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DOI: 10.1055/a-2086-0690
Enantioselective Formal Synthesis of (–)-Catharanthine through Enzyme-Catalyzed Desymmetrization of a meso-Azabicyclo [2.2.2]octane
This work was supported by The Sumitomo Foundation, Futaba Electronics Memorial Foundation, Ube Industries Foundation, the Suzuken Memorial Foundation, The Research Foundation for Pharmaceutical Sciences, Chiba University SEEDS Fund, JSPS-DAAD (DAAD Grant Number 57458216), JSPS KAKENHI (Grant Numbers 22H02741, G21K06471, and 20J20933).
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Abstract
Iboga-type indole alkaloids are a promising compound group of potentially effective drugs. The common indole-fused pentacyclic skeleton is composed of an isoquinuclidine, and both enantiomers of this architecture are naturally present. In this study, we used enzymatic desymmetrization to obtain an optically active isoquinuclidine possessing four chiral carbon centers from a prochiral diester in one step. In addition, we synthesized a pentacyclic intermediate for catharanthine in an enantioenriched form through the late-stage construction of the common Iboga scaffold.
Key words
enzymatic desymmetrization - desymmetrization - carbenes - enantioselective synthesis - alkaloids - isoquinuclidinesSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2086-0690.
- Supporting Information
Publikationsverlauf
Eingereicht: 10. April 2023
Angenommen nach Revision: 04. Mai 2023
Accepted Manuscript online:
04. Mai 2023
Artikel online veröffentlicht:
31. Mai 2023
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References and Notes
- 1a Büchi G, Kulsa P, Ogasawara K, Rosati RL. J. Am. Chem. Soc. 1970; 92: 999
- 1b Neuss N, Gorman M. Tetrahedron Lett. 1961; 2: 206
- 2a Iyer RN, Favela D, Zhang G, Olson DE. Nat. Prod. Rep. 2021; 38: 307
- 2b Lim H, Seong S, Han S. Synthesis 2019; 51: 2737
- 3a Ishikawa H, Colby DA, Seto S, Va P, Tam A, Kakei H, Rayl TJ, Hwang I, Boger DL. J. Am. Chem. Soc. 2009; 131: 4904
- 3b Ishikawa H, Colby DA, Boger DL. J. Am. Chem. Soc. 2008; 130: 420
- 3c Zhang J, Hansen LG, Gudich O, Lassen LM, Schrübbers L, Adhikari KB, Rubaszka P, Carrasquer-Alvarez E, Chen L, D’Ambrosio V, Lehka B, Haidar AK, Nallapareddy S, Giannakou K, Laloux M, Arsovska D, Jørgensen MA. K, Chan LJ. G, Kristensen M, Christensen HB, Sudarsan S, Stander EA, Baidoo E, Petzold CJ, Wulff T, O’Connor SE, Courdavault V, Jensen MK, Keasling MK. Nature 2022; 609: 341
- 4a Caputi L, Franke J, Farrow SC, Chung K, Payne RM. E, Nguyen T.-D, Dang T.-TT, Soares Teto Carqueijeiro I, Koudounas K, Dugé de Bernonville T, Ameyaw B, Jones DM, Vieira IJ. C, Courdavault V, O’Connor SE. Science 2018; 360: 1235
- 4b Farrow SC, Kamileen MO, Caputi L, Bussey K, Mundy JE. A, McAtee RC, Stephenson CR. J, O’Connor SE. J. Am. Chem. Soc. 2019; 141: 12979
- 5 This natural product family includes promising bioactive substances and underutilized natural compounds; see: Lim K.-H, Raja VJ, Bradshaw TD, Lim S.-H, Low Y.-Y, Kam T.-S. J. Nat. Prod. 2015; 78: 1129
- 6a Beatty JW, Stephenson CR. J. J. Am. Chem. Soc. 2014; 136: 10270
- 6b Lim H, Seong S, Kim Y, Seo S, Han S. J. Am. Chem. Soc. 2021; 143: 19966
- 6c Seong S, Lim H, Han S. Chem 2019; 5: 353
- 7a Mizoguchi H, Oikawa H, Oguri H. Nat. Chem. 2014; 6: 57
- 7b Gabriel P, Almehmadi YA, Wong ZR, Dixon DJ. J. Am. Chem. Soc. 2021; 143: 10828
- 8a Gröger H, Asano Y. In Enzyme Catalysis in Organic Synthesis, 3rd ed., Vol. 1, Chap. 1. Drauz K, Gröger H, May O. Wiley-VCH; Weinheim: 2012: 1
- 8b Sperl JM, Carsten JM, Guterl J.-K, Lommes P, Sieber V. ACS Catal. 2016; 6: 6329
- 8c Gianolio E, Mohan R, Berkessel A. Adv. Synth. Catal. 2016; 358: 30
- 8d Li F, Deng H, Renata H. J. Am. Chem. Soc. 2022; 144: 7616
