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Synlett 2024; 35(04): 469-473
DOI: 10.1055/a-2086-0690
DOI: 10.1055/a-2086-0690
cluster
11th Singapore International Chemistry Conference (SICC-11)
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).
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
Publication History
Received: 10 April 2023
Accepted after revision: 04 May 2023
Accepted Manuscript online:
04 May 2023
Article published online:
31 May 2023
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- 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.