Tf₂O-Promoted Morgan–Walls Reaction: From a Flexible Approach to Functionalized Phenanthridines and Quinazolines to the Short and Divergent Total Syntheses of Alkaloids

Abstract

A new protocol for the direct transformation of secondary amides (N-acyl-o-xenylamines) to phenanthridines under mild conditions is reported. The method features trifluoromethanesulfonic anhydride (Tf₂O)/2-fluoropyridine as the efficient amide activation system and MeCN or CH₂Cl₂ as the solvent. For some substrates, MeCN participated in the reaction, which affords a mild access to polysubstituted quinazolines. By employing a Tf₂O/2,4,6-tri-tert-butylpyrimidine (TTBP) combination, the method was extended to an N-formyl-o-xenylamine, which represents a recalcitrant amide substrate type for the dehydrative cyclization reaction. More importantly, a one-pot method was established for the direct and divergent synthesis of four types of phenanthridinoids from o-xenylamines, which features both a tert-N-formyl-o-xenylamine and phenanthridinium salt as key and versatile intermediates. The investigation has resulted in one of the shortest and the most efficient total syntheses of the three natural products trisphaeridine, 5,6-dihydrobicolorine, and N-methylcrinasiadine, and in the formal total syntheses of three other ones: 3-hydroxytrisphaeridine, bicolorine, and zephycandidine A.

Key words

amide activation - N-heterocycles - cyclization - step-economy - chemoselectivity - alkaloids - total synthesis - Morgan–Walls reaction

Publication History

Received: 14 September 2022

Accepted: 07 October 2022

Accepted Manuscript online:
07 October 2022

Article published online:
10 November 2022

• References

• 1a Browning CH, Morgan GT, Robb JV. M, Walls LP. J. Pathol. Bacteriol. 1938; 46: 203
• 1b Browning CH, Calver KM, Leckie MW, Walls LP. Nature 1946; 157: 263
• 2 Tumir L.-M, Stojković MR, Piantanida I. Beilstein J. Org. Chem. 2014; 10: 2930
• 3 Lozada IB, Huang B, Stilgenbauer M, Beach T, Qiu ZH, Zheng YR, Herbert DE. Dalton Trans. 2020; 49: 6557
• 4a Nair JJ, Van Staden J, Bastida J. Stud. Nat. Prod. Chem. 2016; 49: 107
• 4b Lewis JR. Nat. Prod. Rep. 1995; 12: 339
• 4c Lewis JR. Nat. Prod. Rep. 1992; 9: 183

For the isolation and bioactivities, see:
• 5a Ali AA, Elsayed HM, Abdallah OM, Steglich W. Phytochemistry 1986; 25: 2399
• 5b Suau R, Gómez AI, Rico R. Phytochemistry 1990; 29: 1710
• 5c Zupko I, Rethy B, Hohmann J, Molnar J, Ocsovszki I, Falkay G. In Vivo 2009; 23: 41
• 5d Luo Z, Wang F, Zhang J, Li X, Zhang M, Hao X, Xue Y, Li Y, Horgen FD, Yao G, Zhang Y. J. Nat. Prod. 2012; 75: 2113
• 5e Zhu Y.-Y, Li X, Yu H.-Y, Xiong Y.-F, Zhang P, Pi H.-F, Ruan H.-L. Arch. Pharmacal Res. 2015; 38: 604
• 5f Oluyemisi OO, Oriabure AE, Adekunle AJ, Ramsay KS. T, Shyyaula S, Choudhary MI. Pharm. Biol. 2015; 53: 882
• 5g Chen N, Ji Y, Zhang W, Xu Y, Yan X, Sun Y, Song H, Xu C, Cai L, Zheng H, Xiang Z. Lett. Org. Chem. 2016; 13: 536
• 5h Maslah H, Skarbek C, Gourson C, Plamont M.-A, Pethe S, Jullien L, Le Saux T, Labruère R. Angew. Chem. Int. Ed. 2021; 60: 24043
• 6a Viladomat F, Bastida J, Tribo G, Codina C, Rubiralta M. Phytochemistry 1990; 29: 1307

