Letter pubs.acs.org/OrgLett
Asymmetric [3 + 2] Cycloaddition of 3‑Amino Oxindole-Based Azomethine Ylides and α,β-Enones with Divergent Diastereocontrol on the Spiro[pyrrolidine-oxindoles] Guodong Zhu, Qian Wei, Hongbo Chen, Yanpeng Zhang, Wen Shen, Jingping Qu, and Baomin Wang* State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian 116024, P. R. China S Supporting Information *
ABSTRACT: A general and practical organocatalytic asymmetric 1,3-dipolar cycloaddition of 3-amino oxindole-based azomethine ylides and α,β-enones has been developed. This reaction delivered spiro[pyrrolidine-2,3′-oxindole] products in high yields with excellent regio- and enantioselectivities (up to 99% yield, >20:1 rr, 99% ee). In addition, an array of spiro[dihydropyrrole-2,3′-oxindoles] were readily accessed by oxidative dehydrogenation. Notably, the inversion of the diastereoselectivity of the spiro[pyrrolidine-oxindole] product could be easily achieved through a facile oxidation−reduction process.
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restricting the product diversity. On the other hand, with respect to the dipolarophile partner, although an array of electron-deficient alkenes prove to be competent, surprisingly, simple and common α,β-unsaturated ketones, such as chalcones,8 remain underexplored toward the asymmetric construction of spiriooxindoles (Figure 1b). In continuation of our interest in the asymmetric synthesis and modification of pharmaceutically relevant heterocycles,9 very recently, we explored the use of 3-amino oxindoles for the in situ generation of azomethine ylides in [3 + 2] cycloadditions.9c,e Our results indicated that the in situ formed azomethine ylides from 3-amino oxindoles and aldehydes exhibit unique reactivities toward the construction of spiro[pyrrolidine-2,3′-oxindoles], affording either complementary diastereo- or regioselectivity as compared to the isatin/amine combinations.6a,10 In order to extend the synthetic potential of 3-amino oxindoles, herein we report the catalytic asymmetric [3 + 2] cycloadditions between 3-amino oxindole-derived azomethine ylides and α,β-enones, leading to the production of a diverse array of spiro[pyrrolidine-2,3′-oxindoles] with high levels of regio- and enantiocontrol. We initiated our studies by investigating the threecomponent [3 + 2] cycloaddition of 3-amino oxindole hydrochloride 2b, benzaldehyde 3a, and chalcone 4a in a one-pot fashion (Table 1; for full screening, see Table S1 in the Supporting Information). Inspired by the pioneering findings of Gong4a,5a and our recent success in this respect,9c binaphthol-
wing to the prevalence of the spiro[oxindole-pyrrolidine] framework in alkaloid natural products and medicinal chemistry (Figure 1a),1 recent years have witnessed significant
Figure 1. (a) Selected bioactive spiro[pyrrolidine-oxindoles]; (b) Catalytic asymmetric [3 + 2] cycloadditions of α,β-enones.
research efforts toward the asymmetric construction of this valuable structural motif.2 Of particular note in this regard are 1,3-dipolar cycloaddition strategies that employ isatin-derived azomethine ylides by virtue of the versatility of [3 + 2] cycloaddition reactions in constructing five-membered heterocycles.3,4 However, this strategy has met with limited success. For example, only special amines, such as 2-amino malonates,5 benzylamines,6 and trifluoroethyl amine,7 have proven to be viable for the generation of the azomethine ylides, thus severely © XXXX American Chemical Society
Received: March 1, 2017
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DOI: 10.1021/acs.orglett.7b00625 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Screening of Optimal Reaction Conditionsa
entry
1
solvent
t (h)
yield (%)b
rrc
1 2 3 4 5 6 7 8e,f,g
1a 1b 1c 1d 1d 1d 1d 1d
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 THF toluene Et2O Et2O
12 12 12 23 19 108 120 88
99 99 93 79 99 86 80 99
9:1 7:1 10:1 7:1 4:1 3:1 8:1 9:1
Scheme 1. Substrate Scope of 3-Amino Oxindoles and Aldehydesa,b,c,d
eed 84, 76, 77, 90, 89, 91, 94, 96,
50 43 60 87 14 90 80 85
a
The reaction was carried out on a 0.1 mmol scale with 1 (10 mol %) in 1.0 mL of solvent; the ratio of 2b/3a/4a was 1/1.2/1.1. bIsolated yield. cThe rr was determined by 1H NMR of the crude reaction mixture. dThe ee was determined by chiral HPLC. eWithout 3 Å MS. f At 35 °C. gUse 2c as the substrate.
