Collective Total Synthesis of β-Carboline-Type Monoterpenoid Indole Alkaloid Glycosides

Abstract

The collective and efficient asymmetric total syntheses of five β-carboline-type monoterpenoid indole alkaloid glycosides were achieved in fewer than thirteen steps. A Pictet–Spengler reaction with α-cyanotryptamine followed by the removal of the cyano group and autoxidation (aromatization) efficiently constructed the β-carboline motif. In addition, bioinspired reactions were developed to provide different alkaloid skeletons.

Key words

bioinspired reaction - monoterpenoid indole alkaloid - β-carboline - decyanation - Pictet–Spengler reaction

Publication History

Received: 30 January 2023

Accepted after revision: 13 March 2023

Accepted Manuscript online:
13 March 2023

Article published online:
18 April 2023

• References and Notes

• 1a Cordell GA. Introduction to Alkaloids: A Biogenetic Approach . Wiley-Interscience; New York: 1981
• 1b Pelletier SW. In The Alkaloids: Chemical and Biological Perspectives, Vol. 1. Pelletier SW. Wiley; New York: 1983
• 1c Indoles and Biogenetically Related Alkaloids . Phillipson JD, Zenk MH. Academic Press; London: 1980
• 1d The Monoterpenoid Indole Alkaloids. In Indoles, Vol. 25, Part 4. Saxton JE. The Chemistry of Heterocyclic Compounds; Wiley; New York: 1983
• 1e Monoterpenoid Indole Alkaloids. In Indoles, Suppl., Vol. 25, Part 4. Saxton JE. The Chemistry of Heterocyclic Compounds; Wiley; New York: 1994
• 1f Saxton JE. Nat. Prod. Rep. 1997; 14: 559
• 1g Leonard J. Nat. Prod. Rep. 1999; 16: 319
• 1h Cordell GA, Quinn-Beattie ML, Farnsworth NR. Phytother. Res. 2001; 15: 183
• 1i O’Connor SE, Maresh JJ. Nat. Prod. Rep. 2006; 23: 532
• 1j Pickens LB, Tang Y, Chooi Y.-H. Annu. Rev. Chem. Biomol. Eng. 2011; 2: 211
• 1k Amirkia V, Heinrich M. Phytochem. Lett. 2014; 10: xlviii
• 2a Levesque J, Pousset JL, Cave A. C. R. Seances Acad. Sci., Ser. C 1975; 280: 593
• 2b Aimi N, Murakami H, Tsuyuki T, Nishiyama T, Sakai S, Haginiwa J. Chem. Pharm. Bull. 1986; 34: 3064
• 3a Passos CS, Simões-Pires CA, Nurisso A, Soldi TC, Kato L, de Oliveira CM. A, de Faria EO, Marcourt L, Gottfried C, Carrupt P.-A, Henriques AT. Phytochemistry 2013; 86: 8
• 3b dos Santos PC, Soldi TC, Torres AR, Anders AM, Simoes-Pires C, Marcourt L, Gottfried C, Henriques AT. J. Enzyme Inhib. Med. Chem. 2013; 28: 611
• 3c Barreto IM, Moreira PO. L, de Macedo GE. L, Maia DN. B, de Almeida AT. M, de Oliveira DM, Cota BB. Rev. Bras. Farmacogn. 2021; 31: 709
• 4 Aimi N, Tsuyuki T, Murakami H, Sakai S, Haginiwa J. Tetrahedron Lett. 1985; 26: 5299
• 5 Aquino R, Garofalo L, de Tommasi N, de Ugaz OL, Pizza C. Phytochemistry 1994; 37: 1471
• 6 Capasso A, Aquino R, Garofalo L, De Simone F, Sorrentino L. J. Pharm. Pharmacol. 1997; 49: 712
• 7 Pimenta AA. T, Braz-Filho R, Delprete PG, Bezerra de Souza E, Silveira ER, Lima MA. S. Biochem. Systemat. Ecol. 2010; 38: 846
• 8a Rakumitsu K, Sakamoto J, Ishikawa H. Chem. Eur. J. 2019; 25: 8996
• 8b Sakamoto J, Umeda U, Rakumitsu K, Sumimoto M, Ishikawa H. Angew. Chem. Int. Ed. 2020; 59: 13414
• 9 Chan ST. S, Pearce AN, Page MJ, Kaiser M, Copp BR. J. Nat. Prod. 2011; 74: 1972
• 10 Kamal A, Tangella Y, Manasa KL, Sathish M, Srinivasulu V, Chetna J, Alarifi A. Org. Biomol. Chem. 2015; 13: 8652
• 11 Li Z, Chen S, Zhu S, Luo J, Zhang Y, Weng Q. Molecules 2015; 20: 13941
• 12 Kumar S, Wang Y.-H, Chen P.-J, Chang Y.-C, Kashyap HK, Shen Y.-C, Yu H.-P, Hwang T.-L. Bioorg. Chem. 2021; 111: 104846

