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0 202605029

DOI: https://doi.org/10.6023/cjoc202605029

研究论文

酰胺还原炔基化和还原烷基化反应在Schwarzinicines A, B, C及Ficusnotins B, F快捷合成中的应用

  • 陈金权 ,
  • 黄培强
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  • 厦门大学化学化工学院 福建省化学生物学重点实验室（厦门大学） 福建厦门 361005

收稿日期: 2026-05-29

  修回日期: 2026-07-07

  网络出版日期: 2026-07-24

基金资助

国家自然科学基金(Nos. 22571267和21931010 )资助项目.

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Application of Amide Reductive Alkynylation and Reductive Alkylation in the Rapid Synthesis of Schwarzinicines A-C and Ficusnotins B/F

  • Chen Jinquan ,
  • Huang Peiqiang
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  • Department of Chemistry and Fujian Key Laboratory of Chemical Biology (Xiamen University), College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005

Received date: 2026-05-29

  Revised date: 2026-07-07

  Online published: 2026-07-24

Supported by

National Natural Science Foundation of China (Nos. 22571267 and 21931010).

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摘要

Ficusnotins B,F和schwarzinicines A, B, C是近年报道的1,4-二芳基丁烷类天然产物。尽管结构简单,已筛选出一个血管舒张药物的先导化合物。本文报道本实验室发展的两个酰胺转化反应在上述天然产物快捷合成中的应用。（1）通过仲酰胺还原烷基化反应,即铱催化硅氢化-格氏试剂加成,建立了schwarzinicines A,C的两步合成法,总产率分别为74%和75%。（2）通过叔酰胺还原炔基化和形式还原烷基化反应,即铱—铜接力催化还原炔基化,和串联钯催化氢化的“一瓶”反应,建立了schwarzinicine B的“两瓶”合成法,总产率79%。（3）通过后一反应,建立了ficusnotins B, F的三步合成法, 总产率分别为75%和68%。（4）通过叔酰胺催化不对称还原炔基化反应,即铱—铜和有机小分子接力/协同催化,初步发展了schwarzinicines A, B, C的催化不对称合成的“两瓶”法。尽管对映选择性只有2.4:1, 2:1, 2.4:1,所得对映富集的产物使我们得以推测此前未知的schwarzinicines A, B, C的绝对构型。

关键词： 天然产物; 全合成; 酰胺还原炔基化; 酰胺还原烷基化; 绝对构型

本文引用格式

陈金权 , 黄培强 . 酰胺还原炔基化和还原烷基化反应在Schwarzinicines A, B, C及Ficusnotins B, F快捷合成中的应用[J]. 有机化学, 0 : 202605029 . DOI: 10.6023/cjoc202605029

Abstract

Ficusnotins B and F, along with schwarzinicines A, B, and C, are 1,4-diarylbutanoids reported in recent years. Despite their simple structure, structure-activity relationship studies have led to the identification of a lead compound for vasodilation. This article reports the application of two reactions previously developed by Huang’s group—reductive alkynylation and reductive alkylation of amides—in the synthesis of these five natural products. (1) A two-step synthesis of schwarzinicines A and C was established through iridium-catalyzed hydrosilylation of secondary amides followed by in situ Grignard addition, yielding two alkaloids in overall yields of 74% and 75%, respectively. (2) A "two-pot" synthesis of schwarzinicine B was achieved using the iridium-copper relay-catalyzed reductive alkynylation of tertiary amide followed by tandem palladium-catalyzed hydrogenation, resulting in the formation of the alkaloid with an overall yield of 79%. (3) By applying the latter method, a three-step synthesis of ficusnotins B and F was developed with overall yields of 75% and 68%, respectively. (4) Using iridium-copper and organocatalyst relay/synergistic catalysis, a two-step catalytic asymmetric synthesis of schwarzinicines A, B, and C was preliminarily developed. Although the enantioselectivities were only 2.4: 1, 2: 1, and 2.4: 1, respectively, the enantiomerically enriched products thus obtained enabled us to tentatively assign the previously unknown absolute configurations of schwarzinicines A, B, and C.