The structure of dihydrobicolorine proposed in reference 6a was confirmed to be identical to another alkaloid: ismine; see:
• 6b Cowden CJ, Banwell MG, Ho IC. S. J. Nat. Prod. 1994; 57: 1746
• 7 Zhan G, Qu X, Liu J, Tong Q, Zhou L, Sun B, Yao G. Sci. Rep. 2016; 6: 33990
• 8a Gopinatha SK, Soumitra H. RSC Adv. 2014; 4: 56518
• 8b Bernardo PH, Wan K.-F, Sivaraman T, Xu J, Moore FK, Hung AW, Mok HY. K, Yu VC, Chai CL. L. J. Med. Chem. 2008; 51: 6699
• 9a Chen Y.-L, Li F.-H, Bo Z.-S. Macromolecules 2010; 43: 1349
• 9b Pang P, Miao X, Ying L, Kong G, Che C, Deng W. J. Phys. Chem. C 2020; 124: 5665
• 10a Lu L.-Q, Li Y, Junge K, Beller M. J. Am. Chem. Soc. 2015; 137: 2763
• 10b Chen M.-W, Wu B, Chen Z.-P, Shi L, Zhou Y.-G. Org. Lett. 2016; 18: 4650
• 10c Yang Z, Chen F, Zhang S, He Y, Yang N, Fan Q.-H. Org. Lett. 2017; 19: 1458

For selected reviews, see:
• 11a Talukdar V, Vijayan A, Katari NK, Radhakrishnan KV, Das P. Adv. Synth. Catal. 2021; 363: 1202
• 11b Del Tito A, Abdulla HO, Ravelli D, Protti S, Fagnoni M. Beilstein J. Org. Chem. 2020; 16: 1476
• 11c Bisai V, Shaheeda MK. S, Gupta A, Bisai A. Asian J. Org. Chem. 2019; 8: 946
• 11d Walton JC. Molecules 2016; 21: 660
• 11e Zhang B, Studer A. Chem. Soc. Rev. 2015; 44: 3505

For an early review, see:
• 11f Theobald RS, Schofield K. Chem. Rev. 1950; 46: 171

For selected examples, see:
• 11g Candito DA, Lautens M. Angew. Chem. Int. Ed. 2009; 48: 6713
• 11h Tang C, Yuan Y, Jiao N. Org. Lett. 2015; 17: 2206
• 11i Romo-Pérez A, Miranda LD, García A. Tetrahedron Lett. 2015; 56: 6669
• 11j Raju G, Guguloth V, Satyanarayana B. RSC Adv. 2016; 6: 45036
• 11k Kishi A, Moriyama K, Togo H. J. Org. Chem. 2018; 83: 11080
• 11l Maiti D, Halder A, De Sarkar S. Adv. Synth. Catal. 2019; 361: 4941
• 11m Matsushita Y, Ochi R, Tanaka Y, Koike T, Akita M. Org. Chem. Front. 2020; 7: 1243
• 11n Chen J, Tang B, Liu X, Lv G, Shi Y, Huang T, Xing H, Guo X, Hai L, Wu Y. Org. Chem. Front. 2020; 7: 2944
• 11o Xu Y.-S, Yu C.-Y, Zhang X.-Y, Fan X.-S. J. Org. Chem. 2021; 86: 5805
• 11p Nakamura K, Kobayashi E, Moriyama K, Togo H. Tetrahedron 2021; 91: 132244
• 11q Jiang P, Shan Z, Chen S, Wang Q, Jiang S, Zheng H, Deng G.-J. Chin. J. Chem. 2022; 40: 365
• 11r Li J, Wang S, Zhao J, Li P. Org. Lett. 2022; 24: 5977
• 11s Ye H.-B, Zhou X.-Y, Li L, He X.-K, Xuan J. Org. Lett. 2022; 24: 6018
• 11t Pei C, Yang Z, Koenigs RM. Tetrahedron 2022; 123: 132939
• 12a Chen D.-Z, Fan S.-R, Yang B.-J, Yao H.-C, Wang Y.-T, Cai J.-Y, Jing C.-X, Pan Z.-H, Luo M, Yuze Y.-Q, Liu G.-J, Hao X.-J. J. Nat. Prod. 2021; 84: 1175
• 12b Chen D.-Z, Jing C.-X, Cai J.-Y, Wu J.-B, Wang S, Yin J.-L, Li X.-N, Li L, Hao X.-J. J. Nat. Prod. 2016; 79: 180

