Catalytic Asymmetric Desymmetrization of Cyclopentendiones via

An unprecedented asymmetric Diels–Alder reaction of 3-hydroxy-2-pyrones with prochiral cyclopentene-1,3-diones via desymmetrization was efficiently ...
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Catalytic Asymmetric Desymmetrization of Cyclopentendiones via Diels−Alder Reaction of 3‑Hydroxy-2-pyrones: Construction of Multifunctional Bridged Tricyclic Lactones Li-Min Shi,†,‡ Wu-Wei Dong,†,‡ Hai-Yan Tao,†,§ Xiu-Qin Dong,*,† and Chun-Jiang Wang*,†,‡ †

College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, China State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai, 230012, China § State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin, 300071, China ‡

S Supporting Information *

ABSTRACT: An unprecedented asymmetric Diels−Alder reaction of 3-hydroxy-2-pyrones with prochiral cyclopentene1,3-diones via desymmetrization was efficiently realized with high stereoselective control with the aid of fine-tunable cinchona alkaloid derived bifunctional amine−thiourea catalysts bearing multiple hydrogen-bonding donors. This protocol provides an expedient access to the multifunctional-bridged tricyclic lactones featuring four contiguous stereogenic centers and one remote quaternary stereogenic center with a broad substrate scope. The cycloadduct can be readily elaborated into enantioenriched cyclopentane-1,3-diones via ring opening/ aromatization.

T

Scheme 1. Catalytic Asymmetric Diels−Alder Reaction of 3Hydroxy-2-pyrones for the Construction of Bridged Lactones

he catalytic asymmetric Diels−Alder reaction with its rich synthetic diversity has proven to be one of the most powerful synthetic strategies to access chiral six-membered carbo- or heterocycles in an atom-economical manner.1 Owing to the inherent electron-deficient properties of aromatic character,2 2-pyrones were regarded as challenging dienes in asymmetric Diels−Alder reactions and thus less studied in recent decades, although 2-pyrones made great contributions to preparing numerous achiral cyclic lactones with high functionality.3 Recently, Deng and co-workers reported the highly efficient organocatalyzed asymmetric Diels−Alder reaction of 3hydroxy-2-pyrones with α,β-unsaturated ketones,4a α,β-unsaturated nitriles,4b and aliphatic nitroalkenes4c affording the bicyclic lactones with good exo- or endo-diastereoselectivity and excellent enantioselectivity (Scheme 1a). More recently, with N-mesityl maleimide as the dienophile, an elegant bifunctional aminoindanol catalyzed asymmetric Diels−Alder reaction of 3hydroxy-2-pyridones or 3-hydroxy-2-pyrone and N-mesityl maleimide was successfully developed by Tan and co-workers, delivering the tricyclic lactones with good to high endo-selectivity and excellent enantioselectivity (Scheme 1b).4d Among various synthetic methods for the preparation of enantioenriched carbocyclic motifs with multiple stereogenic centers, desymmetrization of prochiral molecules through catalytic enantioselective transformations represents a powerful strategy, which exhibits great capacity for controlling stereochemistry remote from the reaction site.5 Prochiral cyclopentene-1,3-diones have recently been studied intensively as substrates in desymmetrization transformations,6 which were mainly focused on asymmetric Michael addition,6a−f oxidative © 2017 American Chemical Society

Heck,6g and 1,3-dipolar cycloaddition reactions.6h,i To the best of our knowledge, the catalytic asymmetric Diels−Alder reaction of Received: July 11, 2017 Published: August 16, 2017 4532