Other syntheses using our prepared secologanin or strictosidine:
• 13a Nakashima N, Sakamoto J, Kitajima M, Ishikawa H. Chem. Pharm. Bull. 2022; 70: 187
• 13b Sakamoto J, Kitajima M, Ishikawa H. Chem. Pharm. Bull. 2022; 70: 662
• 13c Yoshidome A, Sakamoto J, Kohara M, Shiomi S, Hokaguchi M, Hitora Y, Kitajima M, Tsukamoto S, Ishikawa H. Org. Lett. 2023; 25: 314
• 13d Sakamoto J, Kitajima M, Ishikawa H. Chem. Eur. J. 2023; 29: e202300179
• 14 Typical Experimental Details for the Synthesis of Lyaloside (1) To a solution of lyaloside tetraacetate (8, 6.9 mg, 0.0099 mmol, 1.0 equiv) in MeOH (100 μL), K₂CO₃ (4.1 mg, 0.030 mmol, 3.0 equiv) was added at 0 °C. The reaction mixture was stirred for 10 min at 0 °C under an argon atmosphere. The resulting mixture was directly charged on PTLC and purified (20% MeOH/CHCl₃) to afford lyaloside (1, 5.0 mg, 95%) as a pale yellow amorphous powder; [α]_D ²⁴ –168.3 (c 0.50, MeOH). IR (ATR): ν_max = 3242, 2917, 2853, 2347, 2254, 1698, 1678, 1625, 1567, 1500, 1434, 1384, 1303, 1243, 1186, 1157, 1069, 1019, 947, 924, 896, 822 cm^–1. ¹H NMR (600 MHz, (CD₃)₂SO): δ = 11.37 (s, 1 H), 8.26 (d, J = 4.8 Hz, 1 H), 8.18 (d, J = 7.8 Hz, 1 H), 7.91 (d, J = 4.8 Hz, 1 H), 7.55 (dt, J = 8.4, 0.6 Hz, 1 H), 7.50 (ddd, J = 8.4, 7.2, 1.2 Hz, 1 H), 7.47 (d, J = 1.2 Hz, 1 H), 7.21 (ddd, J = 7.8, 7.2, 0.6 Hz, 1 H), 5.65 (ddd, J = 17.4, 10.2, 9.0 Hz, 1 H), 5.51 (d, J = 4.8 Hz, 1 H), 5.13 (d, J = 4.8 Hz, 1 H), 5.02 (m, 2 H), 4.94 (dd, J = 10.2, 1.8 Hz, 1 H), 4.73 (d, J = 17.4 Hz, 1 H), 4.59 (m, 1 H), 4.56 (d, J = 7.8 Hz, 1 H), 3.72–3.67 (m, 2 H), 3.54 (dd, J = 14.4, 5.4 Hz, 1 H), 3.45 (m, 1 H), 3.35 (s, 3 H), 3.19–3.15 (m, 2 H), 3.13 (dd, J = 14.4, 9.0 Hz, 1 H), 3.07 (br t, J = 9.0 Hz, 1 H), 3.02 (td, J = 7.8, 4.8 Hz, 1 H), 2.72 (dt, J = 10.2, 4.8 Hz, 1 H) ppm. ¹³C NMR (150 MHz, (CD₃)₂SO): δ = 166.6, 151.7, 143.8, 140.3, 134.5, 134.1, 137.3, 127.7, 126.8, 121.6, 121.0, 119.0, 118.8, 112.5, 111.9, 109.9, 98.7, 95.8, 77.3, 76.8, 73.0, 70.0, 61.1, 50.8, 42.9, 32.5, 29.9 (br) ppm. HRMS (ESI): m/z [M + H]⁺ calcd for [C₂₇H₃₁N₂O₉]⁺: 527.2030; found: 527.2044. UV (MeOH): λ_max = 215, 236, 241, 251, 281, 289, 338, 350 nm.
