Citation: Jiang Chongguo, Chen Sijia, Gong Jianxian, Yang Zhen. Synthetic Study Toward the 4,5-Spirocycle Skeleton of Phainanoids[J]. Acta Chimica Sinica, ;2020, 78(9): 928-932. doi: 10.6023/A20060198 shu

Synthetic Study Toward the 4,5-Spirocycle Skeleton of Phainanoids

Jiang Chongguo ^a,† ,
Chen Sijia ^a,† ,
Gong Jianxian ^a,c,, ,
Yang Zhen ^a,b,c,,

a.
Laboratory of Chemical Genomics, State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China
b.
College of Chemistry and Molecular Engineering of Peking University, Beijing 100871, China
c.
Shenzhen Bay Laboratory, Shenzhen 518055, China

Corresponding author: Gong Jianxian, gongjx@pku.edu.cn Yang Zhen, zyang@pku.edu.cn
Received Date: 1 June 2020
Available Online: 9 July 2020
Fund Project: Shenzhen Basic Research Program JCYJ20170818090044432Project supported by the National Basic Research Program of China 21632002Project supported by the National Basic Research Program of China (Nos. 21632002, 21772008), National Key Research and Development Project (No. 2018YFC0310905), Shenzhen Basic Research Program (No. JCYJ20170818090044432) and Funding Project of Shenzhen-Hong Kong Institute of Brain Science (No. 2019SHIBS0004).National Key Research and Development Project 2018YFC0310905Funding Project of Shenzhen-Hong Kong Institute of Brain Science 2019SHIBS0004Project supported by the National Basic Research Program of China 21772008

Figures(8)