DOI: 10.1021/acs.orglett.7b02107 Org. Lett. 2017, 19, 4532−4535

Letter

Organic Letters 3-hydroxy-2-pyrones with prochiral cyclopentene-1,3-diones to construct chiral bridged lactones has not yet been reported, probably due to the difficult stereochemical controllability of the complicated tricyclic adducts containing four contiguous stereogenic centers and one remote quaternary stereogenic carbon center. Recently, a series of fine-tunable bifunctional amine− thioureas bearing multiple hydrogen-bonding donors was elaborately designed by our research group,7 which exhibited excellent catalytic activities and asymmetric inductions in organocatalyzed transformations.7,8 Along this research line, we herein reported the first asymmetric Diels−Alder reaction of 3hydroxy-2-pyrones and prochiral cyclopentene-1,3-diones via desymmetrization catalyzed by fine-tunable cinchona alkaloidderived bifunctional amine−thioureas bearing multiple hydrogen bonding donors, affording highly multifunctional bridged tricyclic lactones containing five stereogenic centers with perfect diastereoselectivity and excellent enantioselectivity (Scheme 1c). Moreover, the bridged lactone moieties are the core structure of numerous natural products and biologically active molecules.9 We began our initial investigation on the proposed Diels− Alder reaction using 3-hydroxy-2-pyrone (1a) and prochiral 2benzyl-2-methylcyclopent-4-ene-1,3-dione (2a) as the model substrates with various (S,S)-cyclohexane-1,2-diamine derived organocatalysts I and II7 as the catalysts. The results are summarized in Figure 1. Although the Diels−Alder reaction proceeded smoothly when catalysts IA−IC were employed, the bridged tricyclic lactone (3a) was formed in acceptable yield with only poor enantioselectivity and moderate diastereoselectivity. The second-generation catalysts IIA−IIC containing aminoalcohol moieties promoted this annulation with good to excellent exo-selectivity, and almost perfect diastereoselectivity (>20:1 dr) and 78% ee were obtained with IIB. Unfortunately, no further improvement could be achieved with this catalyst despite exhaustive optimization. In order to further improve the stereoselectivity, and also inspired by Deng’s related research with the cinchona alkaloid catalyst, we decided to design and systematically synthesize bifunctional amine−thiourea catalysts III−VI incorporating both cinchona alkaloid and amino-alcohol moieties.10 A TBS-protected hydroxyl group in the aminoalcohol could efficiently avoid the scramble of N- and O-atom attack to the corresponding isothiocyanate derived from cinchona alkaloids (see Supporting Information for the details), which impeded the purification of the desired catalyst. With TBS protection and deprotection strategies, 16 bifunctional amine− thioureas bearing multiple hydrogen-bonding donors were readily achieved from the orthogonality of four cinchona alkaloids and four 1,2-diphenyl ethanolamines, which were further tested in the model reaction; the representative results are summarized in Figure 1. The absolute configurations of the cycloadducts were mainly controlled by the configuration of the cinchona alkaloid skeletons, and the enantioselective control was greatly affected by the different configurations of the aminoalcohol moieties. To our delight, good enantioselectivities and excellent diastereoselectivities were observed in the presence of catalysts IIIA, IVB, VA, and VIB, and IIIA was revealed as the best in terms of both diastereo- and enantioselectivity (>20:1 dr, 86% ee). Notably, the bridged tricyclic lactones with opposite configuration could be efficiently achieved with catalysts IIIA/ VA, incorporating both cinchonidine/quinine and (1S,2S)-1,2diphenyl ethanolamine moieties, and catalysts IVB/VIB, incorporating both cinchonine/quinidine and (1R,2R)-1,2diphenyl ethanolamine moieties, respectively. The solvent effect was subsequently studied for this desymmetrization process.

Figure 1. Catalyst screening. All reactions were carried out with 0.20 mmol of 1a and 0.22 mmol of 2a in 0.5 mL of CH2Cl2 for 12 h. a Isolated yield. b Determined by crude 1H NMR. c Determined by HPLC analysis.

Among the tested solvents, CH2Cl2 still was the best choice in terms of yield and stereoselectivity (see Supporting Information for details). When the reaction temperature was decreased from 0 to −20 °C, the cycloadduct was separated in 85% yield with 94% ee. Encouraged by these promising results, the scope and generality of this asymmetric Diels−Alder reaction using 3hydroxy-2-pyrone (1a) and various cyclopentene-1,3-diones (2) were explored under the optimized reaction conditions. As shown in Table 1, a series of cyclopent-4-ene-1,3-diones bearing electron-neutral (2a), electron-deficient (2b−2d), or electron4533