derived phosphoric acids (BPAs)11 were subjected to the model reaction in dichloromethane to identify the optimal conditions. In general, all the tested BPAs with different 3,3′-substituents can smoothly catalyze the model reaction, affording the cycloadduct in high yields with respectable regio- and enantioselectivities, while the 3,3′-(9-phenanthryl)-modified phosphoric acid 1d gave the best enantioselectivity of the major regioisomer in 90% ee albeit with a moderately lowered yield of 79% (entry 4). A brief survey of the reaction media revealed diethyl ether to be a better solvent in terms of enantioinduction, affording 96% ee, 9:1 rr, and a 99% yield with N-benzyl oxindole substrate 2c at 35 °C (entry 8). With the optimal reaction conditions in hand, the generality of the three-component [3 + 2] cycloaddition with respect to aldehyde and 3-amino oxindole partners was evaluated (Scheme 1). The outcome indicated that a broad range of aromatic aldehydes are well compatible with this process, delivering the cycloadducts in good to excellent yields with high regioselectivity and uniformly excellent enantioselectivity, irrespective of the electronic property and substitution pattern of the substituent on the phenyl ring of the aromatic aldehyde (5baa−5cka). The heteroaromatic aldehyde is also well suited to this reaction, as demonstrated by the result with 2thenaldehyde (5cla). Aliphatic aldehydes can also participate in this process, but much lowered regio- and enantioselectivities were observed (5cma). Notably, substitution occurring on the oxindole framework is well accommodated (5daa and 5eaa). The absolute configuration of 5cfa was determined by singlecrystal X-ray diffraction analysis, and those of others were assigned by analogy.12 Based on the stereochemical outcome, a stereocontrol model of the cycloaddition process was proposed and shown in the Supporting Information (Figure S1). Next, the substrate scope with respect to the dipolarophile was investigated. As can be seen from the results shown in Scheme 2, a diverse array of chalcone derivatives are suitable dipolarophiles for the cycloaddition reaction. Various aromatic and heteroaromatic groups at the olefin terminus, i.e. R4, are
a The reaction was carried out on a 0.2 mmol scale with 1d (10 mol %) in 2.0 mL Et2O, the ratio of 2/3/4a was 1/1.2/1.1. bIsolated yields are given. cThe rr was determined by 1H NMR of the crude reaction mixture. dThe ee was determined by chiral HPLC.
well accommodated (5cba−5cak). Similarly, with respect to the ketone terminus, a variety of aromatic and heteroaromatic ketones are competent (5cal−5car). In addition, the aliphatic ketone also works well in this reaction (5cas). 3,4-Dihydro-2H-pyrrole is a useful structural motif of significant synthetic value, which is rarely found to spirally fuse to the oxindole skeleton. To our delight, exposure of the spiro[pyrrolidine-2,3′-oxindole] to DDQ led to a clean dehydrogenation to yield the corresponding dihydropyrrole product with maintained optical purity; selected examples are shown in Scheme 3. With the 3,4-dihydro-2H-pyrrole derivatives being easily accessed, we envisioned the possibility of switching the diastereocontrol on the spiro[pyrrolidine-2,3′oxindole] product by resaturation of the dihydropyrrole moiety. As proof of concept, we were delighted to find that a facile reduction of the C−N double bond of the dihydropyrrole 6caa led to a clean production of the thermodynamically more stable spiro[pyrrolidine-2,3′-oxindole] 7caa, which is epimerized at CB
DOI: 10.1021/acs.orglett.7b00625 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Substrate Scope of α,β-Enonesa,b,c,d
Scheme 3. Synthesis of 3,4-Dihydro-2H-pyrrole Derivativesa,b,c
a b
The reaction was carried out on a 0.1 mmol scale in 1 mL of dioxane. Isolated yields are given. cThe ee was determined by chiral HPLC.