For selected reviews, see:
• 13a Pace V, Holzer W, Olofsson B. Adv. Synth. Catal. 2014; 356: 3697
• 13b Sato T, Yoritate M, Tajima H, Chida N. Org. Biomol. Chem. 2018; 16: 3864
• 13c Kaiser D, Bauer A, Lemmerer M, Maulide N. Chem. Soc. Rev. 2018; 47: 7899
• 13d Matheau-Raven D, Gabriel P, Leitch JA, Almehmadi YA, Yamazaki K, Dixon DJ. ACS Catal. 2020; 10: 8880
• 13e Czerwiński PJ, Furman B. Front. Chem. 2021; 9: 655849
• 13f Wang A.-E, Huang P.-Q. Chin. J. Org. Chem. 2021; 41: 3738
• 13g G.-Simonian N, Guérinot A, Cossy J. Synthesis 2022; in press DOI: 10.1055/s-0040-1720035.
• 14a Morgan GT, Walls LP. J. Chem. Soc. 1931; 2447

For a related report, see:
• 14b Pictet A, Hubert A. Ber. Dtsch. Chem. Ges. 1896; 29: 1182
• 15a Shabashov D, Daugulis O. J. Org. Chem. 2007; 72: 7720
• 15b Bowman WR, Lyon JE, Pritchard GJ. ARKIVOC 2012; (vii): 210
• 16a Movassaghi M, Hill MD, Ahmad OK. J. Am. Chem. Soc. 2007; 129: 10096
• 16b Movassaghi M, Hill MD. Org. Lett. 2008; 10: 3485
• 17 Xi J, Dong Q.-L, Liu G.-S, Wang S, Chen L, Yao Z.-J. Synlett 2010; 1674
• 18a Xiao K.-J, Luo J.-M, Ye K.-Y, Wang Y, Huang P.-Q. Angew. Chem. Int. Ed. 2010; 49: 3037
• 18b Xiao K.-J, Wang Y, Ye K.-Y, Huang P.-Q. Chem. Eur. J. 2010; 16: 12792
• 18c Xiao K.-J, Wang A.-E, Huang P.-Q. Angew. Chem. Int. Ed. 2012; 51: 8314
• 18d Ou W, Huang P.-Q. Sci. China: Chem. 2020; 63: 11
• 18e Huang X.-Z, Guo L.-D, Huang P.-Q. Nat. Commun. 2020; 11: 5314
• 18f Yu S.-J, Ye J.-L, Hong Y.-C, Huang P.-Q. J. Org. Chem. 2021; 86: 16926
• 18g He Q, Ye J.-L, Xu F.-F, Geng H, Chen T.-T, Chen H, Huang P.-Q. J. Org. Chem. 2021; 86: 16300
• 18h Chen D.-H, Sun W.-T, Zhu C.-J, Lu G.-S, Wu D.-P, Wang A.-E, Huang P.-Q. Angew. Chem. Int. Ed. 2021; 60: 8827
• 18i Huang Y.-H, Liu Z.-J, Huang P.-Q. Org. Chem. Front. 2022; 9: 58

For contributions from other groups, see: Charette:
• 19a Barbe G, Charette AB. J. Am. Chem. Soc. 2008; 130: 18
• 19b Pelletier G, Bechara WS, Charette AB. J. Am. Chem. Soc. 2010; 132: 12817
• 19c Bechara WS, Pelletier G, Charette AB. Nat. Chem. 2012; 4: 228
• 19d Cyr P, Régnier S, Bechara WS, Charette AB. Org. Lett. 2015; 17: 3386

Movassaghi:
• 19e Movassaghi M, Hill MD. J. Am. Chem. Soc. 2006; 128: 14254
• 19f ref. 16a.
• 19g ref. 16b.
• 19h Ahmad OK, Medley JW, Coste A, Movassaghi M. Org. Synth. 2012; 89: 549
• 19i Hill MD, Movassaghi M. Tetrahedron Lett. 2008; 49: 4286
• 19j Leypold M, D’Angelo KA, Movassaghi M. Org. Lett. 2020; 22: 8802