DOI: 10.1021/acs.orglett.7b02107 Org. Lett. 2017, 19, 4532−4535

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Organic Letters

cycloadduct product (3a) with opposite configuration can be obtained with 94% ee and >20:1 dr in the presence of catalyst IVB (Table 1, entry 14). Moreover, 2-benzyl and 2-ethyl substituted cyclopentene-1,3-dione also worked well in this annulation, affording product (3n) in 74% yield with exclusive diastereoselectivity (>20:1 dr) and 96% ee (Table 1, entry 16). Notably, almost perfect desymmetrization and excellent stereoselectivity were still achieved even with the subtle difference between the two substituent groups (methyl and ethyl) on the quaternary carbon center in dienophile 2o (Table 1, entry 17). In addition, 2-methyl and 2-phenyl substituted dione (2p) also performed efficiently in this transformation to provide product (3p) with 77% yield and 90% ee (Table 1, entry 18). A 2 mmol scale reaction of 1a was conducted under the standard conditions, and exo-3a was isolated in 87% yield without any loss of stereoselective control (Table 1, entry 15). The absolute configuration of exo-3c was determined as (2S,3aS,4R,7R,7aR) by X-ray analysis. Having succeeded in the asymmetric Diels−Alder reaction of 3-hydroxy-2-pyrones (1a) with various cyclopentene-1,3-diones (2), we then turned our attention to investigate the generality of 3-hydroxy-2-pyrones. 4-/5-Substituted 3-hydroxy-2-pyrones proved to be viable dienes in this asymmetric Diels−Alder reaction, although 3-substituted pyrone was not tolerated probably due to the disfavored steric congestion. As shown in Table 2, the substituted group in the 4-/5-position of 2-pyrones

Table 1. Diels−Alder Reaction of 2-Pyrone 1a and Various Cyclopentenedione 2 Catalyzed by IIIAa,b

Table 2. Diels−Alder Reaction of Various 4- or 5-Substituted 2-Pyrone 1 and Cyclopentenedione 2 Catalyzed by IIIAa,b

entry

R1

R2

R3

4

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8

Me Me Me Cl Et H H H

H H H H H Et Et Et

Ph p-Br-C6H4 o-Me-C6H4 Ph Ph Ph p−Br-C6H4 o-Me-C6H4

4a 4b 4c 4d 4e 4f 4g 4h

82 70 81 76 43 75 78 75

91 90 93 80 91 94 87 92

a

a

rich (2e−2g, 2i) groups on the phenyl ring performed well to afford the corresponding cycloadduct products (3a−3g, 3i, Table 1, entries 1−7 and 9) in high yields with excellent stereoselectivities (up to 91% yield, 96% ee, >20:1 dr). The position and electronic property of the substituents on the phenyl ring had little effect on the reactivities and stereoselectivities. In addition, excellent ee was achieved for substrate naphthyl substituted cyclopentene-1,3-dione (2h) (94% ee, Table 1, entry 8). To our delight, more challenging substrates such as allyl (2j), cinnamyl (2k), 2-methylallyl (2l), isopropyl (2m) substituted 2-methylcyclopentene-1,3-diones proceeded smoothly with excellent results (56−80% yields, 91−94% ee, >20:1 dr, Table 1, entries 10−13). It is worth noting that the

has little effect on this reaction, resulting in the corresponding lactones (4a−4h) with high diastereoselectivities (>20:1 dr) and excellent enantioselectivities (80−94% ee, Table 2, entries 1−8). The multifunctional bridged tricyclic lactone containing five stereogenic centers can be readily converted into biologically important cyclopentan-1,3-dione11 without loss of enantioselectivity. As shown in Scheme 2, under basic conditions cycloadduct 3a was readily transformed into the fused cyclopentan-1,3-dione 5 in 88% yield and 93% ee through ring-open transesterification followed by a spontaneous dehydration− aromatization process. Under reflux in toluene, bridged lactone 3a underwent retro-Diels−Alder reaction via CO2 extrusion followed by oxidative aromatization to afford the fused cyclopentan-1,3-dione 6.

All reactions were carried out with 0.20 mmol of 1 and 0.22 mmol of 2 in 0.5 mL of CH2Cl2. bIsolated yield. c>20:1 dr was determined by crude 1H NMR, and ee was determined by HPLC analysis. dCatalyst IVB was used. eThe reaction was conducted with 2.0 mmol of 1 and 2.2 mmol of 2 in 5 mL of CH2Cl2.