• 15 Typical Experimental Details for the Synthesis of Ophiorines A (3) and B (4) Lyaloside (1, 20 mg, 0.038 mmol) was dissolved in 0.1 M aqueous NH₄OAc solution (760 μL). After stirring the reaction mixture for 3 d at 110 °C, the solvent and NH₄OAc were removed under reduced pressure. The resulting crude material was purified by size exclusion recycle HPLC (Asahipak GS-510 20G and Asahipak GS-310 20G MeOH, 5.0 mL/min, λ = 254 nm) to afford ophiorines A (3, 9.1 mg, 47%) and B (4, 5.4 mg, 28%) as pale yellow amorphous powder, respectively. Compound 3 [α]_D ²⁵ +71.0 (c 0.31, MeOH). IR (ATR): ν_max = 3168, 1735, 1631, 1595, 1525, 1497, 1455, 1380, 1335, 1264, 1228, 1207, 1157, 1063, 1040, 987, 935, 899, 864, 824 cm^–1. ¹H NMR (600 MHz, D₂O): δ = 8.40 (d, J = 6.6 Hz, 1 H), 8.12 (d, J = 6.6 Hz, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.57 (t, J = 7.8 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.21 (t, J = 7.8 Hz, 1 H), 6.62 (s, 1 H), 5.89 (ddd, J = 17.4, 10.8, 6.6 Hz, 1 H), 5.37 (d, J = 10.8 Hz, 1 H), 5.36 (d, J = 17.4 Hz, 1 H), 4.67 (d, J = 9.6 Hz, 1 H), 4.46 (d, J = 7.8 Hz, 1 H), 3.58 (br s, 2 H), 3.49 (d, J = 12.6 Hz, 1 H), 3.36–3.31 (m, 3 H), 3.20–3.15 (m, 3 H), 3.07 (m, 1 H), 2.91 (m, 1 H) ppm. ¹³C NMR (150 MHz, D₂O): δ = 176.3, 145.5, 139.0, 135.9, 134.85, 134.81, 133.9, 133.6, 124.5, 123.7, 121.3, 120.8, 118.4, 114.5, 100.9, 97.4, 90.6, 78.0, 77.4, 74.3, 71.3, 62.2, 48.8, 47.8, 32.3, 25.1 ppm. HRMS (ESI): m/z [M + H]⁺ calcd for [C₂₆H₂₉N₂O₉]⁺: 513.1873; found: 513.1852. UV (MeOH): λ_max = 207, 217, 254, 301, 310, 372 nm. Compound 4 [α]_D ²⁴ +33.0 (c 0.41, MeOH). IR (ATR): ν_max = 3133, 2919, 1735, 1629, 1597, 1529, 1504, 1451, 1387, 1335, 1263, 1225, 1069, 942, 899, 824 cm^–1. ¹H NMR (600 MHz, D₂O): δ = 8.43 (d, J = 6.0 Hz, 1 H), 8.35 (d, J = 6.0 Hz, 1 H), 8.12 (d, J = 7.8 Hz, 1 H), 7.69 (t, J = 7.8 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.34 (t, J = 7.8 Hz, 1 H), 6.63 (s, 1 H), 5.85 (ddd, J = 17.4, 10.8, 6.0 Hz, 1 H), 5.35 (d, J = 10.8 Hz, 1 H), 5.34 (d, J = 17.4 Hz, 1 H), 4.64 (d, J = 10.2 Hz, 1 H), 4.42 (d, J = 8.4 Hz, 1 H), 3.81 (m, 1 H), 3.62 (m, 1 H), 3.53 (d, J = 11.4 Hz, 1 H), 3.35–3.32 (m, 2 H), 