Chida/Sato:
• 19k Shirokane K, Kurosaki Y, Sato T, Chida N. Angew. Chem. Int. Ed. 2010; 49: 6369
• 19l Nakajima M, Oda Y, Wada T, Minamikawa R, Shirokane K, Sato T, Chida N. Chem. Eur. J. 2014; 20: 17565
• 19m Shirokane K, Wada T, Yoritate M, Minamikawa R, Takayama N, Sato T, Chida N. Angew. Chem. Int. Ed. 2014; 53: 512
• 19n Yoritate M, Takahashi Y, Tajima H, Ogihara C, Yokoyama T, Soda Y, Oishi T, Sato T, Chida N. J. Am. Chem. Soc. 2017; 139: 18386
• 19o Sugiyama Y, Soda Y, Yoritate H, Takahashi Y, Shibuya K, Ogihara C, Yokoyama T, Oishi T, Sato T, Chida N. Bull. Chem. Soc. Jpn. 2022; 95: 278

Maulide:
• 19p Valerio V, Petkova D, Madelaine C, Maulide N. Chem. Eur. J. 2013; 19: 2606
• 19q Tona V, Maryasin B, de la Torre A, Sprachmann J, González L, Maulide N. Org. Lett. 2017; 19: 2662
• 19r Li J, Berger M, Zawodny W, Simaan M, Maulide N. Chem 2019; 5: 1883
• 19s Spieß P, Berger M, Kaiser D, Maulide N. J. Am. Chem. Soc. 2021; 143: 10524
• 19t Heindl S, Riomet M, Matyasovsky J, Lemmerer M, Malzer N, Maulide N. Angew. Chem. Int. Ed. 2021; 60: 19123

Dixon and Chiba:
• 19u Gregory AW, Chambers A, Hawkins A, Jakubec P, Dixon DJ. Chem. Eur. J. 2015; 21: 111
• 19v Xie L.-G, Dixon DJ. Chem. Sci. 2017; 8: 7492
• 19w Ong DY, Fan D.-Y, Dixon DJ, Chiba S. Angew. Chem. Int. Ed. 2020; 59: 11903
• 19x Matheau-Raven D, Dixon DJ. Angew. Chem. Int. Ed. 2021; 60: 19725
• 19y Chen JH, Lim JW, Chiba S. Tetrahedron 2022; 114: 132779

See also:
• 19z Mo N.-F, Yu L, Zhang Y, Yao Y.-H, Kou X, Ren Z.-H, Guan Z.-H. CCS Chem. 2020; 2: 1775
• 19aa Li Z.-K, Zhao F, Ou W, Huang P.-Q, Wang X.-M. Angew. Chem. Int. Ed. 2021; 60: 26604
• 19ab He Y.-L, Wang Y.-X, Li S.-J, Lan Y, Wang X.-M. Angew. Chem. Int. Ed. 2022; 61: e202115497
• 19ac Zhao F, Jiang F, Wang X. Sci. China: Chem. 2022; 65: 2231
• 19ad Coelho A, Zafindrajaona MS. S, Vallée A, Behr JB, Vasse JL. Chem. Eur. J. 2022; 28: e202103789