Scheme 4. Inversion of the Diastereoselectivity of Spiro[pyrrolidine-2,3′-oxindole] 5caa to 7caa
a
Scheme 5. Gram-Scale Reaction
5 of the pyrrolidine ring compared to the cycloadduct 5caa (Scheme 4). It is worth noting that this operationally simple transformation readily effected complementary and efficient diastereocontrol on the spiro[pyrrolidine-2,3′-oxindole] product, thus enhancing the stereochemical outcome of the cycloaddition process. In order to further demonstrate the synthetic utility of the cycloaddition procedure, scale-up experiment and elaboration of the spiro[pyrrolidine-2,3′-oxindole] 5caa were conducted. The cycloaddition to enone dipolarophiles can be readily scaled up on a gram scale with maintained efficiency and stereoselectivity (Scheme 5). In addition, the spiro[pyrrolidine-2,3′oxindole] product exhibited interesting reactivity, as revealed by the synthetic transformation of 5caa. Oxidation of 5caa with 1.0 equiv of m-CPBA gave rise to hydroxylamine 8, which can be further oxidized to nitrone 9 upon increasing the amount of m-CPBA. The nitrone can be trapped by dipolarophiles such as
dimethyl acetylenedicarboxylate to give a structurally interesting polyheterocyclic architecture 10 (Scheme 6).13 In conclusion, we have developed a general and practical organocatalytic asymmetric 1,3-dipolar cycloaddition of 3amino oxindole-based azomethine ylides and α,β-enones. This reaction delivered spiro[pyrrolidine-2,3′-oxindole] products in high yields with excellent regio- and enantioselectivities. Notably, the inversion of the diastereoslectivity of the spiro[pyrrolidine-2,3′-oxindoles] could be easily achieved through a facile oxidation−reduction process, thus enabling divergent diastereocontrol of the spirooxindole product.
The reaction was carried out on a 0.2 mmol scale with 1d (10 mol %) in 2.0 mL Et2O; the ratio of 2c/3a/4 was 1/1.2/1.1. bIsolated yields are given. cThe rr was determined by 1H NMR of the crude reaction mixture. dThe ee was determined by chiral HPLC.
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DOI: 10.1021/acs.orglett.7b00625 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
(b) Narayan, R.; Bauer, J. O.; Strohmann, C.; Antonchick, A. P.; Waldmann, H. Angew. Chem., Int. Ed. 2013, 52, 12892. (c) Awata, A.; Arai, T. Angew. Chem., Int. Ed. 2014, 53, 10462. (d) Bai, X.-F.; Song, T.; Xu, Z.; Xia, C.-G.; Huang, W.-S.; Xu, L.-W. Angew. Chem., Int. Ed. 2015, 54, 5255. (e) Yamashita, Y.; Nam, L. C.; Dutton, M. J.; Yoshimoto, S.; Kobayashi, S. Chem. Commun. 2015, 51, 17064. (f) Yang, W.-L.; Tang, F.-F.; He, F.-S.; Li, C.-Y.; Yu, X.; Deng, W.-P. Org. Lett. 2015, 17, 4822. (g) He, F.-S.; Zhu, H.; Wang, Z.; Gao, M.; Yu, X.; Deng, W.-P. Org. Lett. 2015, 17, 4988. (h) Wang, Y.-M.; Zhang, H.-H.; Li, C.; Fan, T.; Shi, F. Chem. Commun. 2016, 52, 1804. (i) Liu, H.-C.; Tao, H.-Y.; Cong, H.; Wang, C.-J. J. Org. Chem. 2016, 81, 3752. (j) Kowalczyk, D.; Albrecht, Ł. J. Org. Chem. 2016, 81, 6800. (k) Cayuelas, A.; Ortiz, R.; Nájera, C.; Sansano, J.; Larrañaga, O.; de Cózar, A.; Cossío, F. P. Org. Lett. 2016, 18, 2926. (l) Wang, H.; Deng, Q.; Zhou, Z.; Hu, S.; Liu, Z.; Zhou, L.