Examination of Diels–Alder/Tsuji–Trost Route towards Kopsia Alkaloids

Abstract

A reaction sequence of Diels–Alder cycloaddition and Tsuji–Trost allylation was examined in terms of its application to the synthesis of kopsinine and the related Kopsia alkaloids. Results of the studies in two synthetic directions are presented herein: 1) synthesis of the properly substituted diene, required for the Diels–Alder step; and 2) model studies and optimization of the key reaction sequence in the absence of side-chain. Details on the challenging introduction of the side-chain into tetrahydrocarboline ketone and its silylation, resulting in rare but unproductive vinylogous Claisen cyclization, and the successful Mannich/Mukaiyama aldol sequence are disclosed in the first direction. In the second direction, the endo-selective Diels–Alder reaction with allyl acrylate and Tsuji–Trost allylation providing incorrect stereochemistry are disclosed. Interaction of both dienes with an alkyne provides carbazoles via Alder–Rickert reaction.

Key words

alkaloids - total synthesis - Diels–Alder reaction - Tsuji–Trost allylation - Alder–Rickert reaction

Publication History

Received: 04 September 2023

Accepted after revision: 05 October 2023

Accepted Manuscript online:
05 October 2023

Article published online:
06 November 2023

• References

• 1 Dewick PM. Medicinal Natural Products: A Biosynthetic Approach 2009
• 2 O’Connor SE, Maresh J. J. Nat. Prod. Rep. 2006; 23: 532
• 3 Kam T.-S, Lim K.-H. Alkaloids of Kopsia. In The Alkaloids:Chemistry and Biology, Vol. 66. Cordell GA. Elsevier; New York: 2008: 1-111
• 4 Bohannon RA, Miller DG, Diamond HD. Cancer Res. 1963; 23: 613
• 5 Sirindil F, Weibel JM, Pale P, Blanc A. Nat. Prod. Rep. 2022; 39: 1574
• 6 David B, Sévenet T, Morgat M, Guénard D, Moisand A, Tollon Y, Thoison O, Wright M. Cell Motil. Cytoskeleton 1994; 28: 317
• 7 Subramaniam G, Hiraku O, Hayashi M, Koyano T, Komiyama K, Kam T.-S. J. Nat. Prod. 2008; 71: 53
• 8 Chen J, Yang ML, Zeng J, Gao K. Phytochem. Lett. 2014; 7: 156
• 9 Saxton JE. Synthesis of the Aspidosperma Alkaloids. In The Alkaloids: Chemistry and Biology, Vol. 50. Cordell GA. Academic Press; San Diego: 1998: 343-376
• 10 Saya JM, Ruijter E, Orru RV. A. Chem. Eur. J. 2019; 25: 8916
• 11 Wang N, Jiang X. Chem. Rec. 2021; 21: 295
• 12 Stork G, Dolfini JE. J. Am. Chem. Soc. 1963; 85: 2872
• 13 Wang N, Xiao X, Liu C.-X, Yao H, Huang N, Zou K. Adv. Synth. Catal. 2022; 364: 2479
• 14 Qin B, Wang Y, Wang X, Jia Y. Org. Chem. Front. 2021; 8: 369
• 15 Kozmin SA, Iwama T, Huang Y, Rawal VH. J. Am. Chem. Soc. 2002; 124: 4628
• 16 Xie J, Wolfe AL, Boger DL. Org. Lett. 2013; 15: 868
• 17 Jones SB, Simmons B, Mastracchio A, MacMillan DW. C. Nature 2011; 475: 183
• 18 Kuehne ME, Seaton PJ. J. Org. Chem. 1985; 50: 4790
• 19 HeinzGötz P, Bats JW, Fritz H. Liebigs Ann. Chem. 1986; 2065