Attempts to synthesize the 4,5-spirocycle skeleton of Phainanoids by rhodium-catalyzed arylative cyclization of alkynone 5 and the addition of Grignard reagent 9 to α-alkoxyl cyclobutone 8, followed by intramolecular S_NAr reaction are reported. Phainanoids, highly modified triterpenoids, were isolated from Phyllanthus hainanensis by Yue and co-workers. They have been found to show intriguing immunosuppressive activities. The most potent of them, Phainanoid F, inhibit the proliferation of T cells with an IC₅₀ value of (2.04±0.01) nmol/L and B cells with an IC₅₀ value <(1.60±0.01) nmol/L. The noteworthy activities and the lack of Phainanoids in nature resources make the synthesis of them for further biological evaluation a challenge for chemists. Our synthesis started from known compound 1, after Birch reduction and alkylation to give alkynone 5. The rhodium-catalyzed arylative cyclization of alkynone 5 to deliver tetrasubstituted cyclobutene 6 was performed by the following procedure. Under an atmosphere of Ar, to an oven-dried Schlenk tube with[Rh(OH)(cod)]₂ (35.5 mg, 0.078 mmol, 0.012n₅), phenylboronic acid (2.0 g, 16.3 mmol, 2.5n₅), were added a solution of ketone 5 (1.9 g, 6.5 mmol, 1.0n₅) in 1,4-dioxane (32.0 mL) and H₂O (0.3 mL) at room temperature. The mixture was stirred at 35℃ for 12 h. Another [Rh(OH)(cod)]₂ (35.5 mg, 0.078 mmol, 0.012n₅) and phenylboronic acid (2.0 g, 16.3 mmol, 2.5n₅) was added to the mixture. The mixture was stirred at 35℃ for 12 h. Subsequently, hydroxyl group was protected with ethoxymethyl (EOM) group to furnish 7, followed by ozonolysis to generate ketone 8. Ketone 8 was reacted with fresh prepared Grignard reagent 9 in Felkin-Anh modelinstead ofthe Cram's chelation-control model to deliver alcohol 10. The explanation of the diastereoselectivity of this reaction could be illustrated from two aspects:(1) the rigid structure of α-alkoxyl cyclobutone 8 increased the energy barrier for the transition state of chelation between magnesium ions and alkoxyl substituent; (2) the magnesium ions were not chelated with the alkoxyl substituent as well as the carbonyl oxygen was due to the intramolecular chelation with fluorine atom. Alcohol 10 underwent intramolecular S_NAr reaction and deprotection to deliver 4,5-spirocycle compound 18.
- Phainanoids,
- 4,5-spirocycle skeleton,
- rhodium-catalyzed arylative cyclization,
- S_NAr,
- Cram's chelation
1. [1]
  Fan, Y.-Y.; Zhang, H.; Zhou, Y.; Liu, H.-B.; Tang, W.; Zhou, B.;Zuo, J.-P.; Yue, J.-M. J. Am. Chem. Soc. 2015, 137, 138.
2. [2]
  Xie, J.; Wang, J.; Dong, G. Org. Lett. 2017, 19, 3017.
3. [3]
  Zhang, C. L.; Nan, F. J. Tetrahedron Lett. 2017, 58, 4357.
4. [4]
  Reviews:(a) Mascareñas, J. L.; Varela, I.; López, F. Acc. Chem. Res. 2019, 52, 465.(b) Kwiatkowski, M. R.; Alexanian, E. J. Acc. Chem. Res. 2019, 52, 1134.(c) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890.(d) Bates, R. W.; Satcharoenb, V. Chem. Soc. Rev. 2002, 31, 12.(e) Inglesby, P. A.; Evans, P. A. Chem. Soc. Rev. 2010, 39, 2791.(f) Marinetti, A.; Jullien, H.; Voituriez, A. Chem. Soc. Rev. 2012, 41, 4884.(g) Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria, M.; Simonneau, A. Chem. Rev. 2011, 111, 1954.(h) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. Rev. 1996, 96, 635.(i) Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev. 2002, 102, 813.(j) Grigg, R.; Sridharan,V. J. Organomet. Chem. 1999, 576, 65.(k) Xiao M. Y.; Zhu S.; Shen Y. B.; Wang L.; Xiao J. N. Chin. J. Org. Chem. 2018, 38, 328.(l) Li J. X.; Lin S.; Huang R. K.; Li C.; Yang S. R. Chin. J. Org. Chem. 2019, 39, 1417.(m) Geng D. G.; Chin. J. Org. Chem. 2019, 39, 301.(n) Qian X. Y.; Xiong P.; Xu H. C. Acta Chim. Sinica 2019, 77, 879.(o) Xu J.; Zhang S. F.; Luo Y.; Zhang, L.; Zhang, F.; Huang, T. J.; Song, Q. L. Acta Chim. Sinica 2019, 77, 932.(p) Liao F. M.; Du Y.; Zhou F.; Zhou J. Acta Chim. Sinica 2018, 76, 862.(q) Wang, W. G.; Huang, S.; Yan, S. K.; Sun, X. J.; Tung, C. H.; Xu, Z. H. Chin. J. Chem. 2020, 38, 445.(r) Zhou, L. J.; Xu, B.; Ji, D. T.; Zhang, Z. M.; Zhang, J. L. Chin. J. Chem. 2020, 38, 577.
