A Stereoselective Entry to Tetrasubstituted Quinolizidines and the Puzzling Structural Assignment of the Lupin Alkaloid Plumerinine

Abstract

A thermodynamically controlled stereoselective synthesis of quinolizidinone (+/-)-13 via α-amidoalkylation of an intermediate N-acyliminium ion derived from α-ethoxy piperidine 9, followed by intramolecular Michael addition is described. Based on their NMR data, quinolizidine alcohols 14 and 15 were ruled out as possible structures of the lupin alkaloid plumerinine.

plumerinine - lupin alkaloid - tetrasubstituted quinoli­zidines - cyclic N-acyliminium ion - α-amidoalkylation - intramolecular Michael reaction

References

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2 D’Oca MGM. Moraes LAB. Pilli RA. Eberlin MN. J. Org. Chem.  2001,  66:  3854 

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8c

Characterization data for compound 11: IR (KBr): 2965, 2936, 2870, 1685, 1627, 1365, 1353, 1315, 1303, 1177 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 6.84 (dd, J = 15.9, 6.6 Hz, 1 H), 6.08 (dd, J = 15.9, 1.5 Hz, 1 H), 4.28 (m, 2 H), 2.82 (dd, J = 15.0, 10.6 Hz, 1 H), 2.68 (dd, J = 15.0, 3.0 Hz, 1 H), 2.46 (m, 1 H), 1.60-1.95 (m, 3 H), 1.44 (s, 9 H), 1.20 (m, 2 H), 1.16 (d, J = 7.1 Hz, 3 H), 1.06 (d, J = 6.8 Hz, 3 H), 1.00 (d, J = 7.1 Hz, 3 H). ¹³C NMR (125.7 MHz, CDCl₃): δ = 198.8, 155.6, 153.8, 127.0, 79.3, 52.4, 46.8, 45.6, 31.0, 29.9, 28.8, 23.8, 21.3, 21.2, 20.9, 20.5, 18.8. HRMS (EI): m/z calcd for C₁₉H₃₃NO₃: 323.2460. Found: 323.2454.

9 Maldaner AO. Pilli RA. Tetrahedron  1999,  55:  13321 

10

Preparation of (4 SR ,6 RS ,9 RS ,9 aRS )-4-isopropyl-6,9-dimethyl quinolizidin-2-one(13):
To a CH₂Cl₂ (3.0 mL) solution of piperidinone 9 (0.032 g, 0.10 mmol) at 0 °C was added TFA (0.110 g, 1.00 mmol). The mixture was stirred 3 h at r.t., quenched with sat. aq NaHCO₃ (3.0 mL) and extracted with CH₂Cl₂ (4 × 5 mL). The residue was taken up in MeOH (3.0 mL) containing 30% aq NH₃ (3.0 mL) and heated at 60 °C for 24 h. After extraction with CH₂Cl₂ (5 × 15 mL), the organic phase was dried over anhyd MgSO₄ and evaporated to afford a residue, which was chromatographed on silica gel (9:1 hexanes-EtOAc) to afford 0.0054 g (0.03 mmol, 30% yield) of quinolizidinone 13. IR (film): 2956, 2925, 2873, 2854, 1709, 1464, 1336, 1260, 1078 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 3.12 (dt, J = 12.5, 3.8 Hz, 1 H), 2.96 (ddd, J = 9.7, 6.4, 1.7 Hz, 1 H), 2.85 (m, 1 H), 2.51 (dd, J = 14.0, 6.6 Hz, 1 H), 2.45 (br d, J = 14.0 Hz, 1 H), 2.35 (dt, J = 14.0, 1.8 Hz, 1 H), 2.02 (ddd, J = 14.0, 2.9, 1.9 Hz, 1 H), 1.96 (m, 1 H), 1.68 (dq, J = 12.8, 6.6 Hz, 1 H), 1.64 (m, 1 H), 1.50 (dq, J = 11.7, 7.0 Hz, 1 H), 1.38 (m, 1 H), 1.26 (m, 1 H), 1.07 (d, J = 5.9 Hz, 3 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.89 (d, J = 6.6 Hz, 3 H), 0.82 (d, J = 7.0 Hz, 3 H).¹³C NMR (125.7 MHz, CDCl₃): δ = 211.6, 62.7, 56.7, 46.7, 38.3, 36.4, 35.7, 34.1, 28.8, 27.5, 21.2, 20.7, 19.8, 18.5. HRMS (EI): m/z calcd for C₁₁H₁₈NO [M⁺ - C₃H₇]: 180.1388. Found: 180.1387.