- 9 Hashimoto Y, Harada S, Kato R, Ikeda K, Nonnhoff J, Gröger H, Nemoto T. ACS Catal. 2022; 12: 14990
- 10a Harada S, Kono M, Nozaki T, Menjo Y, Nemoto T, Hamada Y. J. Org. Chem. 2015; 80: 10317
- 10b Harada S, Kobayashi M, Kono M, Nemoto T. ACS Catal. 2020; 10: 13296
- 10c Furuya T, Ikeda K, Harada S, Nemoto T. Chem. Pharm. Bull. 2023; 71: 117
- 11a Ito T, Harada S, Homma H, Takenaka H, Hirose S, Nemoto T. J. Am. Chem. Soc. 2021; 143: 604
- 11b Harada S, Yanagawa M, Nemoto T. ACS Catal. 2020; 10: 11971
- 12a Bode SE, Wolberg M, Müller M. Synthesis 2006; 557
- 12b Gupta P, Mahajan N, Taneja SC. Catal. Sci. Technol. 2013; 3: 2462
- 12c Gamba-Sánchez D, Prunet J. Synthesis 2018; 50: 3997
- 12d Murata K, Sakamoto K, Fuwa H. Org. Lett. 2019; 21: 3730
- 12e Hayashi Y, Tomikawa M, Mori N. Org. Lett. 2021; 23: 5896
- 13 Kono M, Harada S, Nozaki T, Hashimoto Y, Murata S.-i, Gröger H, Kuroda Y, Yamada K.-i, Takasu K, Hamada Y, Nemoto T. Org. Lett. 2019; 21: 3750
- 14 Moisan L, Thueŕy P, Nicolas M, Doris E, Rousseau B. Angew. Chem. Int. Ed. 2006; 45: 5334
- 15 Kurose T, Tsukano C, Nanjo T, Takemoto Y. Org. Lett. 2021; 23: 676
- 16a Kumar A, Dhar K, Kanwar SS, Arora PK. Biol. Proced. Online 2016; 18: 2
- 16b Ferreira IM, Nishimura RH. V, Souza AB. dos A, Clososki GC, Yoshioka SA, Porto AL. M. Tetrahedron Lett. 2014; 55: 5062
- 16c Csajági C, Szatzker G, Töke ER, Ürge L, Darvas F, Poppe L. Tetrahedron: Asymmetry 2008; 19: 237
- 17 For a review on the previous uses of porcine liver esterase in enantioselective hydrolytic desymmetrization reactions, see: Dominguez de Maria P, Garcia-Burgos CA, Bargeman D, van Gemert RW. Synthesis 2007; 1439
- 18a DePuy CH, King RW. Chem. Rev. 1960; 60: 431
- 18b Atkins GM. Jr, Burgess EM. J. Am. Chem. Soc. 1968; 90: 4744
- 19a Albright JD, Goldman L. J. Org. Chem. 1965; 30: 1107
- 19b Albright JD, Goldman L. J. Am. Chem. Soc. 1967; 89: 2416
- 20 Cacchi S, Morera E, Ortar G. Tetrahedron Lett. 1984; 25: 4821
- 21 Olofson RA, Martz JT, Senet J.-P, Piteau M, Malfroot T. J. Org. Chem. 1984; 49: 2081
- 22a Trost BM, Godleski SA, Genet JP. J. Am. Chem. Soc. 1978; 100: 3930
- 22b Trost BM, Godleski SA, Belletire JL. J. Org. Chem. 1979; 44: 2052
- 23 (1R,4S,6S,7R)-7-Hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.2]octan-6-yl Acetate (6) A solution of substrate 5 (69.5 mg, 0.20 mmol) in PhMe (2.0 mL, 0.1 M) was added to a stirred solution of porcine liver esterase (194.6 mg, 2.8 wt/wt) in 10 mM potassium phosphate buffer (20 mL; pH 7.4, 0.009 M) at 37 °C, and the mixture was stirred at 37 °C for 120 h at 160 rpm with a shaking apparatus (EYELA NTS-4000BM). The mixture was then filtered through Celite and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by flash chromatography [silica gel, hexane–EtOAc (3:1)] to give a pale yellow oil (6); yield: 46.4 mg (76%, 0.15 mmol; er = 98.4:1.6); [α]D 23.9 –39.5 (c 1.0, CHCl3). HPLC [OD-H column, hexane–i-PrOH (95:5), 1 mL/min, λ = 254 nm], t R = 16.5 min (minor), 18.8 min (major). IR (ATR): 3435, 2835, 1730, 1510, 1363, 1240, 1173, 1086, 1022 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.38–1.45 (m, 1 H), 1.48–1.52 (m. 2 H), 1.81–2.02 (m, 3 H), 2.16 (s, 3 H), 2.56 (ddd, J = 9.6, 2.4, 1.6 Hz, 1 H), 2.89 (dd, J = 2.8, 2.0 Hz, 1 H), 3.06 (ddd, J = 10.0, 3.2, 2.8 Hz, 1 H), 3.77 (ddd, J = 8.4, 2.8, 2.4 Hz, 1 H), 3.8 (s, 3 H), 3.83–3.91 (m, 2 H), 4.96 (ddd, J = 10.0, 3.2, 2.4 Hz, 1 H), 6.86 (d, J = 8.8 Hz, 2 H), 7.20 (d, J = 8.8 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 21.3, 25.9, 33.9, 35.6, 54.8, 55.0, 58.2, 61.1, 66.1, 72.8, 113.5 (2C), 129.6 (2C), 131.1, 158.5, 170.2. HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H23NNaO4: 328.1525; found: 328.1520.