Syntheses of cis- and trans-Jamtine and Their N-Oxides via a Benzyl Configuration-Inversion Approach

^◊These authors contributed equally to this work.

Abstract

A novel synthesis of the tetrahydroisoquinoline alkaloid jamtine and its epimer is reported. The synthetic strategy hinges on a one-pot conjugate reduction/Robinson cyclization sequence and an efficient benzyl configuration inversion by an oxidation/reduction approach. The N-oxide derivatives of the jamtine isomers were also synthesized and identified by X-ray crystallographic analysis. Additionally, a density functional theory calculation for the four possible N-oxide structures was exploited to gain further insight into the structure of the natural product in comparison to those of the synthetic N-oxides, because the NMR data of the synthetic derivatives did not match those reported for natural jamtine N-oxide.

Key words

natural products - jamtine - total synthesis - one-pot reaction - conjugate reduction - Robinson cyclization

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• 14 Methyl cis-2,3-Dimethoxy-5,8,10,11,12,12b-hexahydroisoindolo[1,2-a]isoquinoline-12a(6H)-carboxylate (cis-Jamtine) (6) To a solution of cis- 13 (355 mg, 0.82 mmol) in absolute EtOH (10 mL) was added excess Raney-Ni (W-2 type, newly reactivated), and the mixture was vigorously stirred at rt for 2 h. The mixture was then filtered through a plug of Celite that was washed with EtOAc. The filtrate was concentrated, and the residue was purified by chromatography [silica gel, CH₂Cl₂–MeOH (50:1)] to give a white solid; yield: 218 mg (77%); mp 95.2–98.0 °C.¹H NMR (500 MHz, CDCl₃): δ = 6.98 (s, 1 H), 6.56 (s, 1 H), 5.70 (s, 1 H), 4.36 (s, 1 H), 3.88 (s, 3 H), 3.90–3.82 (m, 1 H), 3.84 (s, 3 H), 3.78 (s, 3 H), 3.35 (d, J = 12.8 Hz, 1 H), 2.94–2.85 (m, 1 H), 2.73–2.57 (m, 3 H), 2.16 (dt, J = 12.8, 3.1 Hz, 1 H), 2.12–2.04 (m, 1 H), 2.04–1.94 (m, 1 H), 1.68–1.60 (m, 1 H), 1.44–1.33 (m, 1 H), 0.70 (td, J = 13.6, 3.3 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 176.8, 147.6, 147.0, 138.8, 126.9, 125.0, 121.8, 110.9, 110.6, 68.2, 61.5, 55.8, 55.7, 54.3, 52.2, 46.5, 29.9, 28.6, 23.5, 19.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₆NO₄: 344.1856; found: 344.1854. Methyl trans-2,3-Dimethoxy-5,8,10,11,12,12b-hexahydroisoindolo[1,2-a]isoquinoline-12a(6H)-carboxylate (trans-Jamtine) (2)To a solution of trans- 13 (180 mg, 0.42 mmol) in absolute EtOH (8 mL) was added excess Raney-Ni (W-2 type, newly reactivated), and the mixture was vigorously stirred at rt for 2 h. The mixture was then filtered through a plug of Celite that was washed with EtOAc. The filtrate was concentrated, and the residue was purified by chromatography [silica gel, CH₂Cl₂–MeOH (50:1)] to give a white solid; yield: 108 mg (75%); mp 104.0–106.3 °C. ¹H NMR (500 MHz, CDCl3): δ = 6.79 (s, 1 H), 6.56 (s, 1 H), 5.71 (s, 1 H), 3.98 (dq, J = 12.0, 2.8 Hz, 1 H), 3.87 (s, 3 H), 3.85 (s, 1 H), 3.84 (s, 3 H), 3.42 (d, J = 11.2 Hz, 1 H), 3.29 (s, 3 H), 3.11 (dt, J = 11.9, 4.3 Hz, 1 H), 2.90 (ddd, J = 15.1, 10.1, 4.9 Hz, 1 H), 2.82 (dd, J = 8.9, 3.7 Hz, 1 H), 2.78–2.72 (m, 1 H), 2.52 (dt, J = 15.3, 3.3 Hz, 1 H), 2.14–2.08 (m, 2 H), 1.89–1.82 (m, 1 H), 1.56–1.51 (m, 2 H). ¹³C NMR (125 MHz, CDCl3): δ = 173.3, 147.4, 146.6, 137.8, 128.4, 126.9, 121.1, 111.1, 110.0, 71.3, 57.1, 56.8, 56.0, 55.7, 51.4, 47.8, 31.9, 27.2, 24.3, 19.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₆NO₄: 344.1856; found: 344.1855.