11 Scott RW. Epperson J. Heathcock CH. J. Org. Chem.  1998,  63:  5001 

12a

Gaussian 98W by Gaussian, Inc.

12b

Ab initio calculations (STO-3G and 3-21G) also confirmed the lower energy of cis-fused quinolizidinone 13 when compared to 2, 5 and 16 (at least 1.7 kcal mol^-1 more stable than trans-fused quinolizidinone 16).

13

The experimental conditions employed in this work for the intramolecular Michael reaction (aq NH₃, MeOH, 60 °C) were previously used to carry out epimerization in quinolizidinone and indolizidinone systems (see ref. 8).

14

Data for 14: IR (film): 3384, 2956, 2925, 2871, 2855, 1461, 1374, 1260, 1089, 1071, 1047, 1031 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 4.18 (m, 1 H), 3.22 (m, 1 H), 2.78 (m, 1 H), 2.50 (m, 1 H), 2.20 (m, 1 H), 1.99 (td, J = 13.2, 4.5 Hz, 1 H), 1.65-1.80 (m, 3 H), 1.60 (m, 2 H), 1.10-1.50 (m, 4 H), 0.99 (t, J = 5.8 Hz, 3 H), 0.92 (t, J = 6.6 Hz, 6 H), 0.82 (d, J = 7.1 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 66.7, 59.3, 50.1, 47.4, 36.0, 34.0, 30.1, 27.6, 26.9, 25.3, 21.2, 21.1, 20.4, 18.6. HRMS (EI): m/z calcd for C₁₄H₂₇NO: 225.2093. Found: 225.2092.
Data for 14·HCl: IR (KBr): 3334, 2963, 2875, 2709, 1464, 1455, 1066 cm^-1. ¹H NMR (500 MHz, D₂O): δ = 4.25 (quint, J = 4.4 Hz, 1 H), 3.91 (dt, J = 13.4, 4.1 Hz, 1 H), 3.71 (m, 1 H), 3.42 (m, 1 H), 2.59 (m, 1 H), 2.36 (ddd, J = 15.6, 13.4, 5.1 Hz, 1 H), 2.18 (m, 1 H), 2.10 (m, 1 H), 1.94-2.04 (m, 2 H), 1.74-1.88 (m, 2 H), 1.50-1.65 (m, 2 H), 1.37 (d, J = 6.3 Hz, 3 H), 1.08 (d, J = 6.7 Hz, 3 H), 1.07 (d, J = 6.7 Hz, 3 H), 0.98 (d, J = 7.1 Hz, 3 H). ¹³C NMR (125.7 MHz, D₂O): δ = 64.8, 62.8, 55.8, 53.9, 32.6, 31.8, 29.0, 25.8, 25.0, 24.9, 19.7, 19.1, 17.5, 17.1.
Data for 15: IR (film): 3345, 2954, 2926, 2870, 1463, 1366, 1260, 1084, 1058, 1024 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 3.83 (m, 1 H), 2.80 (m, 2 H), 2.61 (m, 1 H), 1.75-1.90 (m, 3 H), 1.50-1.60 (m, 2 H), 1.30-1.45 (m, 3 H), 1.20-1.30 (m, 3 H), 0.95 (d, J = 5.8 Hz, 3 H), 0.89 (d, J = 6.6 Hz, 3 H), 0.88 (t, J = 6.6 Hz, 3 H), 0.84 (J = 7.1 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 67.5, 60.4, 53.9, 46.1, 36.3, 34.5, 28.6, 28.1, 27.2, 27.1, 21.4, 20.9, 20.8, 18.9. HRMS (EI): m/z calcd for C₁₄H₂₇NO: 225.2093. Found: 225.2092.
Data for 15·HCl: ¹H NMR (500 MHz, D₂O): δ = 3.99 (m, 1 H), 3.78 (m, 1 H), 3.65 (dt, J = 13.2, 3.6 Hz, 1 H), 3.32 (ddd, J = 10.1, 5.1, 2.5 Hz, 1 H), 2.11 (m, 1 H), 1.85-2.05 (m, 3 H), 1.81 (m, 1 H), 1.58-1.73 (m, 3 H), 1.35-1.48 (m, 2 H), 1.17 (d, J = 6.4 Hz, 3 H), 0.89 (d, J = 6.4 Hz, 3 H), 0.88 (d, J = 6.4 Hz, 3 H), 0.78 (d, J = 6.8 Hz, 3 H).