3.19–3.14 (m, 4 H), 3.08 (m, 1 H), 2.78 (m, 1 H) ppm. ¹³C NMR (150 MHz, D₂O): δ = 176.0, 145.0, 139.1, 135.1 (2C), 134.2, 133.4, 133.3, 124.1, 123.1, 120.6 (2 C), 117.6, 113.8, 100.3, 96.5, 89.8, 77.2, 76.6, 73.6, 70.6, 61.6, 45.6, 44.4, 31.6, 27.7 ppm. HRMS (ESI): m/z [M + H]⁺ calcd for [C₂₆H₂₉N₂O₉]⁺: 513.1873; found: 513.1848. UV (MeOH): λ_max = 208, 217, 254, 301, 310, 372 nm.
• 16 Sakamoto J, Ishikawa H. Chem. Eur. J. 2022; 28: e202104052
• 17 Jarret M, Tap A, Kouklovsky C, Poupon E, Evanno L, Vincent G. Angew. Chem. Int. Ed. 2018; 57: 12294
• 18 Typical Experimental Details for the Synthesis of Lyalosidic Acid (2) To a solution of lyalosidic acid tetraacetate (19, 27.5 mg, 0.0404 mmol, 1.0 equiv) in MeOH (400 μL), K₂CO₃ (16.8 mg, 0.121 mmol, 3.0 equiv) was added at 0 °C. The reaction mixture was stirred for 20 min at 0 °C under an argon atmosphere. The resulting mixture was neutralized with 1.0 M aqueous HCl solution and then concentrated under reduced pressure. The crude materials were purified by PTLC (SiO₂, 30% MeOH/CHCl₃) to afford lyalosidic acid (2, 19.0 mg, 92%) as a pale yellow amorphous powder. The structure of 2 was determined as HCl salt by measuring the spectral data, including 2D NMR; [α]_D ²⁵ –142.4 (c 0.63, MeOH). IR (ATR): ν_max = 3223, 2906, 1639, 1630, 1540, 1507, 1426, 1393, 1322, 1250, 1192, 1156, 1072, 1039, 951, 928, 903, 877, 822 cm^–1. ¹H NMR (600 MHz, CD₃OD): δ = 8.52 (dd, J = 6.0, 1.2 Hz, 1 H), 8.38 (d, J = 8.4 Hz, 1 H), 8.32 (d, J = 6.0, 1.2 Hz, 1 H), 7.79 (t, J = 7.8 Hz, 1 H), 7.77 (d, J = 7.8 Hz, 1 H), 7.64 (s, 1 H), 7.45 (ddd, J = 8.4, 7.8, 1.2 Hz, 1 H), 5.97 (ddd, J = 17.4, 10.2, 8.4 Hz, 1 H), 5.94 (d, J = 8.4 Hz, 1 H), 5.24 (d, J = 17.4 Hz, 1 H), 5.22 (d, J = 10.2 Hz, 1 H), 4.84 (d, J = 7.8 Hz, 1 H), 3.99 (dd, J = 12.0, 2.4 Hz, 1 H), 3.70 (dd, J = 12.0, 6.6 Hz, 1 H), 3.65–3.63 (m, 2 H), 3.57 (td, J = 7.8, 5.4 Hz, 1 H), 3.43 (t, J = 9.0 Hz, 1 H), 3.41 (m, 1 H), 3.28 (t, J = 9.0 Hz, 1 H), 3.25 (dd, J = 9.0, 7.8 Hz, 1 H), 2.74 (td, J = 8.4, 5.4 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CD₃OD): δ = 170.0, 155.6, 145.2, 141.5, 135.9, 135.0, 134.8, 133.0, 129.6, 124.2, 123.0, 121.4, 120.3, 116.7, 113.8, 109.1, 100.4, 97.1, 78.7, 78.0, 74.7, 71.7, 62.9, 45.4, 35.9, 33.3 ppm. HRMS (ESI): m/z [M + H]⁺ calcd for [C₂₆H₂₉N₂O₉]⁺: 513.1873, found: 513.1853. UV (MeOH): λ_max = 209, 240, 249, 293, 305, 372 nm.