All reactions were carried out with 0.20 mmol of 1 and 0.22 mmol of 2 in 0.5 mL of CH2Cl2. bIsolated yield. c>20:1 dr was determined by crude 1H NMR, and ee was determined by HPLC analysis.

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Nakamura, Y.; Iwagawa, T.; Nakatani, M. Tetrahedron Lett. 2000, 41, 4147. (d) Shimizu, H.; Okamura, H.; Iwagawa, T.; Nakatani, M. Tetrahedron 2001, 57, 1903. (4) (a) Wang, Y.; Li, H.; Wang, Y.-Q.; Liu, Y.; Foxman, B. M.; Deng, L. J. Am. Chem. Soc. 2007, 129, 6364. (b) Singh, R. P.; Bartelson, K.; Wang, Y.; Su, H.; Lu, X.; Deng, L. J. Am. Chem. Soc. 2008, 130, 2422. (c) Bartelson, K. J.; Singh, R. P.; Foxman, B. M.; Deng, L. Chem. Sci. 2011, 2, 1940. (d) Soh, J. Y.-T.; Tan, C.-H. J. Am. Chem. Soc. 2009, 131, 6904. For early examples on the catalytic asymmetric Diels−Alder reaction of 3-hydroxy-2-pyrone, see: (e) Okamura, H.; Nakamura, Y.; Iwagawa, T.; Nakatani, M. Chem. Lett. 1996, 25, 193. (f) Okamura, H.; Morishige, K.; Iwagawa, T.; Nakatani, M. Tetrahedron Lett. 1998, 39, 1211. (5) (a) Zhou, L.; Liu, X.; Ji, J.; Zhang, Y.; Hu, X.; Lin, L.; Feng, X. J. Am. Chem. Soc. 2012, 134, 17023. (b) Gu, Q.; You, S.-L. Chem. Sci. 2011, 2, 1519. (c) Xu, S.-M.; Wang, Z.; Zhang, X.; Zhang, X.-M.; Ding, K.-L. Angew. Chem., Int. Ed. 2008, 47, 2840. (d) Martín-Santos, C.; JaravaBarrera, C.; del Pozo, S.; Parra, A.; Díaz-Tendero, S.; Mas-Ballesté, R.; Cabrera, S.; Alemán, J. Angew. Chem., Int. Ed. 2014, 53, 8184. (e) Zhuo, C.-X.; Zhang, W.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 12662. (f) Mori, K.; Katoh, T.; Suzuki, T.; Noji, T.; Yamanaka, M.; Akiyama, T. Angew. Chem., Int. Ed. 2009, 48, 9652. (g) Jiang, J.; He, L.; Luo, S.-W.; Cun, L.-F.; Gong, L.-Z. Chem. Commun. 2007, 736. (h) Yao, L.; Zhu, Q.; Wei, L.; Wang, Z.-F.; Wang, C.-J. Angew. Chem., Int. Ed. 2016, 55, 5829. (i) Yao, L.; Liu, K.; Tao, H.-Y.; Qiu, G.-F.; Zhou, X.; Wang, C.-J. Chem. Commun. 2013, 49, 6078. (j) Liu, K.; Teng, H.-L.; Yao, L.; Tao, H.-Y.; Wang, C.-J. Org. Lett. 2013, 15, 2250. (6) (a) Manna, M. S.; Mukherjee, S. J. Am. Chem. Soc. 2015, 137, 130. (b) Manna, M. S.; Mukherjee, S. Chem. Sci. 2014, 5, 1627. (c) Manna, S.; Sarkar, R.; Mukherjee, S. Chem. - Eur. J. 2016, 22, 14912. (d) Aikawa, K.; Okamoto, T.; Mikami, K. J. Am. Chem. Soc. 2012, 134, 10329. (e) Dou, X.; Lu, Y.; Hayashi, T. Angew. Chem., Int. Ed. 2016, 55, 6739. (f) Zhi, Y.; Zhao, K.; Wang, A.; Englert, U.; Raabe, G.; Enders, D. Adv. Synth. Catal. 2017, 359, 1867. (g) Walker, S. E.; Lamb, C. J. C.; Beattie, N. A.; Nikodemiak, P.; Lee, A.-L. Chem. Commun. 2015, 51, 4089. (h) Das, T.; Saha, P.; Singh, V. K. Org. Lett. 2015, 17, 5088. (i) Liu, H.-C.; Liu, K.; Xue, Z.-Y.; He, Z.-L.; Wang, C.-J. Org. Lett. 2015, 17, 5440. (7) (a) Fang, X.; Wang, C.-J. Chem. Commun. 2015, 51, 1185. (b) Wang, C.-J.; Zhang, Z.-H.; Dong, X.-Q.; Wu, X.-J. Chem. Commun. 2008, 1431. (c) Zhang, Z.-H.; Dong, X.