Home Journals Articles Updates About
CN
image
收藏切换
Highly efficient enantioselective synthesis of bispiro [benzofuran-oxindole/benzofuran-chromanone]s through organocatalytic inter-/intramolecular Michael cycloaddition
收藏切换
PDF
Min Zhanga, Jun-Xin Wanga, Shun-Qin Changa, Xiong-Li Liua, *, Xiong Zuoa, Ying Zhoub
Chinese Chemical Letters | 2020, 31(2) : 381 - 385
Less
收藏切换
Chinese Chemical Letters | 2020, 31(2): 381-385
• Communication •
Highly efficient enantioselective synthesis of bispiro [benzofuran-oxindole/benzofuran-chromanone]s through organocatalytic inter-/intramolecular Michael cycloaddition
Full
Min Zhanga, Jun-Xin Wanga, Shun-Qin Changa, Xiong-Li Liua, *, Xiong Zuoa, Ying Zhoub
Affiliations
  • a Guizhou Engineering Center for Innovative Traditional Chinese Medicine and Ethnic Medicine, Guizhou University, Guiyang 550025, China
  • b College of Pharmaceutical Sciences, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China
Published: 2020-02-15 doi: 10.1016/j.cclet.2019.06.015
Outline
收藏切换

A quinine-derived thiourea-catalyzed inter-/intramolecular Michael cycloaddition of chromoneoxindole/benzofuranone synthons with 3-substituted methylenebenzofuranones has been established, which constructed enantiomerically pure bispiro[benzofuran-oxindole/benzofuran-chromanone]s bearing five consecutive stereocenters including two spiro quaternary carton centers in good yields (up to 93%) with high diastereoselectivities (up to >20:1 dr) and good enantioselectivities (up to >99% ee). Moreover, this is the first example of bifunctional chromone-benzofuranone synthon directed organocatalytic tandem reaction, and also the first example of the bispiro[benzofuran-oxindole] and bispirobenzofuranone, potentially useful in medicinal chemistry.

Chromone-oxindole synthon  /  Chromone-benzofuranone synthon  /  Inter-/intramolecular Michael cycloaddition  /  Bispiro[benzofuran-oxindole-chromanone]  /  Bispirobenzofuranone
Min Zhang, Jun-Xin Wang, Shun-Qin Chang, Xiong-Li Liu, Xiong Zuo, Ying Zhou. Highly efficient enantioselective synthesis of bispiro [benzofuran-oxindole/benzofuran-chromanone]s through organocatalytic inter-/intramolecular Michael cycloaddition[J]. Chinese Chemical Letters, 2020 , 31 (2) : 381 -385 . DOI: 10.1016/j.cclet.2019.06.015
Full Text
Less
The rich structural diversity and complexity of molecules has always captured the attention of chemists to design cost-effective and sustainable synthetic ways [1], especially diversity-oriented synthesis of known natural and synthetic bioactive compounds [2]. In this context, spirocyclic benzofuranones have attracted considerable interest due to their privileged structural motifs found in natural and unnatural compounds with diverse and important biological activities (Fig. 1) [3]. There are some examples, concerning the catalytic asymmetric construction of such typically spirocyclic benzofuranones, have been disclosed [4, 5]. In spite of these elegant progresses, catalytic asymmetric methods for catalytic asymmetric assembly of spirocyclohexane-based benzofuranones have been less studied (Scheme 1a).
Spirocyclic oxindoles [6] with carbocyclic six-membered rings are also important substructures that are widely present in numerous bioactive natural products (Fig. 1) [7]. Consequently, considerable effort has been devoted to asymmetric approaches to access enantioenriched spirocyclohexane oxindoles [7, 8]. However, highly efficient, diastereoselective, and enantioselective reactions generating complex and structurally diverse chiral spirocyclohexane oxindoles in one step remain a challenging but highly desirable goal in organic synthesis (Scheme 1a).
Chromanones are an important class of heterocycles containing the core structure of dihydrobenzopyranone. Even though there exist many strategies for the asymmetric synthesis of chiral chromanones with only one chiral center [9], attempts toward the direct asymmetric synthesis of enantioenriched fused chromanone systems bearing two consecutive stereocenters are limited [10]. Especially, fused ring chromanone skeletons are also abundant in natural products like cyclopentene, cyclohexanone or cyclohexane fused chromanones (Fig. 1) [11]. The use of readily available chromones as a class of two-carbon building blocks to participate Michael cycloaddition reactions presents a promising one [12]. However the activation of the chemically inert chromones retards the development of this methold. Therefore, the stereoselective construction of fused ring chromanones is also a highly desirable but challenging goal.
