I.從 Horner 教授團隊發現兩性膦離子物種開始，親核膦催化成為建構碳-碳鍵重要而強大的合成工具。膦通過形成多樣的兩性離子中間體來活化缺電子烯烴，並根據不同反應物性質發展出多樣的反應類型。然而，至今對於透過膦催化劑活化缺電性丙二烯試劑進行1,4-加成反應的研究仍在探索中。
在本研究中，我們藉由γ-乙烯基炔酸酯與3-高醯基香豆素之化學選擇性 1,4-/1,7-加成反應研究。在不加入酸性添加劑的條件下，經膦催化劑會促使3-高醯基香豆素對γ-乙烯基炔酸酯進行1,4-加成反應。而當利用苯酚添加劑調控反應環境酸鹼值時，發現能影響γ-乙烯基炔酸酯的反應位置，進而生成1,7-加成產物。此外，1,4-加成反應的進行亦可透過親和性三級胺的催化來達成，並能提供相對膦催化系統更佳的效率。

II.由於亞烷基米氏酸其特殊的反應性，至今已被廣泛地用作建構雜環的實用合成子。其所具備雙親電反應位置的特性使得雙親核性試劑能夠在對亞烷基進行共軛加成後，接續與米氏酸的高活性的羰基反應並引發後續的脫羧過程達成環化的結果。然而，亞烷基米氏酸對 1,3-偶極的不對稱有機催化 (3+2) 環加成/環化反應的研究仍在探索中。
在此研究中，我們利用亞烷基米氏酸與鄰位接有羥基的亞胺葉立德作為 1,3-偶極經鏡像選擇性合成出 chromeno[4,3-b]pyrrolidines。藉由低催化量接有硫脲氫鍵片段的奎寧衍生物-QN-T (1 mol%)，幫助後續 (3+2) 合環反應及內酯化建構出具有 3 個連續立體中心的 chromeno[4,3-b]pyrrolidines，在產率及優異立體選擇性上皆有優秀的表現。特別的是，接有芳香類及雜芳香類取代基的反應物在30 ˚C 的反應環境下可以非常有效率地完成反應 (15-120 分鐘)。此外，經由更換掌性催化劑為 CN-T 的簡單操作，即可得到高產率及鏡像選擇性的產物的鏡像異構物。

I.Since Prof. Horner firstly reported the synthesis of phosphorus zwitterionic species, nucleophilic phosphine catalysis has becomed one of the most powerful tools for constructing C–C bonds. With the activation of phosphine catalysts, various zwitterionic intermediates generated from electron-deficient alkenes cpuld be applied in different types of reactions depending on the nature of other reaction partners. Among all the electron-deficient alkenes, the investigation of phosphine-catalyzed 1,4-addition reactions of γ-vinyl alkynoates was still under exploration.
Herein, we report the phosphine-catalyzed chemoselective 1,4-/1,7- addition of 3-homoacyl coumarins towards γ-vinyl alkynoates to afford substituted dienoates. Moreover, an acidic additive was found to be crucial for selectivity. It was discovered that the 1,4-addition on γ-vinyl alkynoates occurred under additive-free conditions, while the 1,7-addition takes place in presence of phenol as the additive. Furthermore, the nucleophilic tertiary amines were also found to be excellent catalysts for the 1,4-addition reactions, providing higher efficiency.

II.Alkylidene Meldrum's acids has been widely used as a practical synthon for the synthesis of annulated heterocycles according to its interesting reactivity profiles that allow the conjugated addition of a nucleophile on alkylidene and further decarboxylative annulation on the nucleophile-sensitive carbonyl groups. However, the research of alkylidene Meldrum's acids on asymmetric organocatalytic (3+2) cycloaddition/annulation reaction with 1,3-dipoles is still under exploration.
Herein, we report an enantioselective synthesis of chromeno[4,3-b]pyrrolidines from alkylidene Meldrum's acids with ortho-hydroxy azomethine ylides as 1,3-dipoles. The (3+2) cycloaddition/decarboxylative annulation pathway was achieved by employing low catalyst loading of quinine-derived thiourea QN-T (1.0 mol%), which afforded a broad range of chromeno[4,3-b]pyrrolidines bearing three contiguous stereocenters in high yields with excellent stereoselectivities. Remarkably, the reactions for substrates with aryl and heteroaryl substituents proceeded very efficiently at 30 ˚C (15-120 min). Moreover, the enantiomer of the product could be easily afforded in excellent results by simply utilizing the cinchonine-derived thiourea catalyst (CN-T).

1.(a) Xie, C.; Smaligo, A. J.; Song, X.-R.; Kwon, O. ACS Cent. Sci. 2021, 7, 536–558. (b) Guo, H.-C.; Fan, C.-Y.; Sun, Z.-H.; Yang Wu, Y.; Kwon, O. Chem. Rev. 2018, 118, 10049–10293.
2. Horner, L.; Jurgeleit, W.; Klupfel, K. Liebigs Ann. Chem. 1955, 591, 108–117.
3. Rauhut, M. M.; Currier, H. Preparation of dialkyl 2-methyleneglutarates. U.S. Patent 3074999, 1963.
4. Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815–2816.
