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

Adriano O. Maldaner; Ronaldo A. Pilli

doi:10.1055/s-2004-825614

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Synlett 2004(8): 1343-1346
DOI: 10.1055/s-2004-825614

LETTER

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

Adriano O. Maldaner, Ronaldo A. Pilli*
Instituto de Química, Unicamp P.O. Box 6154 13084-971 Campinas, SP Brazil
Fax: +55(19)37883023; e-Mail: pilli@iqm.unicamp.br;

Further Information

Publication History

Received 1 March 2004
Publication Date:
18 May 2004 (online)

Abstract
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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.

Key words

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

References

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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.

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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).

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.

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).