Synthesis, Table of Contents Synthesis 2023; 55(11): 1671-1689DOI: 10.1055/a-1777-2477 paper Special Issue dedicated to Prof. Cristina Nevado, recipient of the 2021 Dr. Margaret Faul Women in Chemistry Award Synthetic Studies towards Pyrido[1,2-a]azepine Stemona Alkaloids Martin Morgenstern‡ , Camilla Mayer‡ , Alexander Pöthig , Thorsten Bach ∗ Recommend Article Abstract Buy Article All articles of this category Abstract The carbon skeleton of the Stemona alkaloids stemokerrin and cochinchistemonine was assembled from three building blocks (a piperidine, a furan, and a tetronate). Key steps linking the fragments included a Stille cross-coupling (piperidine/furan) and an aldol-type addition of a tetronate. The furan served as a latent 1,4-difunctional compound which was converted into a γ-ketolactone by a type II photooxygenation. Attempts to construct the C12–C13 double bond of stemokerrin by a late-stage oxidation or by an elimination remained unsuccessful. The non-natural products dihydrostemokerrin and furostemokerrin were obtained instead. Key words Key wordsalkaloids - cross-coupling - diastereoselectivity - oxidation - pyridines - total synthesis Full Text References References 1 De Loureiro J. Flora cochinchinensis: sistens plantas in regno Cochinchina nascentes. Linnaeanum 2. Typis, et expensis Academicis; Ulyssipone: 1790. 401, 404 Accessed December 02, 2021 at: https://www.biodiversitylibrary.org/page/654094#page/49/mode/1up 2 Ginzrot JC. Die Wagen und Fahrwerke der Griechen und Römer und anderer alten Völker (Band 1). Lentner; München: 1817. 3a Jiang RW, Hon PM, Xu YT, Chan YM, Xu HX, Shaw PC, But PP. H. Phytochemistry 2006; 67: 52 3b But PP. H, Shaw PC, Lin G, Jiang RW, Xu YT. Adv. Bot. Res. 2012; 62: 1 3c Christenhusz MJ. M, Byng JW. Phytotaxa 2016; 261: 201 4a Jiang RW, Hon PM, But PP. H, Chung HS, Lin G, Ye WC, Mak TC. W. Tetrahedron 2002; 58: 6705 4b Xu YT, Hon PM, Jiang RW, Cheng L, Li SH, Chan YP, Xu HX, Shaw PC, But PP. H. J. Ethnopharmacol. 2006; 108: 46 4c Xu YT, Shaw PC, Jiang RW, Hon PM, Chan YM, But PP. H. J. Ethnopharmacol. 2010; 128: 679 5a Sekine T, Ikegami F, Fukasawa N, Kashiwagi Y, Aizawa T, Fujii Y, Ruangrungsi N, Murakoshi I. J. Chem. Soc., Perkin Trans. 1 1995; 391 5b Brem B, Seger C, Pacher T, Hofer O, Vajrodaya S, Greger H. J. Agric. Food Chem. 2002; 50: 6383 5c Chanmahasathien W, Ampasavate C, Greger H, Limtrakul P. Phytomedicine 2011; 18: 199 5d Huang SZ, Kong FD, Ma QY, Guo ZK, Zhou LM, Wang Q, Dai HF, Zhao YX. J. Nat. Prod. 2016; 79: 2599 5e Pudjiastuti P, Puspaningsih NN. T, Siswanto I, Fanani MZ, Ariga YK, Hase T, Sarker SD, Nahar L. J. Parasitol. Res. 2018; 3469132 5f Jung KH, Kil YS, Jung J, Park S, Shin D, Lee K, Seo EK, Bae H. Phytomedicine 2016; 23: 79 6a Greger H. Phytochem. Rev. 2019; 18: 463 6b Liu Y, Shen Y, Teng L, Yang L, Cao K, Fu Q. J. Ethnopharmacol. 