5. Baylis, A. B.; Hillman, M. E. D. Patent 2155113, 1972.
6. (a)Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535-544.
(b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035-1055.
7. Guo, H.; Fan, Y. C.; Sun, Z.; Wu, Y.; Kwon, O. Chem. Rev. 2018, 118, 10049–10293.
8. Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167-3168.
9. Zhang, C.; Lu, X. Synlett. 1995, 6, 645-646.
10. Guo, H.; Fan, Y. C.; Sun, Z.; Wu, Y.; Kwon, O. Chem. Rev. 2018, 118, 10049–10293
11. Martin, T. J.; Tran, S. Y.;Vakhshori, V. G.; Kwon, O. Org. Lett. 2011, 13, 2586-2589.
12. Guan, X.; Wei, Y.; Shi, M. Eur. J. Org. Chem., 2011, 2673-2677.
13. Li, E.; Xie, P.; Yang, L.; Liang, L.; Huang, Y. Chem. – Asian J. 2013, 8, 603-610.
14. Gandi, V.; Lu, Y. Chem. Commun. 2015, 51, 16188-16190.
15. Feng, J.; Huang, Y. ACS Catalysis 2020, 10, 3541-3547.
16.(a) Li, X.-H.; Huang, Y. Chem. Commun. 2021, 57, 9934-9937. (b) Feng, J.-X.; Huang, Y. Chem. Commun. 2019, 55, 14011-14014. (c) Feng, Jiaxu, Chen, Y.-Y.; Qin, W.-H.; Huang, Y. Org. Lett. 2019, 22, 433-437. (d) Li, X.-H.; Cai, Wei; Huang, Y. Adv. Synth. Catal. 2022, 364, 1879-1883.
17.(a) Breul, A. M.; Hager, M. D.; Schubert, U. S. Chem. Soc. Rev., 2013, 42, 5366. (b) Shi, W.; Ma, H. Chem. Commun., 2012, 48, 8732.
18. (a)Medina, F. G.; Marrero, J. G.; M. Macias-Alonso, M. C. Gonzalez, I. Cordova-Guerrero, A. G. Teissier Garcia; S. Osegueda-Robles Nat. Prod. Rep. 2015, 32, 1472. (b) J. Grover and S. M. Jachak RSC Adv. 2015, 5, 38892. (c) S. Sandhu, Y. Bansal, O. Silakari; G. Bansal , Bioorg. Med. Chem., 2014, 22, 3806. (d)Sandhu, S.; Bansal, Y.; Silakari, O.; Bansal, G. Bioorg. Med. Chem. 2014, 22, 3806-3814.
19. S. Sandhu, Y. Bansal, O. Silakari; G. Bansal Bioorg. Med. Chem., 2014, 22, 3806.
20. (a) A. Song, X. Zhang, X. Song, X. Chen, C. Yu, H. Huang, H. Li; W. Wang Angew. Chem., Int. Ed. 2014, 53, 4940. (b) Y.-T. Lee, U. Das, Y.-R. Chen, C.-J. Lee, C.-H. Chen , M.-C. Yang and W. Lin Adv. Synth. Catal. 2013, 355, 3154. (c) Y. Wang, Z.-H. Yu , H.-F. Zheng and D.-Q. Shi Org. Biomol. Chem. 2012, 10, 7739.
21. Chen, Y.-R.; Reddy, G. M.; Hsieh, K.-H.; Chen, K.-H.; Karanam, P.; Vagh, S. S.; Liou, Y.-C.; Lin, W.* Chem. Commun. 2018, 54, 12702-12705.
22.(a) Xiaohu Li, Wei Cai, You Huang. Adv. Synth. Catal. 2022, 364, 1879-1883.
(b) Feng, J.; Chen, Y.; Qin, W.; Huang, Y. Org. Lett. 2020, 22, 433–437.
23. Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815–2816.
24. Dongqiu Li, Fang Cheng, Yuhai Tang, Jing Li, Yang Li, Jiao Jiao, Silong Xu. J. Org. Chem. 2022, 87, 6362-6370.
25. Tsai, Y.-L.; Syu, S.; Yang, S.-M.; Das, U.; Fan, Y.-S.; Lee, C.-J.; Lin, W.* Tetrahedron 2014, 70, 5038-5045.
26. Pàmies, O., & Bäckvall, J.-E. Chemical Reviews, 2003, 103, 3247–3262.
27. Li, Y., Chen, S., Xu, Z.-X., Wu, X., Zhang, H., & Zhang, J. CrystEngComm. 2021 23, 4748–4751.
28. B. D. Vineyard, W. S. Knowles, M. J. Sabacky, G. L. Bachman, and D. J. Weinkauff Contribution from Monsanto Company, St. Louis, Missouri 63166. Received March 3, 1977
29. Hall, M. RSC Chemical Biology 2021, 2, 958–989.
30. Friest, J. A.; Maezato, Y.; Broussy, S.; Nelson, D. L.; Berkowitz, D. B. J. Am. Chem. Soc. 2010, 132, 5930-5931.
31.List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395– 2396.