Considering the wide occurrence of chromanones, spirocyclohexanebenzofuranones and spirocyclohexaneoxindoles in natural products and drugs, integrating these medicinally relevant motifs to generate unprecedented polycyclic skeletons would be highly desirable [1, 2]. The intimating challenge lies in the scarcity of efficient pathways to rapidly install these structural units simultaneously. Herein, we hypothesized that highly functionalized chiral bispiro[benzofuran-oxindole/benzofuran-chromanone]s could be constructed via an organocatalytic domino inter-/intramolecular Michael cycloaddition of 3-substituted methylenebenzofuranone and bifunctional chromone-oxindole/benzofuran synthon. To the best of our knowledge, if successful, this is the first example of bifunctional chromone-benzofuranone synthon directed organocatalytic tandem reaction, and also the first example of the bispiro [benzofuran-oxindole]s and bispirobenzofuranone (Scheme 1b).
Initially, the reaction of tert-butyl ester substituted methylenebenzofuranone 1a with chromone-oxindole synthon 2a [13] was investigated under the catalysis of quinine-derived squaramidetertiary amine C1 (Fig. 2) (Table 1, entry 1). Gratifyingly, the designed inter-/intramolecular Michael cycloaddition reaction indeed afforded the desired product 3a in a 78% yield albeit with 99% ee and >20:1 dr. This preliminary result demonstrated the feasibility of our design. In order to improve the yield, other chiral bifunctional tertiaryamine catalysts C2-C10 (Fig. 2) were utilized as catalysts in the reaction (entries 2–10). It was found that 10 mol% of quinine-derived thiourea-tertiary amine catalyst C2 fully converted chromone-oxindole synthon 1a into the desired product 3a with good control over the stereochemistry (90% yield, 99% ee, >20:1 dr) (entry 2). The subsequent evaluation of solvents discovered that Et2O could deliver the cycloaddition with better enantioselectivity than other solvents (entry 2 vs. entries 11–13). Thus, the optimal reaction conditions were chosen as those illustrated in entry 2.
After establishing the optimal reaction conditions, the substrate scope and limitations were explored. Initially, the possibility to employ various 3-substituted methylenebenzofuranones 1 was evaluated using chromone-oxindole synthon 2a as a model substrate (Scheme 2, products 3a-d). The reaction proved unbiased towards the substituents of substrates 1. Notably, in all of the cases high yields and high stereoselectivities were observed. Replacement of a tert-butyl ester substituent with an ethyl ester group in 2 was also well tolerated, could deliver the desired products 3 with excellent dr and ee (products 3b, 3d, 3f, 3h, 3j, 3m, 3o and 3q). Moreover, the reaction was shown to work well with benzoyl substituted substrates 1 to give the desired products 3t-w with very good yields (70%–85%), diastereoselectivities (all cases >20:1 dr), and good enantioselectivities (93%–98% ee).
Then, various chromone-oxindole synthons 2 were reacted with 3-substituted methylenebenzofuranones 1 (Scheme 2). To our delight, a highly efficient synthesis was observed under the reaction conditions in highly enantioselective fashions (products 3e-s with 96% to >99% ee). The reactions were shown to work well with a range of chromone-oxindole synthons 2 bearing either electronwithdrawing or electron-donating groups in the chromone ring to give the desired products 3e-k and 3s with very good yields (up to 93%), excellent diastereoselectivities (all cases >20:1 dr) and enantioselectivities (96% to >99% ee).
Inspired by the success in the chromone-oxindole synthons 2, and based on diverse structural library design, considering that bispiro[bibenzofuran-chromanone]s 5 would be medicinally important hybrids for the development of new biological molecules, subsequently, we further designed and synthesized a novel bifunctional benzofuran-chromone 4 as a 4C synthon and was then subjected to methylene benzofuranone 1 in 3.0 mL of Et2O/DCM (1:1, v/v) at room temperature for 3 day. The reaction proceeded smoothly, affording the medicinally important bispiro [benzofuran-benzofuran-chromanone]s 5a in 68% yield with 98%ee, 92:8 dr. The reaction scope generally proved to be broad with respect to a wide variety of electron-rich and -poor reagents 1 and 4 to give diversely substituted bispiro[bibenzofuran-chromanone]s 5a-k in 58%–80% yields with 93% to >99% ee and up to >20:1 dr.
The absolute configuration was unambiguously assigned on the basis of the X-ray analysis of the products 3a, 3c and 5a (Fig. 3). The absolute configurations of all remaining products 3 and 5 were given by analogy.