2021; 265: 113112 6c Wang L, Wu H, Liu C, Jiang T, Yang X, Chen X, Tang L, Wang Z. Phytochem. Rev. 2021; in press 6d Weng FP, Chen QH. Nat. Prod. Commun. 2014; 9: 1809 7a Greger H. Planta Med. 2006; 72: 99 7b Schinnerl J, Brem B, But PP. H, Vajrodaya S, Hofer O, Greger H. Phytochemistry 2007; 68: 1417 8a Pilli RA, Rosso GB, Oliveira MC. F. Nat. Prod. Rep. 2010; 27: 1908 8b Pilli RA, Oliveira MC. F. Nat. Prod. Rep. 2000; 17: 117 8c Ye Y, Qin GW, Xu RS. J. Nat. Prod. 1994; 57: 655 9 Pyne SG, Ung AT, Jatisatienr A, Mungkornasawakul P. Mj. Int. J. Sci. Tech. 2007; 1: 157 10 Kaltenegger E, Brem B, Mereiter K, Kalchhauser H, Kählig H, Hofer O, Vajrodaya S, Greger H. Phytochemistry 2003; 63: 803 11 Lin LG, Tang CP, Dien PH, Xu RS, Ye Y. Tetrahedron Lett. 2007; 48: 1559 Reviews: 12a Olivier WJ, Smith JA, Bissember AC. Chem. Rec. 2022; 22: 202100277 12b Wu X, Ma K. Prog. Chem. 2020; 32: 752 12c Brito GA, Pirovani RV. Org. Prep. Proced. Int. 2018; 50: 245 12d Li Y, Li J, Ding H, Li A. Natl. Sci. Rep. 2017; 4: 397 12e Pyne SG, Jatisatienr A, Mungkornasawakul P, Ung AT, Limtrakul P, Sastraruji T, Sastraruji K, Chaiyong S, Umsumarng S, Baird MC, Dau XD, Ramli RA. Nat. Prod. Commun. 2017; 12: 1365 12f Liu XY, Wang FP. Nat. Prod. Commun. 2015; 10: 1093 12g Alibes R, Figueredo M. Eur. J. Org. Chem. 2009; 15: 2421 For recent syntheses, see: 13a Huang PQ, Huang SY, Gao LH, Mao ZY, Chang Z, Wang AE. Chem. Commun. 2015; 51: 4576 13b Ma K, Yin X, Dai M. Angew. Chem. Int. Ed. 2018; 57: 15209 13c Rebmann H, Gerlinger CK. G, Gaich T. Chem. Eur. J. 2019; 25: 2704 13d Hou Y, Shi T, Yang Y, Fan X, Chen J, Cao F, Wang Z. Org. Lett. 2019; 21: 2952 13e Siitonen JH, Csokas D, Papai I, Pihko PM. Synlett 2020; 31: 1581 13f Matsuo R, Miyashita A, Kuwabara M, Adachi S, Matsuzawa A, Sugita K. Synlett 2020; 31: 1800 13g Soda Y, Sugiyama Y, Yoritate M, Tajima H, Shibuya K, Ogihara C, Oishi T, Sato T, Chida N. Org. Lett. 2020; 22: 7502 13h Huang XZ, Gao LH, Huang PQ. Nat. Commun. 