-Q.; Chen, D.; Wang, C.-J. Chem. - Eur. J. 2008, 14, 8780. (d) Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue, Z.-Y.; Teng, H.-L. J. Am. Chem. Soc. 2008, 130, 8606. (8) For selected examples on the application of the strategy of multiple hydrogen bonding donor activation in amine−thiourea catalyst design, see: (a) Zhao, M.-X.; Bi, H.-L.; Jiang, R.-H.; Xu, X.-W.; Shi, M. Org. Lett. 2014, 16, 4566. (b) Zhao, M.-X.; Dai, T.-L.; Liu, R.; Wei, D.-K.; Zhou, H.; Ji, F.-H.; Shi, M. Org. Biomol. Chem. 2012, 10, 7970. (c) Ogura, Y.; Akakura, M.; Sakakura, A.; Ishihara, K. Angew. Chem., Int. Ed. 2013, 52, 8299. (9) (a) Buta, J. G.; Flippen, J. L.; Lusby, W. R. J. Org. Chem. 1978, 43, 1002. (b) Sun, N.-J.; Xue, Z.; Liang, X.-T.; Huang, L. Acta Pharm. Sin. 1979, 14, 39. (c) Du, J.; Chiu, M. H.; Nie, R. L. J. Nat. Prod. 1999, 62, 1664. (d) Evanno, L.; Jossang, A.; Nguyen-Pouplin, J.; Delaroche, D.; Herson, P.; Seuleiman, M.; Bodo, B.; Nay, B. Planta Med. 2008, 74, 870. (10) (a) Zhao, M.-X.; Tang, W.-H.; Chen, M.-X.; Wei, D.-K.; Dai, T.L.; Shi, M. Eur. J. Org. Chem. 2011, 2011, 6078. (b) Shi, X.; He, W.; Li, H.; Zhang, X.; Zhang, S. Tetrahedron Lett. 2011, 52, 3204. (c) Meninno, S.; Vidal-Albalat, A.; Lattanzi, A. Org. Lett. 2015, 17, 4348. (11) (a) Kurteva, V. B.; Afonso, C. A. Chem. Rev. 2009, 109, 6809. (b) Das, S.; Chandrasekhar, S.; Yadav, J. S.; Gree, R. Chem. Rev. 2007, 107, 3286. (c) Biellmann, J. F. Chem. Rev. 2003, 103, 2019. (d) Silva, L. F., Jr. Tetrahedron 2002, 58, 9137. (e) Mehta, G.; Srikrishna, A. Chem. Rev. 1997, 97, 671.

Scheme 2. Synthetic Transformation

In summary, the first asymmetric Diels−Alder reaction of 3hydroxy-2-pyrones with prochiral cyclopentene-1,3-diones via a desymmetrization process was realized with perfect stereoselectivity with the aid of fine-tunable cinchona alkaloid derived amine−thiourea catalysts bearing multiple hydrogen-bonding donors. This protocol provides an efficient method to construct bridged lactones featuring five stereogenic centers in an atomeconomic manner with a broad substrate scope. Further studies to probe the mechanistic details and synthetic applications are currently underway in our laboratory.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02107. Experimental details and NMR and HPLC spectra for obtained compounds (PDF) X-ray data for 3c (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Chun-Jiang Wang: 0000-0003-3629-6889 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by NSFC (21372180, 21525207) and the Large-scale Instrument and Equipment Sharing Founding of Wuhan University. The Program of Introducing Talents of Discipline to Universities of China (111 Program) is also appreciated.

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REFERENCES

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DOI: 10.1021/acs.orglett.7b02107 Org. Lett. 2017, 19, 4532−4535