Eur. J. 2016, 22, 16429–16432. (7) Sakamoto, M.; Shiratsuki, K.; Uemura, N.; Ishikawa, H.; Yoshida, Y.; Kasashima, Y.; Mino, T. Asymmetric Synthesis by Using Natural Sunlight under Absolute Achiral Conditions, Chem. Eur. J. 2017, 23, 1717–1721. (8) Kawasaki, T.; Takamatsu, N.; Aiba, S.; Tokunaga, Y. Spontaneous Formation and Amplification of an Enantioenriched α-Amino Nitrile: a Chiral Precursor for Strecker Amino Acid Synthesis, Chem. Commun., 2015, 51, 14377–14380. (9) Ishikawa, H.; Uemura, N.; Yagishita, F.; Baba, N.; Yoshida, Y.; Mino, T.; Kasashima, Y.; Sakamoto, M. Asymmetric Synthesis Involving Reversible Photodimerization of a Prochiral

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Mach, M.; Szewczyk, K.; Sko´ra, S.; Ciunik, Z. Synthesis of Sugar-derived 2’- and 3’-Substituted Furans and Their Application in Diels-Alder Reactions, Eur. J. Org. Chem. 2001, 2955-2964.

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