Stereoselective Approach to the Pyrroloquinoline Core of Martinelline

Abstract

The synthesis of α-aminonitrile 4, a potent precursor to the martinellines is described. The preparation of the pyrroloquinoline core was realized in one step (90% yield) using a formal [4π+2π] cyclocondensation involving the cationic aza-diene 6 and the 1-(benzyloxy)carbonyl-2-pyrroline 5 as dienophile. The stereo­chemical outcome of the cyanation procedure performed on the tricyclic core thus obtained is discussed.

martinelline - stereoselective synthesis - nitriles - natural products

References

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11

5-Ethyl-2,3,3a,4,5,9b-hexahydro-furo-[3,2- c ]quinoline(12):
To a cooled (-80 °C) solution (10 mL, CH₂Cl₂) containing the aminoacetal 8 (1.0 g, 5.58 mmol) was added dropwise (by syringe) and under an argon atmosphere 0.870 g (6.17 mmol) of BF₃·OEt₂. The reaction mixture turned slightly green and was stirred at that temperature for one hour. A solution (CH₂Cl₂, 5 mL) of 2,3-dihydrofuran (0.470 g, 6.71 mmol) was added dropwise over a 5 min period and was allowed to react at -80 °C with the iminium salt 6 for two hours. The crude mixture was quenched with water, and extracted with CH₂Cl₂ in the presence of Na₂CO₃. The combined organic layers were dried over MgSO₄ and evaporated in vacuo to yield the crude material which was purified by column chromatography (ether/petroleum ether, 1/2) to afford 12 (0.850 g, 75%) as a slightly yellow oil. ¹H NMR (300 MHz, CDCl₃): δ =1.13 (t, J = 7.10 Hz, 3 H, CH₂-CH₃), 1.69-1.80 (m, 1 H, 3-Ha), 2.17-2.29 (m, 1 H, 3-Hb), 2.37-2.48 (m, 1 H, 3a-H), 2.85 (t, J = 11.30 Hz, 1 H, 4-Ha), 3.00 (dd, J = 11.30 and 5.35 Hz, 1 H, 4-Hb), 3.27 (dq, J = 14.30 and 7.15 Hz, 1 H, CH₂-CH₃), 3.50 (dq, J = 14.30 and 7.15 Hz, 1 H, CH₂-CH₃), 3.80 (td, J = 8.60 and 6.20 Hz, 1 H, 2-Ha), 3.94 (td, J = 8.45 and 5.90 Hz, 1 H, 2-Hb), 4.54 (d, J = 5.35 Hz, 1 H, 9b-H), 6.67-6.72 (m, 2 H), 7.15 (td, J = 9.60 and 1.71 Hz, 1 H), 7.32 (dm, J = 7.00 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 10.60, 30.01, 35.65, 45.29, 49.24, 65.00, 76.08, 111.59, 116.55, 121.28, 129.02, 131.74, 145.42. C₁₃H₁₇NO: Calcd C, 76.81; H, 8.43; N, 6.89; O, 7.87. Found: C, 76.38; H, 8.43; N, 7.13; O, 7.47.

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14

A trans fused adduct displaying a coupling constant of 13.80 Hz between 3a-H and 9b-H has been recently isolated in 5% yield and was reported by Lovely and co-workers in ref. [2m]

15

Crystallographic data for the structure cis- 14 reported in this paper has been deposited at the Cambridge Crystallographic Data Center as supplementary publication no: CCDC 186783. Copies of the data can be obtained free of charge on application to The Director CCDC, 12 Union Road, Cambridge CB2 IEZ, UK [fax: [phone], e-mail: [e-mail]].

16

4-Cyano-5-ethyl-2,3,3a,4,5,9b-hexahydro-pyrrolo[3,2- c ]quinolin-1-carboxylic Acid Benzyl Ester(4):
0.5 g (1.48 mmol) of 3 were dissolved in methanol (50 mL) containing AcOLi (20 g/L) and 0.520 g (10.6 mmol) of NaCN. The amine was oxidized at controlled potential (Ep = +0.75 V/SCE) and after the consumption of 2.0 F per mole of substrate, the electrolysis was stopped. Classical work-up and chromatographic purification (diethyl ether/petroleum ether, 1/2) afforded 4 (0.460 g, 85%) as a pale yellow oil. ¹H NMR (300 MHz, C₆D₆, 343 K): δ = 0.89 (t, J = 7.15 Hz, 3 H, CH₂-CH₃), 1.21-1.34 (m, 1 H, 3-Ha), 1.44-1.58 (m, 1 H, 3-Hb), 1.94-2.04 (m, 1 H, 3a-H), 2.75-2.87 (dd, J = 15.0 and 7.15 Hz, 1 H, CH₂-CH₃), 2.90-3.11 (m, 2 H, CH₂-CH₃ and 2-Ha), 3.29 (d, J = 2.60, 1 H, 4-H), 3.33-3.36 (br, coal., 1 H, 2-Hb), 5.12 (AB, J = 13.40 Hz, 1 H, O-CH₂-C₆H₅), 5.27 (AB, J = 13.40 Hz, 1 H, O-CH₂-C₆H₅), 5.50 (d, J = 7.50 Hz, 1 H, 9b-H, 6.41 (d, J = 8.30 Hz, 1 H), 6.72 (t, J = 8.70 Hz, 1 H), 6.98 (t, J = 8.80 Hz, 1 H), 7.05 (m, 5 H), 7.30-7.33 (m, 2 H). ¹³C NMR (75 MHz, C₆D₆, 343 K): δ = 11.99, 26.15, 40.23, 45.05, 45.10, 50.67, 54.70, 67.21, 112.60, 118.88, 119.96, 123.68, 127.72, 128.04, 128.73, 128.98, 131.15, 137.63, 141.34, 156.07. C₂₂H₂₃N₃O₂: Calcd 361.1790. Found 361.1787 (MS).

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