• 20 Bleile M, Otto HH. Monatsh. Chem. 2005; 136: 1799
• 21 Pindur U, Pfeuffer L. Tetrahedron Lett. 1987; 28: 3079
• 22 Harada S, Morikawa T, Nishida A. Org. Lett. 2013; 15: 5314
• 23 Qin B, Lu Z, Jia Y. Angew. Chem. Int. Ed. 2022; 61: e202201712
• 24 Tsuji J, Minami I, Shimizu I. Chem. Lett. 1983; 12: 1325
• 25 Vulovic B, Gruden-Pavlovic M, Matovic R, Saicic RN. Org. Lett. 2014; 16: 34
• 26 Braun J, Ariëns MI, Matsuo BT, De Vries S, Van Wordragen ED. H, Ellenbroek BD, Vande Velde CM. L, Orru RV. A, Ruijter E. Org. Lett. 2018; 20: 6611
• 27 Faltracco M, Sukowski V, Van Druenen M, Hamlin TA, Bickelhaupt FM, Ruijter E. J. Org. Chem. 2020; 85: 9566
• 28 Li W, Chen Z, Yu D, Peng X, Wen G, Wang S, Xue F, Liu XY, Qin Y. Angew. Chem. Int. Ed. 2019; 58: 6059
• 29 Chittari P, Thomas A, Rajappa S. Tetrahedron Lett. 1994; 35: 3793
• 30 Thomas A, Rajappa S. Tetrahedron 1995; 51: 10571
• 31 Swaney BE, Gai S, Clark MR, Hawkins BC. Chem. Asian J. 2019; 14: 1102
• 32 Hızlıateş CG, Gülle S. J. Heterocycl. Chem. 2016; 53: 1584
• 33 Gartshore CJ, Lupton DW. Aust. J. Chem. 2013; 66: 882
• 34 Li Z, Zhang S, Wu S, Shen X, Zou L, Wang F, Li X, Peng F, Zhang H, Shao Z. Angew. Chem. Int. Ed. 2013; 52: 4117
• 35 Yasuda M, Chiba K, Ohigashi N, Katoh Y, Baba A. J. Am. Chem. Soc. 2003; 125: 7291
• 36 Yasuda M, Shigeyoshi Y, Shibata I, Baba A. Synthesis 2005; 233
• 37 Leng L, Zhou X, Liao Q, Wang F, Song H, Zhang D, Liu XY, Qin Y. Angew. Chem. Int. Ed. 2017; 56: 3703
• 38 Zhang YA, Milkovits A, Agarawal V, Taylor CA, Snyder SA. Angew. Chem. Int. Ed. 2021; 60: 11127
• 39 Krapcho AP, Weimaster JF, Eldridge JM, Jahngen EG. E, Lovey AJ, Stephens WP. J. Org. Chem. 1978; 43: 138
• 40 Azuma T, Takemoto Y, Takasu K. Chem. Pharm. Bull. 2011; 59: 1190
• 41 Paquette LA, Sivik MR. Synth. Commun. 1991; 21: 467
• 42 Dilman AD, Ioffe SL. Chem. Rev. 2003; 103: 733
• 43 Minowa N, Mukaiyama T. Chem. Lett. 1987; 16: 1719
• 44 Schuppe AW, Liu Y, Gonzalez-Hurtado E, Zhao Y, Jiang X, Ibarraran S, Huang D, Wang X, Lee J, Loria JP, Dixit VD, Li X, Newhouse TR. Chem 2022; 8: 2856
• 45 Dwulet NC, Chahine Z, Le Roch KG, Vanderwal CD. J. Am. Chem. Soc. 2023; 145: 3716
• 46 Goh YW, Danczak SM, Lim TK, White JM. J. Org. Chem. 2007; 72: 2929
• 47 Geng X, Danishefsky SJ. Org. Lett. 2004; 6: 413
• 48 Yu J, Yang M, Guo Y, Ye T. Org. Lett. 2019; 21: 3670
• 49 Arcadi A, Cacchi S, Marinelli F, Pace P. Synlett 1993; 743
• 50 Sha SC, Zhang J, Carroll PJ, Walsh PJ. J. Am. Chem. Soc. 2013; 135: 17602
• 51 Purgatorio R, de Candia M, Catto M, Carrieri A, Pisani L, De Palma A, Toma M, Ivanova OA, Voskressensky LG, Altomare CD. Eur. J. Med. Chem. 2019; 177: 414
• 52 Perrotta D, Racine S, Vuilleumier J, De Nanteuil F, Waser J. Org. Lett. 2015; 17: 1030
• 53 Wenzel AG, Jacobsen EN. J. Am. Chem. Soc. 2002; 124: 12964
• 54 Klán P, Beňovský P. Monatsh. Chem. 1992; 123: 469
• 55 Adair GR. A, Edwards MG, Williams JM. J. Tetrahedron Lett 2003; 44: 5523