32. Friest, J. A.; Maezato, Y.; Broussy, S.; Nelson, D. L.; Berkowitz, D. B. J. Am. Chem. Soc. 2010, 132, 5930-5931.
33. J. Gerencs¦r, G. Dorman, F. Darvas, QSAR Comb. Sci. 2006, 25, 439.
34. Bourin, M., Chue, P., & Guillon, Y. CNS Drug Reviews, 2006, 7, 25–47.
35. A. N. Meldrum J. Chem. Soc. 1908, 93, 598.
36. D. Davidson, S. A. Bernhard J. Am. Chem. Soc. 1948, 70, 3426.
37. (a) H. McNab Chem. Soc. Rev. 1978, 7, 345. b) B.-C. Chen Heterocycles
1991, 32, 529.
38. A. S. Ivanov Chem. Soc. Rev. 2008, 37, 789.
39. (a) H. McNab Chem. Soc. Rev. 1978, 7, 345. (b) B.-C. Chen Heterocycles 1991, 32, 529. (c) A. M. Dumas, E. Fillion Acc. Chem. Res. 2010, 43, 440.
40. (a) V. V. Lipson, N. Y. Gorobets Mol. Div. 2009, 13, 399. (b) Mierin¸ a, M. Jure Chem. Heterocycl. Compd. 2016, 52, 7.
41. (a) J. Gerencs¦r, G. ChemCatChem 2016, 8, 1882–1890. (b) H Verlag GmbH; Co. KGaA, Weinheim Minireviews Dorm‚n, F. Darvas QSAR Comb. Sci. 2006, 25, 439. 42. J. Gerencs¦r, G Dorm‚n, F. Darvas QSAR Comb. Sci. 2006, 25, 439.
43. O. Bassas, J. Huuskonen, K. Rissanen, A. M. P. Koskinen Eur. J. Org. Chem. 2009, 9, 1340-1351.
44. Pair, E., Berini, C., Noël, R., Sanselme, M., Levacher, V., & Brière, J. F. Chem. Comm. 2014, 50, 10218-10221.
45. Mizukami, S.; Kihara, N.; Endo, T. Tetrahedron Lett. 1993, 34, 7437-7440.
46. Bassas, O.; Huuskonen, J.; Rissanen, K.; Koskinen, A. M. P. Eur. J. Org. Chem. 2009, 9, 1340-1351.
47. Pair, E., Berini, C., Noël, R., Sanselme, M., Levacher, V., & Brière, J. F. Chem. Comm. 2014, 50, 10218-10221.
48. Frankowski, S., Gajda, T., Albrecht, Ł. Adv. Synth. Catal. 2018, 360, 1822–1832.
49. Huisgen, R. Angew. Chem. Int. Ed. Engl. 1963, 2, 565–598.
50. Vicario, J. L., Reboredo, S., Badía, D., & Carrillo, L. Angew. Chem. 2007, 119, 5260–5262.
51. Huang, Zu.; Bao, Y.; Zhang, Y.; Yang, F.; Lu, T.; Zhou, Q. J. Org. Chem. 2017, 82, 12726–12734.
52. Painter, T. O.; Kaszas, K.; Gross, J.; Douglas, J. T.; Day, V. W.; Iadarola, M. J.; Santini, C. Bioorg. Med. Chem. Lett. 2014, 24, 963-968.
53. Kakuda, S.; Ninomiya, M.; Tanaka, K.; Koketsu, M. ChemistrySelect 2016, 1, 4203-4208.
54. (a) Lovely, C.; Bararinarayana, V. Curr. Org. Chem. 2008, 12, 1431– 1453. (b) Confalone, P. N.; Huie, E. M. J. Am. Chem. Soc. 1984, 106, 7175– 7178. (c) Arumugam, N.; Raghunathan, R.; Almansour, A. I.; Karama, U. Bioorg. Med. Chem. Lett. 2012, 22, 1375– 1379. (d) Bolognesi, M. L.; Andrisano, V.; Bartolini, M.; Minarini, A.; Rosini, M.; Tumiatti, V.; Melchiorre, C. J. Med. Chem. 2001, 44, 105– 109. (e) Gong, Y. D.; Najdi, S.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 1998, 63, 3081– 3086.
55. Yang, S.-M.; Reddy, G.-M.; Wang, T.-P.; Yeh, Y.-S.; Wang, M.; Lin, W. Chem. Commun. 2017, 54, 7649- 7652.
56. Kowalczyk, D.; Albrecht, L. J. Org. Chem. 2016, 81, 6800-6807.
57. Zhou, Q.; Chen, B.; Huang, X.-B.; Zeng, Y.-L.; Chu, W.-D.; He, L.; Liu, Q.-Z. J. Am. Chem. Soc. 2012, 134, 42, 17823–17831.
58. Yu, J.-K.; Chien, H.-W.; Lin, Y.-J.; Karanam, P.; Chen, Y.-H.; Lin, W.* Chem. Commun. 2018, 54, 9921-9924.