• 19 Typical Experimental Details for the Synthesis of Correantosine F (5) Lyalosidic acid (2, 35 mg, 0.068 mmol) was dissolved in a mixture of TFAA (1.18 mL) and TFA (118 μL) at 0 °C under an argon atmosphere, and the resulting mixture was stirred for 3 h at room temperature under an argon atmosphere. After the removal of reagents under reduced pressure, pyridine (110 μL, 1.37 mmol) and MeOH (1.3 mL) were added to the resulting residue at –60 °C. The reaction mixture was warmed up to room temperature over 15 min. The resulting mixture was directly filtered through a short plug of amino silica gel eluted with 30% MeOH/CHCl₃, and the filtrate was concentrated under reduced pressure. The crude materials were purified by PTLC (SiO₂, 15% MeOH/CHCl₃) to afford correantosine F (5, 26.4 mg, 78%, pale yellow amorphous powder) with 2.3 mg of lyaloside (1, 6%). [α]²⁴ _D –171.7 (c 0.50, MeOH). IR (ATR): ν_max = 3366, 2928, 1740, 1669, 1618, 1581, 1448, 1416, 1335, 1308, 1275, 1243, 1200, 1129, 1076, 1038, 916, 849, 824 cm^–1. ¹H NMR (600 MHz, CD₃OD): δ = 8.63 (d, J = 8.4 Hz, 1 H), 8.18 (d, J = 5.4 Hz, 1 H), 8.11 (d, J = 7.8 Hz, 1 H), 7.91 (d, J = 1.8 Hz, 1 H), 7.66 (br d, J = 5.4 Hz, 1 H), 7.66 (ddd, J = 8.4, 7.2, 1.2 Hz, 1 H), 7.49 (ddd, J = 7.8, 7.2, 1.2 Hz, 1 H), 5.86 (dt, J = 16.8, 10.2 Hz, 1 H), 5.67 (d, J = 3.0 Hz, 1 H), 5.50 (dd, J = 16.8, 1.2 Hz, 1 H), 5.38 (dd, J = 10.2, 1.8 Hz, 1 H), 4.73 (d, J = 7.8 Hz, 1 H), 3.92 (dd, J = 12.0, 2.4 Hz, 1 H), 3.68 (dd, J = 12.0, 6.0 Hz, 1 H), 3.38–3.32 (m, 3 H), 3.25 (dd, J = 10.2, 9.0 Hz, 1 H), 3.21–3.15 (m, 3 H), 2.86 (ddd, J = 9.0, 5.4, 3.0 Hz, 1 H) ppm. ¹³C NMR (150 MHz, CD₃OD): δ = 168.6, 155.8, 147.8, 142.3, 142.2, 134.2, 133.9, 133.7, 131.2, 125.3, 125.0, 122.2, 121.1, 119.6, 114.3 (2 C), 99.9 97.7, 78.5, 77.7, 74.4, 71.6, 62.8, 46.6, 39.6, 30.9 ppm. HRMS (ESI): m/z [M + H]⁺ calcd for [C₂₆H₂₇N₂O₈]⁺: 495.1767; found: 495.1757. UV (MeOH): λ_max = 206, 228, 275, 283, 319, 332 nm.