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

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

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.