Download PDF
Synlett 2004(8): 1343-1346  
DOI: 10.1055/s-2004-825614
LETTER
© Georg Thieme Verlag Stuttgart · New York

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)

    Permissions and Reprints All articles of this category

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

  • 1a Hiemstra H. Speckamp WN. In Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Pergamon Press; New York: 1991.  p.1047 
    CrossrefGoogle Scholar
  • 1b Speckamp WN. Hiemstra H. Tetrahedron  1985,  41:  4367 
    CrossrefGoogle Scholar
  • 1c Koning H. Speckamp WN. In Stereoselective Synthesis (Houben-Weyl)   Vol E21:  Helmchen G. Hoffmann RW. Mulzer J. Schaumann E. Georg Thieme Verlag; Stuttgart: 1996.  p.1953 
    CrossrefGoogle Scholar
  • 1d Pilli RA. Rosso GB. In Science of Synthesis (Houben-Weyl)   Vol. 27:  Padwa A. Georg Thieme Verlag; Stuttgart: 2004.  Chapt. 10. p.375 
    CrossrefGoogle Scholar
  • 2 D’Oca MGM. Moraes LAB. Pilli RA. Eberlin MN. J. Org. Chem.  2001,  66:  3854 
    CrossrefGoogle Scholar
  • 3a Shono T. Matsumura Y. Tsubata K. Uchida K. J. Org. Chem.  1986,  51:  2590 
    CrossrefGoogle Scholar
  • 3b Irie K. Aoe K. Tanaka T. Saito S. J. Chem. Soc., Chem. Commun.  1985,  633 
    CrossrefGoogle Scholar
  • 3c Leclercq S. Thirionet I. Broeders F. Daloze D. Meer RV. Braekman JC. Tetrahedron  1994,  50:  8465 
    CrossrefGoogle Scholar
  • 3d Ludwig C. Wistrand L.-G. Acta Chem. Scand.  1994,  48:  367 
    CrossrefGoogle Scholar
  • 4 Hoffmann RW. Chem. Rev.  1989,  89:  1841 
    CrossrefGoogle Scholar
  • 5a Luker T. Hiemstra H. Speckamp WN. J. Org. Chem.  1997,  62:  3592 
    CrossrefGoogle Scholar
  • 5b Plehiers M. Hootelé C. Can. J. Chem.  1996,  74:  2444 
    CrossrefGoogle Scholar
  • 5c Maldaner AO. Pilli RA. Tetrahedron Lett.  2000,  41:  7843 
    CrossrefGoogle Scholar
  • 6 Kazmi SN. Ahmed W. Malik A. Heterocycles  1989,  29:  1901 
    Google Scholar
  • 7 Comins DL. Zheng X. Goehring RR. Org. Lett.  2002,  4:  1611 
    CrossrefGoogle Scholar
  • 8a Pilli RA. Dias LC. Maldaner AO. Tetrahedron Lett.  1993,  34:  2729 
    CrossrefGoogle Scholar
  • 8b Pilli RA. Dias LC. Maldaner AO. J. Org. Chem.  1995,  60:  717 
    CrossrefGoogle Scholar
  • 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.
    Crossref
  • 9 Maldaner AO. Pilli RA. Tetrahedron  1999,  55:  13321 
    CrossrefGoogle Scholar
  • 11 Scott RW. Epperson J. Heathcock CH. J. Org. Chem.  1998,  63:  5001 
    CrossrefGoogle Scholar
  • 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).