2020; 11: 5314 13i Uphade MB, Prasad KR. Tetrahedron 2020; 76: 131623 13j Olivier WJ, Bissember AC, Smith JA. Org. Lett. 2021; 23: 3437 13k Zheng Y, Yang HD, Wei K, Yang YR. J. Org. Chem. 2021; 86: 6025 13l Olivier WJ, Lucas NT, Bissember AC, Smith JA. Chem. Eur. J. 2021; 27: 15382 13m Deng Y, Liang X, Wei K, Yang YR. J. Am. Chem. Soc. 2021; 143: 20622 For general studies towards the construction of pyrido[1,2-a]azepines, see: 14a Fozard A, Jones G. J. Org. Chem. 1965; 30: 1523 14b Tietze LF, Wünsch JR, Noltemeyer M. Tetrahedron 1992; 48: 2081 14c Marx K, Eberbach W. Tetrahedron 1997; 53: 14687 14d Chou SS. P, Liang CF, Lee TM, Liu CF. Tetrahedron 2007; 63: 8267 14e Funeta MC, Dominguez D. J. Org. Chem. 2007; 72: 8804 14f Chendrasekhar B, Rao BV, Rao KV. M, Jagadeesh B. Tetrahedron: Asymmetry 2009; 20: 1217 14g Wang N, Zhang LH, Ye XS. Org. Biomol. Chem. 2010; 8: 2639 14h Gregory AW, Chambers A, Hawkins A, Jakubec P, Dixon DJ. Chem. Eur. J. 2015; 21: 111 14i Disadee W, Ruchirawat S. Org. Biomol. Chem. 2018; 16: 707 15a Mungkornasawakul P, Pyne SG, Jatisatienr A, Supyen D, Lie W, Ung AT, Skelton BW, White AH. J. Nat. Prod. 2003; 66: 980 15b Chaiyong S, Jatisatienr A, Mungkornasawakul P, Sastraruji T, Pyne SG, Ung AT, Urathamakul T, Lie W. J. Nat. Prod. 2010; 73: 1833 16 Shengule SR, Willis AC, Pyne SG. Tetrahedron 2013; 69: 8042 17 Duc XD, Willis AC, Pyne SG. Eur. J. Org. Chem. 2015; 35: 7682 18a Duc XD. Lett. Org. Chem. 2021; 18: 58 18b Duc XD. Lett. Org. Chem. 2022; in press, DOI: 19 Mayer C, Romek A, Bach T. Synlett 2015; 26: 1505 20a Chênevert R, Dickman M. J. Org. Chem. 1996; 61: 3332 20b Chênevert R, Ziarani GM, Morin MP, Dasser M. Tetrahedron: Asymmetry 1999; 10: 3117 21a Honda T, Matsukawa T, Takahashi K. Org. Biomol. Chem. 2011; 9: 673 21b Nakayama Y, Maeda Y, Kotatsu M, Sekiya R, Ichiki M, Sato T, Chida N. Chem. Eur. J. 2016; 22: 3300 22 Mungkornasawakul P, Matthews H, Ung AT, Pyne SG, Jatisatienr A, Lie W, Skelton BW, White AH. ACGC Chem. Res. Commun. 2005; 19: 30 23 For a review, see: Bhat C, Bugde ST, Tilve SG. Synthesis 2014; 46: 2551 24 Nahm S, Weinreb SM. Tetrahedron Lett. 1981; 22: 3815 25a Corey EJ, Bakshi RK, Shibata S. J. Am. Chem. Soc. 1987; 109: 5551 25b Corey EJ, Shibata S, Bakshi RK. J. Org. Chem. 1988; 53: 2861 25c Corey EJ, Helal CJ. Angew. Chem. Int. Ed. 1998; 37: 1986 25d For a recent application by our group, see: Proessdorf J, Zech A, Jandl C, Bach T. Synlett 2020; 31: 1598 26 Coe D, Drysdale M, Philps O, West R, Young DW. J. Chem. Soc., Perkin Trans. 1 2002; 2459 27 For a review, see: Plietker B. Synthesis 2005; 2453 28 Kurose T, Tsukano C, Takemoto Y. Org. Lett. 2017; 19: 4762 29a Robba M, Zaluski M.-C, Roques B. C. R. Acad. Sci., Ser. C 1967; 264: 413 29b Zaluski M.