Based on the experimental results, we suggested a possible bifunctional catalytic mode to account for the observed stereoselectivities (Scheme 3), The tertiary amine group of the catalyst C2 acted as a base to deprotonate the OH group of the enolized substrate 2 or 4. Meanwhile, the carbonyl group of substrate 1 was activated by catalyst C2 via forming a hydrogen bond. Subsequently, the Re-face of the 1 was preferably attacked by the Si-face of enolated substrate 2 or 4, delivering the transient Michael adduct intermediate under this dual activating mode of chiral catalyst C2. Finally, the α-position of the resulting prochiral nucleophile intermediate initiates an intermolecular annulation process through the attack to the Si-face of the electron-defficient chromone moiety to accomplish the desired (C1'S, C2'R, C4'S, C5'S, C6'S)-configured 3 or 5.
Subsequently, we carried out two gram-scale inter-/intramolecular Michael cycloadditions to examine the applicability of the reaction. As shown in Scheme 4, the gram-scale reaction could smoothly take place to give products 3c and 5a with excellent enantio-and, diastereoselectivities, which was similar to the results of the small-scale reaction (for details, see the Supporting infomation).
In summary, we have demonstrated that a wide range of complex bispiro[benzofuran-oxindole/benzofuran-chromanone]s 3 and 5 can be efficiently assembled in high stereoselectivity in a single step from bifunctional chromone-oxindole/benzofuran synthons 2 and 4 servring as starting materials. The transformation provides products 3 and 5 comprised of five consecutive stereocenters including two spiro quaternary carton centers, in high yields and stereoselectivities (up to 93% yield, >20:1 dr and >99% ee). Moreover, this is the first example of the bifunctional chromonebenzofuranone synthon 4 directed organocatalytic tandem reaction, and also the first example of the bispiro[benzofuran-oxindole] and bispirobenzofuranone, potentially useful in medicinal chemistry. We believe this strategy would broaden the synthetic utility of bifunctional chromone synthon in the assembly of biologically valuable compounds.
Acknowledgments
Less
This work was received financial support from the National Nature Science Foundation of China (Nos. 81760625, 81660576 and 81560563) and Projects of Guizhou Province (Nos. [2016]5623, JG [2016]06, [2019]1402, [2017]5609 and [2018]5781).
Appendix A. Supplementary data
Less
Supplementary material related to this article can befound, inthe online version, at doi: https://doi.org/10.1016/j.cclet.2019.06.015.
References
Less
[1]
(a) C. Viegas-Junior, A. Danuello, V.D.S. Bolzani, E.J. Barreiro, C.A.M. Fraga, Curr. Med. Chem. 14 (2007) 1829-1852;(b) S. Fortin, G. Bérubé Expert Opin. Drug Discov. 8 (2013) 1029-1047;(c) E.J. Sorensen, H.M.L. Davies, Chem. Soc. Rev. 38 (2009) 2969-2969;(d) C. Ma, F. Jiang, F.T. Sheng, et al., Angew. Chem. Int. Ed. 58 (2019) 3014-3020;(e) X.P. Zeng, J. Zhou, J. Am. Chem. Soc. 138 (2016) 8730-8733.
[2]
(a) D.S. Tan, Nat. Chem. Biol. 1 (2005) 74-84;(b) M.D. Burke, S.L. Schreiber, Angew. Chem. Int. Ed. 43 (2004) 46-58;(c) C. Ma, J.Y. Zhou, Y.Z. Zhang, et al., Chem. -Asian J. 13 (2018) 2549-2558;(d) M. Sun, C. Ma, S.J. Zhou, et al., Angew. Chem. Int. Ed. 58 (2019) 8703-8708.
[3]
(a) A.A. Hussein, J.J.M. Meyer, M.L. Jimeno, B. Rodríguez, J. Nat. Prod. 70 (2007) 293-295;(b) H.M. Ge, C.H. Zhu, D.H. Shi, et al., Chem. -Eur. J. 14 (2008) 376-381;(c) L. Pérez-Fons, M.T. Garzón, V. Micol, J. Agric. Food Chem. 58 (2010) 161-171;(d) M.W. Pertino, C. Theoduloz, J.A. Rodríguez, V. Lazo, J. Nat. Prod. 73 (2010) 639-643;(e) K.C. Nicolaou, T.R. Wu, Q. Kang, D.Y.K. Chen, Angew. Chem. Int. Ed. 48 (2009) 3440-3443;(f) K.C. Nicolaou, Q. Kang, T.R. Wu, C.S. Lim, D.Y.K. Chen, J. Am. Chem. Soc. 132 (2010) 7540-7548;(g) B.Sontag, M.Ruth, P.Spiteller, etal., Eur.J.Org.Chem.2006 (2006)1023-1033;(h) N. Nakatani, R. Inatani, Agric. Biol. Chem. 47 (1983) 353-358.