Key words： Natural products; Total synthesis; Reductive alkynylation of amides; Reductive alkylation of amides; Absolute configuration

参考文献

[1] (a) Daly, J. W.; Spande, T. F.; Garraffo, H. M. Alkaloids from Amphibian Skin: A Tabulation of Over Eight-Hundred Compounds. J. Nat. Prod. 2005, 68, 1556-1575;
(b) Marshall, C. M.; Federice, J. G.; Bell, C. N.; Cox, P. B.; Njardarson, J. T. An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013-2023). J. Med. Chem. 2024, 67, 11622-11655.
[2] (a) Zhao, Z. M.; Zheng, J. F.; Huang, P. Q. Chin. J. Org. Chem. 2026, 46, 1-20 (in Chinese);
(b) Chen, X.-Y.; Zhang, Y.; Gao, C.; Xu, G.-Q. Org. Chem. Front. 2026, 13, 1373-1423;
(c) Ha, X.; Hua, Y. Z.; Xu, G.-Q. Chem. Commun. 2025, 61, 17989-18016;
(d) Jia, J.; Xu, Q.-Q.; Fan, H.-T.; Lv, Y.-P.; Li, D. Org. Chem. Front. 2025, 12, 960-974;
(e) Yang, J. F.; Zhao, Y. Q.; Shi, L. Chin. J. Org. Chem. 2025, 45, 559-573 (in Chinese);
(f) Zhang, T. F.; Chang, J.;Chen, C. X.; Peng, J. S. Chin. J. Org. Chem 2025, 45, 168-188 (in Chinese);
(g) Tao, Y.; Guo, K.-G.; Chen, H.; Yan, G.-B.; Guo, M. Org. Chem. Front.2024, 11, 3270-3280;
(h) Escorihuela, J.; Lledós, A.; Ujaque, G. Chem. Rev. 2023, 123, 9139-9203;
(i) Ricci, A.; Bernardi, L. Methodologies in Amine Synthesis: Challenges and Applications; Wiley-VCH: Weinheim, 2021;
(j) Trowbridge, A.; Walton, S. M.; Gaunt, M. J. New Strategies for the Transition-Metal Catalyzed Synthesis of Aliphatic Amines. Chem. Rev. 2020, 120, 2613-2692; For selected recent examples, see:
(k) Zhang, Y. F.; Wang, B.; Chen, Z.; Liu, J. R.; Yang, N. Y.; Xiang, J. M.; Liu, J.; Gu, Q. S.; Hong, X.; Liu, X. Y. Science 2025, 388, 283-291;
(l) Lu, G.-S.; Ruan, Z.-L.; Wang, Y.; Lü, J.-F.; Ye, J.-L.; Huang, P.-Q. Angew. Chem. Int. Ed. 2025, 64, e202422742;
(m) Meng, Q.; Qin, T.; Miao, H.-R.; Zhang, G.; Zhang, Q. Sci. China Chem. 2024, 67, 2002-2008.
[3] (a) Pace, V.; Holzer, W.; Olofsson, B.Adv. Synth. Catal. 2014, 356, 3697-3736
(b) Sato T.; Chida, N. Org. Biomol. Chem.2014, 12, 3147-3150;
(c) Sato, T.; Yoritate, M.; Tajima, H.; Chida, N. Org. Biomol. Chem. 2018, 16, 3864-3875;
(d) Kaiser, D.; Bauer, A.; Lemmerer, M.; Maulide, N. Chem. Soc. Rev. 2018, 47, 7899–7925;
(e) Sato, T.; Yoritate, M.; Tajima, H.; Chida, N. Org. Biomol. Chem. 2018, 16, 3864–3875;
(f) Matheau-Raven, D.; Gabriel, P.; Leitch, J. A.; Almehmadi, Y. A.; Yamazaki, K.; Dixon, D. J. ACS Catal. 2020, 10, 8880–8897;
(g) Czerwiński, P. J.; Furman, B. Trends Chem. 2020, 2, 782–784;
(h) Czerwiński, P. J.; Furman, B. Front. Chem. 2021, 9, 655849;
(i) Ou, W.; Huang, P.-Q. Acc. Chem. Res. 2025, 58, 2332–2349.