-C, Robba M, Bonhomme M. Bull. Soc. Chim. Fr. 1970; 1838 30 Occiato EG, Galbo FL, Guarna A. J. Org. Chem. 2005; 70: 7324 31a Bose KS, Marder TB. Org. Lett. 2014; 16: 4562 31b Smith MJ, Lawler MJ, Kopp N, McLeod DD, Davulcu AH, Lin D, Katipally KR, Sfouggatakis C. Org. Process. Res. Dev. 2017; 21: 1859 32 Wüst FR, Höhne A, Metz P. Org. Biomol. Chem. 2005; 3: 503 33 Farina V, Kapadia S, Krishnan B, Wang C, Liebeskind LS. J. Org. Chem. 1994; 59: 5905 34 Del Pozo J, Carrasco D, Perez-Temprano M, Garcia-Melchor M, Alvarez R, Casares JA, Espinet P. Angew. Chem. Int. Ed. 2013; 52: 2189 35 Khurana JM, Gogia A. Org. Prep. Proced. Int. 1997; 29: 1 36 Eibl C, Tomassoli I, Munoz L, Stokes C, Papke RL, Gündisch D. Bioorg. Med. Chem. 2013; 21: 7283 37 Wu C, Miller PA, Miller MJ. Bioorg. Med. Chem. Lett. 2011; 21: 2611 38 Xu F, Desmond R, Hoerrner RS, Humphrey RS, Humphrey GR, Itoh T, Journet M, Yoshikawa N, Zacuto MJ. WO2010/144293 A1, 2010 Reviews: 39a Clennan EL, Pace A. Tetrahedron 2005; 61: 6665 39b Montagnon T, Tofi M, Vassilikogiannakis G. Acc. Chem. Res. 2008; 41: 1001 39c Montagnon T, Kalaitzakis D, Triantafyllakis M, Stratakis M, Vassilikogiannakis G. Chem. Commun. 2014; 50: 15480 39d Ghogare AA, Greer A. Chem. Rev. 2016; 116: 8884 39e Makarov AS, Uchuskin MG, Trushkov IV. Synthesis 2018; 50: 3059 40 Luche JL. J. Am. Chem. Soc. 1978; 100: 2226 41 Xiao Q, Ren WW, Chen ZX, Sun TW, Li Y, Ye QD, Gong JX, Meng FK, You L, Liu YF, Zhao MZ, Xu LM, Shan ZH, Shi Y, Tang YF, Chen JH, Yang Z. Angew. Chem. Int. Ed. 2011; 50: 7373 42 CCDC 2141828 contains the supplementary crystallographic data for compound 30. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures 43a Zimmerman DM, Leander JD, Cantrell BE, Reel JK, Snoddy J, Mendelsohn LG, Johnson BG, Mitch CH. J. Med. Chem. 1993; 36: 2833 43b Hirokawa Y, Morie T, Yamazaki H, Yoshida N, Kato S. Bioorg. Med. Chem. Lett. 1998; 8: 619 44a Lindsay KB, Pyne SG. Synlett 2004; 779 44b Markovic R, Baranac M, Stojanovic M. Synlett 2004; 1034 44c Hu H, Peng Y, Yu T, Cheng S, Luo S, Zhu Q. Org. Lett. 2021; 23: 3636 45 Higashi T, Isobe Y, Ouchi H, Suzuki H, Okazaki Y, Asakawa T, Furuta T, Wakimoto T, Kan T. Org. Lett. 2011; 13: 1089 46 Lin LG, Dien PH, Tang CP, Ke CQ, Yang XZ, Ye Y. Helv. Chim. Acta 2007; 90: 2167 47 Starr J, Brown MF, Aschenbrenner L, Caspers N, Che Y, Gerstenberger BS, Huband M, Knafels JD, Lemmon MM, Li C, McCurdy SP, McElroy E, Rauckhorst MR, Tomaras AP, Young JA, Zaniewski RP, Shanmugasundaram V, Han S. J. Med. Chem. 2014; 57: 3845 48 For the synthesis of tetronate 10a, see: Knight DW, Pattenden G. J. Chem. Soc., Perkin Trans. 