[4]
(a) X. Li, C. Yang, J.L. Jin, X.S. Xue, J.P. Cheng, Chem. -Asian J. 8 (2013) 997-1003;(b) C. Cassani, X. Tian, E.C. Escudero-Adán, P. Melchiorre, Chem. Commun. 47 (2011) 233-235.
[5]
(a) X. Li, M.H. Lin, Y. Han, F. Wang, J.P. Cheng, Org. Lett. 16 (2014) 114-117;(b) K. Albertshofer, B. Tan, C.F. Barbas III, Org. Lett. 15 (2013) 2958-2961;(c) X. Companyó A. Zea, A.N.R. Alba, et al., Chem. Commun. 46 (2010) 6953-6955.
[6]
(a) D. Cheng, Y. Ishihara, B. Tan, C.F. Barbas III, ACS Catal. 4 (2014) 743-762;(b) G.S. Singh, Z.Y. Desta, Chem. Rev. 112 (2012) 6104-6155;(c) L. Hong, R. Wang, Adv. Synth. Catal. 355 (2013) 1023-1053;(d) W.Y. Han, J.Q. Zhao, J. Zuo, et al., Adv. Synth. Catal. 357 (2015) 3007-3031;(e) J.S. Yu, F. Zhou, Y.L. Liu, J. Zhou, Synlett 26 (2015) 2491-2504;(f) F. Zhou, Y.L. Liu, J. Zhou, Adv. Synth. Catal. 352 (2010) 1381-1407;(g) L. Hong, R. Wang, Adv. Synth. Catal. 355 (2013) 1023-1053;(h) G. Mei, F. Shi, Chem. Commun. 54 (2018) 6607-6621;(i) Z.Y. Cao, F. Zhou, J. Zhou, Acc. Chem. Res. 51 (2018) 1443-1454;(j) Y. Zhu, J. Zhou, S. Jin, et al., Chem. Commun. 53 (2017) 11201-11204;(k) J. Guo, X. Bai, Q. Wang, Z. Bu, J. Org. Chem. 83 (2018) 3679-3687;(l) Y. Chen, B.D. Cui, Y. Wang, et al., J. Org. Chem. 83 (2018) 10465-10475;(m) H. Lu, X. Li, F. Shi, S.J. Tu, Chem. -Eur. J. 20 (2014) 11382-11389;(n) G.J. Mei, D. Li, G.X. Zhou, et al., Chem. Commun. 53 (2017) 10030-10033;(o) Y. Zhu, J. Zhou, S. Jin, et al., Chem. Commun. 53 (2017) 11201-11204.
[7]
(a) F. Wong, H. Watson, A. Gerbes, et al., Gut 61 (2012) 108;(b) P. Ginès, F. Wong, H. Watson, et al., Hepatology 48 (2008) 204-213;(c) G.C. Bignan, K. Battista, P.J. Connolly, et al., Bioorg. Med. Chem. Lett. 15 (2005) 5022-5026.
[8]
(a) Y.K. Liu, M. Nappi, E. Arceo, S. Vera, P. Melchiorre, J. Am. Chem. Soc. 133 (2011) 15212-15218;(b) I. Chatterjee, D. Bastida, P. Melchiorre, Adv. Synth. Catal. 355 (2013) 3124-3130;(c) B. Zhou, Y. Yang, J. Shi, Z. Luo, Y. Li, J. Org. Chem. 78 (2013) 2897-2907;(d) K. Jiang, Z.J. Jia, S. Chen, L. Wu, Y.C. Chen, Chem. -Eur. J. 16 (2010) 2852-2856.
[9]
(a) J. Chen, J.M. Chen, F. Lang, et al., J. Am. Chem. Soc. 132 (2010) 4552-4553;(b) M.K. Brown, S.J. Degrado, A.H. Hoveyda, Angew. Chem. Int. Ed. 44 (2005) 5306-5310;(c) D. Xiong, W. Zhou, Z. Lu, S. Zeng, J. Wang, Chem. Commun. 53 (2017) 6844-6847;(d) L. Meng, M.Y. Jin, J. Wang, Org. Lett. 18 (2016) 4986-4989;(e) B.M. Trost, E. Gnanamani, C.A. Kalnmals, C. Hung, J.S. Tracy, J. Am. Chem. Soc. 141 (2019) 1489-1493.