[4] (a) Sheng, T.; Zhuang, Z.; Zhao, Z.-H.; Hoque, M. E.; Yu, J.-Q.Angew. Chem. Int. Ed. 2025, 64, e202416634;
(b) Faculak, M. S.; Veatch, A. M.; Alexanian, E. J. Science 2024, 383, 77-81
(c) Zhang, R.; Yu, T. T.; Dong, G. B. Science 2023, 382, 951-957;
(d) Winn, M.; Rowlinson, M.; Wang, F.; Bering, L.; Francis, D.; Levy, C.; Micklefield, J. Nature 2021, 593, 391-398;
(e) Huo, H.-H.; Gorsline, B. J.; Fu, G. C. Science 2020, 367, 559–564;
(f) Hong, S. Y.; Park, Y.; Hwang, Y.; Kim, Y. B.; Baik, M. H.; Chang, S. Science 2018, 359, 1016–1021;
(g) Choi, G. J.; Zhu, Q. L.; Miller, D. C.; Gu, C. J.; Knowles, R. R. Nature 2016, 539, 268;
(h) Clark, P.; Keenan, T.; Liu, S.; Huang, J.; Ma, Y.-R.; Hasija, A.; Huang, P.-Q.; Jean, A.; Leitch, D. C.; Arseniyadis, S. Chem. Commun. 2025, 61, 19064–19067;
(i) Lü, J.-F.; Wu, J.-F.; Ye, J.-L.; Huang, P.-Q. Beilstein J. Org. Chem. 2025, 21, 2072–2081.
[5] (a) Huang, P.-Q. Acta Chim. Sinica 2018, 76, 357-365;
(b) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2000, 122, 4583-4592.
[6] (a) Efficiency in Natural Product Total Synthesis; Huang, P.-Q., Yao, Z.-J., Hsung, R. P., Eds.; Wiley: Hoboken, NJ, 2018;
(b) Zhao, Y. C.; Yu,B. Acta Chim. Sinica 2025, 83, 1397-1413 (in Chinese);
(c) Chen, L.-J; Chen, P.; Jia, Y.-X. Acc. Chem. Res. 2024, 57, 3524-3540;
(d) Gao, Y.; Ma, D. W. Acc. Chem. Res. 2021, 54, 569-582;
(e) Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38, 3010-3021;
(f) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res.2008, 41, 40-49;
(g) Trost, B. M.; Dong, G. Nature 2008, 456, 485-488.
[7] (a) Xiao K.-J.; Luo J.-M.; Ye K.-Y.; Wang Y.; Huang, P.-Q. Angew. Chem., Int. Ed.2010, 49, 3037-3040
(b) Xiao K.-J.; Wang Y.; Ye K.-Y.; Huang, P.-Q. Chem. Eur. J.2010, 16, 12792-12796;
(c) Huang, P.-Q.; Ou, W.; Han, F. Chem. Commun. 2016, 52, 11967-11970;
(d) Ou, W.; Han, F.; Hu, X.-N.; Chen, H.; Huang, P.-Q. Angew. Chem. Int. Ed. 2018, 57, 11354-11358;
(e) Wang, X.-G.; Ou, W.; Liu, M.-H.; Liu, Z.-J.; Huang, P.-Q. Org. Chem. Front. 2022, 9, 3237–3246;
(f) Xu, F.-F.; Chen, J.-Q.; Shao, D.-Y.; Huang, P.-Q. Nat. Commun. 2023, 14, 6251;
(g) Xu, F.-F.; Chen, J.-Q.; Huang, P.-Q. Chem. Eur. J. 2026, 32, e70919;
(h) Lu, G.-S.; Han, Z.; Ye, J.-L.; Huang, P.-Q. Acta Chim. Sinica 2026, 84, 476–483;
(i) Weng, Z.-Y.; Li, Y.-Q.; He, W.-X.; Chen, Z.-Y.; Huang, P.-Q. CCS Chem. 2026, 8, https://doi.org/10.31635/ccschem.025.202506810
[8] (a) Xu Y. B.; Ruan Y.; Zheng J. F.; Huang, P. Q. Chin. J. Org. Chem.2025, 45, 988-995(in Chinese);
(b) Huang X.-Z.; Gao L.-H.; Huang P.-Q. Nat. Commun.2020, 11, 5314.
[9] (a) Fang W.; Luo Z. W.; Wang Y. C.; Zhou W.; Li L.; Chen Y. M.; Zhang X. K.; Dai M. J.; Dai, J. J. Angew. Chem. Int. Ed.2024, 63, e202317570;