-Y. Org. Lett. 2016, 18, 404. (5) For examples, see: (a) Shi, F.; Tao, Z.-L.; Luo, S.-W.; Tu, S.-J.; Gong, L.-Z. Chem. - Eur. J. 2012, 18, 6885. (b) Xiao, J.-A.; Liu, Q.; Ren, J.-W.; Liu, J.; Carter, R. G.; Chen, X.-Q.; Yang, H. Eur. J. Org. Chem. 2014, 2014, 5700. (c) Dai, W.; Jiang, X.-L.; Wu, Q.; Shi, F.; Tu, S.-J. J. Org. Chem. 2015, 80, 5737. (6) For examples, see: (a) Tian, L.; Hu, X.-Q.; Li, Y.-H.; Xu, P.-F. Chem. Commun. 2013, 49, 7213. (b) Zhao, H.-W.; Yang, Z.; Meng, W.; Tian, T.; Li, B.; Song, X.-Q.; Chen, X.-Q.; Pang, H.-L. Adv. Synth. Catal. 2015, 357, 2492. (7) For examples, see: (a) Ma, M.; Zhu, Y.; Sun, Q.; Li, X.; Su, J.; Zhao, L.; Zhao, Y.; Qiu, S.; Yan, W.; Wang, K.; Wang, R. Chem. Commun. 2015, 51, 8789. (b) Li, X.; Su, J.; Liu, Z.; Zhu, Y.; Dong, Z.; Qiu, S.; Wang, J.; Lin, L.; Shen, Z.; Yan, W.; Wang, K.; Wang, R. Org. Lett. 2016, 18, 956. (c) Wang, H.-H.; Wu, Z.-J.; Yue, D.-F.; Hu, W.-F.; Zhang, X.-M.; Xu, X.-Y.; Yuan, W.-C. Chem. Commun. 2016, 52, 11708. (8) For examples, see: (a) Hernández-Toribio, J.; Arrayás, R. G.; Martín-Matute, B.; Carretero, J. C. Org. Lett. 2009, 11, 393. (b) Oura, I.; Shimizu, K.; Ogata, K.; Fukuzawa, S. Org. Lett. 2010, 12, 1752. (c) Bai, X.-F.; Xu, Z.; Xia, C.-G.; Zheng, Z.-J.; Xu, L.-W. ACS Catal. 2015, 5, 6016. (9) For examples, see: (a) Zou, L.; Wang, B.; Mu, H.; Zhang, H.; Song, Y.; Qu, J. Org. Lett. 2013, 15, 3106. (b) Zhang, H.; Wang, B.; Cui, L.; Li, Y.; Qu, J.; Song, Y. Org. Biomol. Chem. 2014, 12, 9097. (c) Zhu, G.; Wang, B.; Bao, X.; Zhang, H.; Wei, Q.; Qu, J. Chem. Commun. 2015, 51, 15510. (d) Bao, X.; Wang, B.; Cui, L.; Zhu, G.; He, Y.; Qu, J.; Song, Y. Org. Lett. 2015, 17, 5168. (e) Wei, Q.; Zhu, G.; Zhang, H.; Qu, J.; Wang, B. Eur. J. Org. Chem. 2016, 2016, 5335. (10) (a) Sarrafi, Y.; Hamzehloueian, M.; Alimohammadi, K.; Yeganegi, S. J. Mol. Struct. 2012, 1030, 168. (b) Xiao, J.-A.; Zhang, H.-G.; Liang, S.; Ren, J.-W.; Yang, H.; Chen, X.-Q. J. Org. Chem. 2013, 78, 11577. (11) For reviews, see: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (c) Terada, M. Chem. Commun. 2008, 4097. (12) CCDC 1463859 (5cfa). See the Supporting Information for details. (13) Ashburn, S. P.; Coates, R. M. J. Org. Chem. 1985, 50, 3076.
Scheme 6. Derivatization of the Cycloadducts
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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.7b00625. Experimental procedures and full spectroscopic data for all new compounds (PDF) Crystallographic data for 5cfa (CIF) Crystallographic data for 5can′ (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jingping Qu: 0000-0002-7576-0798 Baomin Wang: 0000-0001-9058-4983 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (No. 21542007), the Program for New Century Excellent Talents in University (NCET-11-0053), and the Fundamental Research Funds of the Central Universities (DUT15TD25) for support of this work.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b00625 Org. Lett. XXXX, XXX, XXX−XXX