5. [5]
  Miura, T.; Shimada, M.; Murakami, M. Tetrahedron 2007, 63, 6131.
6. [6]
  (a) Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748.(b) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191.(c) Chen, X.; Hortelano, E. R.; Eliel, E. L. J. Am. Chem. Soc. 1990, 112, 6130.(d) Fan, X. Y.; Walsh, P. J. Acc. Chem. Res. 2017, 50, 2389.(e) Bartolo, N. D.; Read, J. A.; Valentín, E. M.; Woerpel, K. A. Chem. Rev. 2020, 120, 1513.(f) Stanton, G. R.; Koz, G.; Walsh, P. J. J. Am. Chem. Soc. 2011, 133, 7969.(g) Ye, J. L.; Huang, P. Q.; Lu, X. J. Org. Chem. 2007, 72, 35.(h) Bailey, W. F.; Reed, D. P.; Clark, D. R.; Kapur, G. N. Org. Lett. 2001, 3, 1865.
7. [7]
  Ciceri, P.; Demnitz, F. W. J. Tetrahedron Lett. 1997, 38, 389.
8. [8]
  Ali, A.; Guile, S. D.; Saxton, J. E.; Thornton-Pett, M. Tetrahedron 1991, 41, 6407.
9. [9]
  (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.(b) Toyooka, N.; Okumura, M.; Nemoto, H. J. Org. Chem. 2002, 67, 6078.
10. [10]
  Moustafa, G. A. I.; Saku, Y.; Aoyama, H.; Yoshimitsu, T. Chem. Commun. 2014, 50, 15706.
11. [11]
  Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 9, 2199.
12. [12]
  Butenschn, H. Chem. Ber. 1994, 127, 137.
13. [13]
  Hegedus, L. S.; Ranslow, P. B. Synthesis 2000, 7, 953.
14. [14]
  (a) Yamazaki, T.; Ando, M.; Kitazume, T.; Kubota, T.; Omura, M. Org. Lett. 1999, 1, 905.(b) Yamazaki, T.; Kawashita, S.; Kitazume, T; Kubota, T. Chem. Eur. J. 2009, 15, 11461.(c) Tenza, K.; Northen, J. S.; O'Hagan, D.; Slawin, A. M. Z. J. Fluorine Chem. 2004, 125, 1779.(d) Sazonov, P. K.; Oprunenko, Y. F.; Khrustalev, V. N.; Beletskaya, I. P. J. Fluorine Chem. 2011, 132, 587.(e) Kulawiec, R. J.; Holt, E. M.; Lavin, M.; Crabtree, R. H. Inorg. Chem. 1987, 26, 2559.(f) Ooi, T.; Kagoshima, N.; Maruoka, K. J. Am. Chem. Soc. 1997, 119, 5754.(g) Kawachi, A.; Tani, A.; Machida, K.; Yamamoto, Y. Organometallics 2007, 26, 4697.(h) Bizet, V.; Cahard, D. Chimia. 2014, 68, 378.(i) Carrell, H. L.; Glusker, J. P.; Piercy, E. A.; Stallings, W. C.; Zacharias, D. E.; Davis, R. L.; Astbury, C.; Kennard, C. H. L. J. Am. Chem. Soc. 1987, 109, 8067.
15. [15]
  Nakamura, K.; Ohmori, K.; Suzuki, K. Angew. Chem., Int. Ed.2017, 56, 182.
1. [1]
  Wentao Lin , Wenfeng Wang , Yaofeng Yuan , Chunfa Xu . Concerted Nucleophilic Aromatic Substitution Reactions. University Chemistry, 2024, 39(6): 226-230. doi: 10.3866/PKU.DXHX202310095
2. [2]
  Aiyi Xin , Jiawei Li , Xinyang Ran , Chuanjiang Fu , Zhiguo Wang . Collaborative Science and Education Based Experimental Design in Organic Chemistry: A Case Study of the Nucleophilic Substitution Reaction of 2-Hydroxymethyl-4,6-Di-Tert-Butylphenol. University Chemistry, 2025, 40(5): 366-375. doi: 10.12461/PKU.DXHX202407031
3. [3]
  Caixia Lin , Ting Liu , Zhaojiang Shi , Hong Yan , Keyin Ye , Yaofeng Yuan . Innovative Experiment of Electrochemical Dearomative Spirocyclization of N-Acyl Sulfonamides. University Chemistry, 2025, 40(4): 359-366. doi: 10.12461/PKU.DXHX202406107
4. [4]
  Yue Zhao , Yanfei Li , Tao Xiong . Copper Hydride-Catalyzed Nucleophilic Additions of Unsaturated Hydrocarbons to Aldehydes and Ketones. University Chemistry, 2024, 39(4): 280-285. doi: 10.3866/PKU.DXHX202309001
5. [5]
  Daojuan Cheng , Fang Fang . Exploration and Implementation of Science-Education Integration in Organic Chemistry Teaching for Pharmacy Majors: A Case Study on Nucleophilic Substitution Reactions of Alkyl Halides. University Chemistry, 2024, 39(11): 72-78. doi: 10.12461/PKU.DXHX202403105
6. [6]
  Jinwang Wu , Qijing Xie , Chengliang Zhang , Haifeng Shi . 自旋极化增强ZnFe_1.2Co_0.8O₄/BiVO₄ S型异质结光催化性能降解四环素. Acta Physico-Chimica Sinica, 2025, 41(5): 100050-. doi: 10.1016/j.actphy.2025.100050
7. [7]
  Lei Shi . Nucleophilicity and Electrophilicity of Radicals. University Chemistry, 2024, 39(11): 131-135. doi: 10.3866/PKU.DXHX202402018
