Enantioselective Formal Synthesis of (–)-Catharanthine through Enzyme-Catalyzed Desymmetrization of a meso-Azabicyclo [2.2.2]octane

Kotaro Ikeda; Shingo Harada; Yoshinori Hashimoto; Haruka Homma; Masato Kono; Nadine Zumbrägel; Harald Gröger; Tetsuhiro Nemoto

doi:10.1055/a-2086-0690

Synlett, Table of Contents

Synlett 2024; 35(04): 469-473
DOI: 10.1055/a-2086-0690

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11th Singapore International Chemistry Conference (SICC-11)

Enantioselective Formal Synthesis of (–)-Catharanthine through Enzyme-Catalyzed Desymmetrization of a meso-Azabicyclo [2.2.2]octane

Kotaro Ikeda

^aGraduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan

,

Shingo Harada∗

^aGraduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan

,

Yoshinori Hashimoto

^aGraduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan

,

Haruka Homma

^aGraduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan

,

Masato Kono

^aGraduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan

,

Nadine Zumbrägel

^bChair of Industrial Organic Chemistry and Biotechnology, Faculty of Chemistry, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany

,

Harald Gröger ∗

^bChair of Industrial Organic Chemistry and Biotechnology, Faculty of Chemistry, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany

,

Tetsuhiro Nemoto∗

^aGraduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan

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Abstract

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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 - isoquinuclidines

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References

References and Notes

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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.

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