1 1975; 635 49a Baylis AM, Davies MP. H, Thomas EJ. Org. Biomol. Chem. 2007; 5: 3139 49b Nagaki A, Yamashita H, Takahashi Y, Ishiuchi S, Imai K, Yoshida J. Chem. Lett. 2018; 47: 71 50 Caravano A, Mengin-Lecreulx D, Brondello JM, Vincent SP, Sinay P. Chem. Eur. J. 2003; 9: 5888 51a Muzart J. Eur. J. Org. Chem. 2010; 3779 51b Wendlandt AE, Stahl SS. Angew. Chem. Int. Ed. 2015; 54: 14638 51c Nicolaou KC, Zhong YL, Baran PS. J. Am. Chem. Soc. 2000; 122: 7596 51d Fraga BM, Bressa C, Gonzalez-Vallejo V, Suarez S, Guillermo R. Tetrahedron Lett. 2011; 52: 7138 51e Chen Y, Romaire JP, Newhouse TR. J. Am. Chem. Soc. 2015; 137: 5875-5878 52a Punniyamurthy T, Rout L. Coord. Chem. Rev. 2008; 252: 134 52b McCann SD, Stahl SS. Acc. Chem. Res. 2015; 48: 1756 53a MacAlpine GA, Raphael RA, Shaw A, Taylor AW, Wild HJ. J. Chem. Soc., Perkin Trans. 1 1976; 410 53b Baylis AM, Helliwell M, Regan AC, Thomas EJ. J. Chem. Soc., Perkin Trans. 1 1993; 411 54a Csuk R, Glanzer BI. Tetrahedron 1991; 47: 1655 54b Bannai K, Toru T, Oba T, Tanaka T, Okamura N, Watanabe K, Hazato A, Kurozumi S. Tetrahedron 1986; 42: 6735 54c Solladie G, Dominguez C. J. Org. Chem. 1994; 59: 3898 54d Frederic CJ. M, Tikad A, Fu J, Pan W, Zheng RB, Koizumi A, Xue X, Lowary TL, Vincent SP. Chem. Eur. J. 2016; 22: 15913 55a Gedge DR, Pattenden G, Smith AG. J. Chem. Soc., Perkin Trans. 1 1986; 2127 55b Airiau E, Chemin C, Girard N, Lonzi G, Mann A, Petricci E, Salvadori J, Taddei M. Synthesis 2010; 2901 55c Walker JA. II, Chen JJ, Wise DS, Townsend LB. J. Org. Chem. 1996; 61: 2219 56a Urban M, Pohl R, Klepetarova B, Hocek M. J. Org. Chem. 2006; 71: 7322 56b Toribio G, Marjanet G, Alibes R, March P, Font J, Bayon P, Figueredo M. Eur. J. Org. Chem. 2011; 1534 56c Alonso-Fernandez J, Benaiges C, Casas E, Alibes R, Bayon P, Busque F, Alvarez-Larena A, Figueredo M. Tetrahedron 2016; 72: 3500 57a Kates MJ, Schauble JH. J. Org. Chem. 1994; 59: 494 57b Nicola T, Vieser R, Eberbach W. Eur. J. Org. Chem. 2000; 527 57c Minami Y, Yamada K, Hiyama T. Angew. Chem. Int. Ed. 2013; 52: 10611 58a Cacchi S, Fabrizi G, Moro L. J. Org. Chem. 1997; 62: 5327 58b Ferraz HM. C, Sano MK, Nunes MR. S, Bianco GG. J. Org. Chem. 2002; 67: 4122 58c Valduga CJ, Stefani HA, Petragnami N. J. Heterocycl. Chem. 2002; 39: 639 58d Gulias M, Rodriguez JR, Castedo L, Mascarenas JL. Org. Lett. 2003; 5: 1975 58e Fang Y, Li C. Chem. Commun. 2005; 3574 58f Kusakabe T, Kawai Y, Shen R, Mochida T, Kato K. Org. Biomol. Chem. 2012; 10: 3192 58g Liu Y, Zhang Q, Du Y, Yu A, Zhang K, Meng X. RSC Adv. 2014; 4: 52629 59 Kong C, Jana N, Driver TG. Org. Lett. 2013; 15: 824 60 Beng TK, Gawley RE. J. Am. Chem. Soc. 2010; 132: 12216 61 Harmata M, Hong X. J. Am. Chem. Soc. 2003; 125: 5754 62 Knight DW, Pattenden G. J. Chem. Soc., Perkin Trans. 1 1979; 62 Supplementary Material Supplementary Material Supporting Information