8. [8]
  Jianyin He , Liuyun Chen , Xinling Xie , Zuzeng Qin , Hongbing Ji , Tongming Su . ZnCoP/CdLa₂S₄肖特基异质结的构建促进光催化产氢. Acta Physico-Chimica Sinica, 2024, 40(11): 2404030-. doi: 10.3866/PKU.WHXB202404030
9. [9]
  Jingzhuo Tian , Chaohong Guan , Haobin Hu , Enzhou Liu , Dongyuan Yang . Waste plastics promoted photocatalytic H₂ evolution over S-scheme NiCr₂O₄/twinned-Cd_0.5Zn_0.5S homo-heterojunction. Acta Physico-Chimica Sinica, 2025, 41(6): 100068-. doi: 10.1016/j.actphy.2025.100068
10. [10]
  Jingzhao Cheng , Shiyu Gao , Bei Cheng , Kai Yang , Wang Wang , Shaowen Cao . 4-氨基-1H-咪唑-5-甲腈修饰供体-受体型氮化碳光催化剂的构建及其高效光催化产氢研究. Acta Physico-Chimica Sinica, 2024, 40(11): 2406026-. doi: 10.3866/PKU.WHXB202406026
11. [11]
  Jiahui YU , Jixian DONG , Yutong ZHAO , Fuping ZHAO , Bo GE , Xipeng PU , Dafeng ZHANG . The morphology control and full-spectrum photodegradation tetracycline performance of microwave-hydrothermal synthesized BiVO₄:Yb³⁺,Er³⁺ photocatalyst. Journal of Fuel Chemistry and Technology, 2025, 53(3): 348-359. doi: 10.1016/S1872-5813(24)60514-1
12. [12]
  Jiaxing Cai , Wendi Xu , Haoqiang Chi , Qian Liu , Wa Gao , Li Shi , Jingxiang Low , Zhigang Zou , Yong Zhou . 具有0D/2D界面的InOOH/ZnIn₂S₄空心球S型异质结用于增强光催化CO₂转化性能. Acta Physico-Chimica Sinica, 2024, 40(11): 2407002-. doi: 10.3866/PKU.WHXB202407002
13. [13]
  Yi Yang , Xin Zhou , Miaoli Gu , Bei Cheng , Zhen Wu , Jianjun Zhang . Femtosecond transient absorption spectroscopy investigation on ultrafast electron transfer in S-scheme ZnO/CdIn₂S₄ photocatalyst for H₂O₂ production and benzylamine oxidation. Acta Physico-Chimica Sinica, 2025, 41(6): 100064-. doi: 10.1016/j.actphy.2025.100064
14. [14]
  Yadan Luo , Hao Zheng , Xin Li , Fengmin Li , Hua Tang , Xilin She . Modulating reactive oxygen species in O, S co-doped C₃N₄ to enhance photocatalytic degradation of microplastics. Acta Physico-Chimica Sinica, 2025, 41(6): 100052-. doi: 10.1016/j.actphy.2025.100052
15. [15]
  Hong RAO , Yang HU , Yicong MA , Chunxin LÜ , Wei ZHONG , Lihua DU . Synthesis and in vitro anticancer activity of phenanthroline-functionalized nitrogen heterocyclic carbene homo- and heterobimetallic silver/gold complexes. Chinese Journal of Inorganic Chemistry, 2024, 40(12): 2429-2437. doi: 10.11862/CJIC.20240275
16. [16]
  Kexin Dong , Chuqi Shen , Ruyu Yan , Yanping Liu , Chunqiang Zhuang , Shijie Li . Integration of Plasmonic Effect and S-Scheme Heterojunction into Ag/Ag₃PO₄/C₃N₅ Photocatalyst for Boosted Photocatalytic Levofloxacin Degradation. Acta Physico-Chimica Sinica, 2024, 40(10): 2310013-. doi: 10.3866/PKU.WHXB202310013
17. [17]
  Hongrui Zhang , Miaoying Cui , Yongjie Lv , Yongfang Rao , Yu Huang . A short review on research progress of ZnIn₂S₄-based S-scheme heterojunction: Improvement strategies. Chinese Chemical Letters, 2025, 36(4): 110108-. doi: 10.1016/j.cclet.2024.110108
18. [18]
  Zhiwen HUANG , Qi LIU , Jianping LANG . W/Cu/S cluster-based supramolecular macrocycles and their third-order nonlinear optical responses. Chinese Journal of Inorganic Chemistry, 2025, 41(1): 79-87. doi: 10.11862/CJIC.20240184
19. [19]
  Yi DING , Peiyu LIAO , Jianhua JIA , Mingliang TONG . Structure and photoluminescence modulation of silver(Ⅰ)-tetra(pyridin-4-yl)ethene metal-organic frameworks by substituted benzoates. Chinese Journal of Inorganic Chemistry, 2025, 41(1): 141-148. doi: 10.11862/CJIC.20240393
20. [20]
  Bairu Meng , Zongji Zhuo , Han Yu , Sining Tao , Zixuan Chen , Erik De Clercq , Christophe Pannecouque , Dongwei Kang , Peng Zhan , Xinyong Liu . Design, synthesis, and biological evaluation of benzo[4,5]thieno[2,3-d]pyrimidine derivatives as novel HIV-1 NNRTIs. Chinese Chemical Letters, 2024, 35(6): 108827-. doi: 10.1016/j.cclet.2023.108827

Get Citation

PDF

XML

Metrics

PDF Downloads(18)
Abstract views(3276)
HTML views(469)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142