(b) Huang, W.-W.; Cheng, J.-T.; Hsiao, W.-T.; Chiou, W.-H. J. Org. Chem. 2024, 89, 5091-5097
(c) Shu X.; Zhong D.; Lin Y.; Qin X.; Huo, H. J. Am. Chem. Soc.2022, 144, 8797-8806;
(d) Agrawal, T.; Perez-Morales, K. D.; Cort, J. A.; Sieber, J. D. J. Org. Chem. 2022, 87, 6387-6392;
(e) Gujarati, P. D.; Reber, K. P. Synthesis 2022, 54, 1404;
(f) Song, Q.; Wang, S.; Lei, X.; Liu, Y.; Wen, X.; Wang, Z. Molecules 2022, 27, 4698;
(g) Lindemann, C.; Schneider, C. Synthesis 2016, 48, 828–844;
(h) Guérot, C.; Tchitchanov, B. H.; Knust, H.; Carreira, E. M. Org. Lett. 2011, 13, 780–783.
[10] Latayada F. S.; Uy M. M.; Akihara Y.; Ohta E.; Nehira T.; Ômura H.; Ohta S. Phytochemistry2017, 141, 98-104.
[11] Krishnan P.; Lee F.-K.; Yap V. A.; Low Y.-Y.; Kam T.-S.; Yong K.-T.; Ting K.-N.; Lim, K.-H. J. Nat. Prod.2020, 83, 152-158.
[12] (a) Kanaoka Y.; Terashima M.; Kimura, T. Chem. Pharm. Bull.1959, 7, 648-649
(b) Yoon J. A.; Ahn S.; Han, Y. T. Synthesis of Ficusnotins, Rare 1,4-Diarylbutanoids Derived from Ficus nota, via Ruthenium-Catalyzed Conjugate Addition. Nat. Prod. Commun.2018, 13, 351-353.
[13] (a) Mak Y.-Y.; Loong B.-J.; Millns P.; Bauer C. C.; Bon R. S.; Mbaki Y.; Lee F.-K.; Lim K.-H.; Kong C.; Then S.-M.; Ting K.-N. Phytotherapy Res.2022, 36, 2952
(b) Mak Y. Y.; Lee F. K.; Lee M. K.; Mbaki Y.; Then S. M.; Yap C. S. A.; Fung S. Y.; Kong C.; Lim K. H.; Ting, K. N. Brit. J. Pharmacol.2023, 180, 546-548.
[14] (a) Lee F.-K.; Krishnan P.; Muhamad A.; Low Y.-Y.; Kam T.-S.; Ting K.-N.; Lim, K.-H. Nat. Prod. Res.2022, 36, 3972-3978
(b) Lee F.-K.; Chan N. J.-Y.; Krishnan P.; Salam D. S. D. A.; Chee X. W.; Muhamad A.; Low Y.-Y.; Ting K.-N.; Lim, K.-H. J. Nat. Prod.2024, 87, 675-691;
(c) Govindaraju, K.; Mak, Y. Y.; Lee, F. K.; Bauer, C. C.; Lim, K. H.; Bon, R. S.; Kong, C.; Then, S. M.; Ting, K. N. Phytochem. Lett. 2024, 59, 24-35.
[15] Bharate S. B.; Lindsley, C. W. J. Med. Chem.2024, 67, 20723-20730.
[16] Annapurna K.; Narsaiah A. V. Tetrahedron2024, 155, 133909.
[17] Wang M. H.; Lu J. X.; Yu Y.; Li Z. H.; Deng L. ACS Catal.2025, 15, 14392-14402.
[18] Xu H.-B.; Lin Z.-Z.; Bai J.-H.; Guo Y.-L.; Ma S. ACS Catal.2024, 14, 262-270.
[19] Shi C. Y.; Wang G. C.; Zhao C. Y.; Gu Q. N.; Hao X. J.; Zhou Y.CN 118063382 A (in Chinese).
[20] Suphaporn L.; Poonsakdi P.; Somsak R.; Chatphorn T.; Winai, I. Chem Asian J.2025, 20, e202401754.
[21] Lurie I. S.; Berrier A. L.; Casale J. F.; Iio R.; Bzenko Jr, J. S. Forensic Sc. Int.2012, 220, 191-196.
[22] Venkov A. P.; Vodenichrov D. M.; Ivanov I. I.Synthesis 1991, 476-478.
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