[10]
(a) G. Wen, Y. Su, G. Zhang, et al., Org. Lett. 18 (2016) 3980-3983;(b) A. Khilevich, A. Mar, M.T. Flavin, et al., Tetrahedron Asymmetry 7 (1996) 3315-3326;(c) E. Sekino, T. Kumamoto, T. Tanaka, T. Ikeda, T. Ishikawa, J. Org. Chem. 69 (2004) 2760-2767;(d) J. Garcia, S. Barluenga, K. Beebe, L. Neckers, N. Winssinger, Chem. -Eur. J. 16 (2010) 9767-9771;(e) M.M. Biddle, M. Lin, K.A. Scheidt, J. Am. Chem. Soc. 129 (2007) 3830-3831;(f) R.L. Farmer, K.A. Scheidt, Chem. Sci. 4 (2013) 3304-3309;(g) B.R. McDonald, A.E. Nibbs, K.A. Scheidt, Org. Lett. 17 (2015) 98-101.
[11]
(a) K.S. Masters, S. Bräse, Chem. Rev. 112 (2012) 3717-3776;(b) R.N. Kharwar, A. Mishra, S. Gond, K.A. Stierle, D. Stierle, Nat. Prod. Rep. 28 (2011) 1208-1228;(c) S. Sato, Y. Suga, T. Yoshimura, et al., Bioorg. Med. Chem. Lett. 9 (1999) 2653-2656;(d) S.H. Shim, J. Baltrusaitis, J.B. Gloer, D.T. Wicklow, J. Nat. Prod. 74 (2011) 395-401;(e) R. Goel, V. Sharma, A. Budhiraja, M.P.S. Ishar, Bioorg. Med. Chem. Lett. 22 (2012) 4665-4667;(f) F. Zhang, L. Li, S. Niu, et al., J. Nat. Prod. 75 (2012) 230-237;(g) P.S. Wang, P. Liu, Y.J. Zhai, et al., J. Am. Chem. Soc. 137 (2015) 12732-12735;(h) M.C. Brohmer, E. Bourcet, M. Nieger, S. Brase, Chem. -Eur. J. 17 (2011) 13706-13711;(i) K.C. Nicolaou, A. Li, Angew. Chem. Int. Ed. 47 (2008) 6579-6582;(j) J.L. Li, S.L. Zhou, P.Q. Chen, et al., Chem. Sci. 3 (2012) 1879-1882.
[12]
(a) Ł. Albrecht, F. CruzAcosta, A. Fraile, et al., Angew. Chem. Int. Ed. 51 (2012) 9088-9092;(b) A. Albrecht, J. Bojanowski, Adv. Synth. Catal. 359 (2017) 2907-2911;(c) A. Danda, N. Kesava-Reddy, C. Golz, C. Strohmann, K. Kumar, Org. Lett. 18 (2016) 2632-2635.
[13]
(a) X.L. Liu, G. Zhou, Y. Gong, et al., Org. Lett. 21 (2019) 2528-2531;(b) X.L. Liu, Y. Gong, S. Chen, et al., Org. Chem. Front. 6 (2019) 1603-1607.
Appendix
Less
Year 2020 volume 31 Issue 2
PDF
45
24
Cite this Article
BibTeX
Article Info
doi: 10.1016/j.cclet.2019.06.015
  • Receive Date：2019-05-09
  • Online Date：2026-01-31
  • Published：2020-02-15
Article Data
Affiliations
History
  • Received：2019-05-09
  • Revised：2019-05-30
  • Accepted：2019-06-06
Affiliations
    a Guizhou Engineering Center for Innovative Traditional Chinese Medicine and Ethnic Medicine, Guizhou University, Guiyang 550025, China
    b College of Pharmaceutical Sciences, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China
References
Share
https://castjournals.cast.org.cn/joweb/ccl/EN/10.1016/j.cclet.2019.06.015
Share to
QR

Scan QR to access full text

Cite this article
BibTeX
Citations
表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
关闭全屏
  • BibTeX
  • EndNote
  • RefWorks
  • TxT
Links
Articles
Latest Articles
Most Read
Collections
Updates
Events
News
Multimedia
About
About Us
Contact
No. 86 Xueyuan South Road, Haidian District, Beijing
100081
010-62199257
qkjq@cast.org.cn

Copyright © 2025 China Association for Science and Technology. All rights reserved. For all open access content, the relevant licensing terms apply.
Sponsored by the Office of the Leading Group for Cybersecurity and Informatization of CAST, and supported by Science and Technology Review Publishing House