For selected reviews on Tf₂O, see:
• 20a Huang H, Kang JY. Synthesis 2022; 54: 1157
• 20b Stang PJ, Hanack M, Subramanian LR. Synthesis 1982; 85
• 21a Banwell MG, Cowden CJ. Aust. J. Chem. 1994; 47: 2235
• 21b Harayama T, Akamatsu H, Okamura K, Miyagoe T, Akiyama T, Abe H, Takeuchi Y. J. Chem. Soc., Perkin Trans. 1 2001; 523
• 21c Banwell MG, Lupton DW, Ma X, Renner J, Sydnes MO. Org. Lett. 2004; 6: 2741
• 21d Portela-Cubillo F, Lymer J, Scanlan EM, Scott JS, Walton JC. Tetrahedron 2008; 64: 11908
• 21e Alonso R, Caballero A, Campos PJ, Rodríguez MA. Tetrahedron 2010; 66: 8828
• 21f Baechler SA, Fehr M, Habermeyer M, Hofmann A, Merz K.-H, Fiebig H.-H, Marko D, Eisenbrand G. Bioorg. Med. Chem. 2013; 21: 814
• 21g Linsenmeier AM, Williams CM, Bräse S. Eur. J. Org. Chem. 2013; 3847
• 21h Tummatorn J, Krajangsri S, Norseeda K, Thongsornkleeb C, Ruchirawat S. Org. Biomol. Chem. 2014; 12: 5077
• 21i Guo W, Li S, Tang L, Li M, Wen L, Chen C. Org. Lett. 2015; 17: 1232
• 21j Chen W.-L, Chen C.-Y, Chen Y.-F, Hsieh J.-C. Org. Lett. 2015; 17: 1613
• 21k Borah A, Gogoi P. Eur. J. Org. Chem. 2016; 2200
• 21l Fan-Chiang T.-T, Wang H.-K, Hsieh J.-C. Tetrahedron 2016; 72: 5640
• 21m Chowdhury D, Dana S, Mandal A, Baidya M. Chem. Commun. 2019; 55: 11908
• 21n Cai B.-G, Luo S.-S, Li L, Li L, Xuan J, Xiao W.-J. CCS Chem. 2020; 2: 2764
• 21o Chen P, Nan J, Hu Y, Kang Y, Wang B, Ma Y, Szostak M. Chem. Sci. 2021; 12: 803
• 21p Zhan Y.-L, Dai C.-H, Zhu Z.-T, Liu P, Sun P.-P. Chem. Asian J. 2022; 17: e202101388
• 22 Razafimbelo J, Andriantsiferana M, Baudouin G, Tillequin F. Phytochemistry 1996; 41: 323
• 23a Ref. 6b.
• 23b Kuwata Y, Sonoda M, Tanimori S. J. Heterocycl. Chem. 2017; 54: 1645
• 23c Asamdi M, Chauhan PM, Patel JJ, Chikhalia KH. Tetrahedron 2019; 75: 3485
• 24a ref. 21a.
• 24b Banwell MG, Bissett BD, Busato S, Cowden CJ, Hockless DC. R, Holman JW, Read RW, Wu AW. J. Chem. Soc., Chem. Commun. 1995; 2551
• 24c Cahiez G, Chaboche C, Mahuteau-Betzer F, Ahr M. Org. Lett. 2005; 7: 1943
• 24d Sanz R, Fernández Y, Castroviejo MP, Pérez A, Fañanás FJ. Eur. J. Org. Chem. 2007; 62
• 24e Yeung CS, Zhao XD, Borduas N, Dong VM. Chem. Sci. 2010; 1: 331
• 24f Pimparkar S, Jeganmohan M. Chem. Commun. 2014; 50: 12116
• 24g Shen WQ, Li J, Zhang CY, Shi M, Zhang J. Chem. Asian J. 2016; 11: 1883
• 24h ref. 21l.
• 24i Zou S, Zhang Z, Chen C, Xi C. Asian J. Org. Chem. 2021; 10: 355
• 24j Wang N, Wang D, He Y, Xi J, Wang T, Liang Y, Zhang Z. Adv. Synth. Catal. 2022; 364: 1150
• 25 Cernak T, Dykstra KD, Tyagarajan S, Vachal P, Krska SW. Chem. Soc. Rev. 2016; 45: 546
• 26 Li X.-Q, Li X.-W, Liu F, Li S, Shi D.-Y. J. Med. Chem. 2021; 64: 10581
• 27 Henninger J, Polborn K, Mayr H. J. Org. Chem. 2000; 65: 3569
• 28a Wender PA, Verma VA, Paxton TJ, Pillow TH. Acc. Chem. Res. 2008; 41: 40
• 28b Huang P.-Q. Synlett 2020; 31: 1681
• 29 Efficiency in Natural Product Total Synthesis . Huang P.-Q, Yao Z.-J, Hsung RP. John Wiley & Sons; Hoboken: 2018
• 30 Murphy PJ, Tibble-Howlings J, Kowalczyk RM, Stevens K. Tetrahedron Lett. 2020; 61: 151785
• 31 Prager R, Tsopelas C, Heisler T. Aust. J. Chem. 1991; 44: 277 ; and references cited therein