LETTER
-Lactam-based Route to Indolzidine and Quinolizidine Derivatives
87
bicyclic systems as opposed to the bridged systems. See, for
example: (a) Kang, S. H.; Kim, W. J. Synlett 1991, 520.
(b) Kang, S. H.; Lee, H. S. Tetrahedron Lett. 1995, 36,
6713. (c) Junk, M. E.; Vu, B. T. J. Org. Chem. 1996, 61,
4427.
Acknowledgement
Support for this work by the DGI-MCYT (Project BQU2000-0645)
is gratefully acknowledged. E. S. B. thanks the M. E. C. for a pre-
doctoral grant.
(12) Related nitrones derived from -amino and -hydroxy acids
behave almost identically in terms of their
References
stereoselectivities. The stereocenter at the -position
effectively controls the formation of the new contiguous
stereocenters. See, for example: (a) Chiacchio, U.;
(1) See, for example: (a) Asano, N.; Nash, R. J.; Molynuex, R.
J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645.
(b) Stuetz, A. E. In Iminosugars as Glycosidase Inhibitors,
Nojirimycin and Beyond; Wiley-VCH: Weinheim, 1999.
(c) Vlietinck, A. J.; De Bruyne, T.; Apers, S.; Pieters, L. A.
Planta Med. 1998, 64, 97. (d) Howard, A. S.; Michael, J. P.
In The Alkaloids, Vol. 28; Brosi, A., Ed.; Academic Press:
Orlando, 1986, 183. (e) Format for theses: Goering, B. K.
Ph. D. Dissertation; Cornell University: Cornell, 1995.
(2) For reviews, see: (a) Ojima, I. Adv. Asym. Synth. 1995, 1,
95. (b) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide,
M. Amino-acids 1999, 16, 321. (c) Ojima, I.; Delaloge, F.
Chem. Soc. Rev. 1997, 26, 377. (d) Manhas, M. S.; Wagle,
D. R.; Chiang, J.; Bose, A. K. Heterocycles 1988, 27, 1755.
(3) Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F.;
Torres, M. R. Synlett 2001, 1531.
(4) For the applications of 4-oxoazetidine-2-carbaldehydes as
efficient chiral synthons, see: Alcaide, B.; Almendros, P.
Chem. Soc. Rev. 2001, 30, 226.
(5) (a) Alcaide, B.; Alonso, J. M.; Aly, M. F.; Sáez, E.;
Martínez-Alcázar, M. P.; Hernández-Cano, F. Tetrahedron
Lett. 1999, 40, 5391. (b) Alcaide, B.; Sáez, E. Tetrahedron
Lett. 2000, 41, 1647.
(6) For reviews, see: (a) Tufariello, J. J. In 1,3-Dipolar
Cycloaddition Chemistry, Vol. 2; Padwa, A., Ed.; John
Wiley and Sons: New York, 1984, Chap. 9, 83. (b) Wade,
P. A. In Comprehensive Organic Synthesis, Vol. 4; Trost, B.
M.; Fleming, I.; Semmelhack, M. E., Eds.; Pergamon Press:
Oxford, 1991, Chap. 4.10, 1111. (c) Frederickson, M.
Tetrahedron 1997, 53, 403. (d) Gothelf, K. V.; Jorgensen,
K. A. Chem. Rev. 1998, 98, 863.
(7) For the synthesis of bicyclic alkaloid systems involving 1,3-
dipolar cycloadditions, see: (a) Broggini, G.; Zecchi, G.
Synthesis 1999, 905; and references cited therein. (b) El
Nemr, A. Tetrahedron 2000, 56, 8579.
(8) For very recent selected examples, see: Indolizidines:
(a) Klitzke, C. F.; Pilli, R. A. Tetrahedron Lett. 2001, 42,
5605. (b) Groaning, M. D.; Meyers, A. I. Chem. Commun.
2000, 1027. (c) Pourashraf, M.; Delair, P.; Rasmusen, M.
O.; Greene, A. E. J. Org. Chem. 2000, 65, 6966.
(9) Quinolizidines: (a) Gebarowski, P.; Sas, W. Chem.
Commun. 2001, 915. (b) Ledoux, S.; Marchalant, E.;
Célérier, J.-P.; Lhommet, G. Tetrahedron Lett. 2001, 42,
5397.
Casuscelli, F.; Corsaro, A.; Librando, V.; Rescifina, A.;
Romeo, R.; Romeo, G. Tetrahedron 1995, 51, 5689.
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Xue, F. J. Org. Chem. 1998, 63, 414. (See also ref.6).
(13) All new compounds were fully characterised by
spectroscopic methods and microanalysis and/or HRMS.
General Procedure for the Synthesis of Compounds 1
from Alcohols 9: A solution of dimethyl sulfoxide (5.1 L,
0.72 mmol) in dichloromethane (0.2 mL) was added
dropwise to a stirred solution of oxalyl chloride (3.1 L, 0.36
mmol) in CH2Cl2 (0.4 mL) at –78 °C. After 20 min, a
solution of the appropriate alcohol 9 (0.15 mmol) in CH2Cl2
(0.5 mL) was added and the mixture was stirred for 2 h at –
78 °C. Et3N (0.12 mL) was added at –78 °C, and the mixture
was allowed to warm to r.t. Water (5 mL) was added and the
mixture was partitioned between CH2Cl2 and water. The
organic extract was washed with brine, dried (MgSO4), and
concentrated under reduced pressure to give aldehyde 10,
which was used without further purification. N-methyl-
hydroxylamine (19 mg, 0.22 mmol) and Et3N (6.2 L, 0.44
mmol) was added to a stirred solution of aldehyde 10 in
anhyd toluene (9 mL), and the mixture was refluxed for 90
min. At the end of this time the solvent was removed under
reduced pressure and the solid residue extracted with
CH2Cl2, washed with water and dried (MgSO4). Evaporation
of the solvent and silica flash chromatography of the residue
(EtOAc–MeOH) gave analytically pure compounds 1.
Selected data: Quinolizidinone (+)-1a: From 50 mg (0.15
mmol) of compound (–)-9a, 33 mg (62%) of compound (+)-
1a was obtained as a colorless oil. [ ]D +33.4 (c 0.8, CHCl3).
1H NMR (300 MHz, CDCl3): = 2.26 (1 H, m), 2.38 (1 H,
d, J = 11.5 Hz), 2.55 (3 H, s), 2.69 (3 H, s),2.96 (1 H, dd,
J = 8.9, 2.2 Hz), 3.01 (1 H, d, J = 4.8 Hz), 3.31 (1 H, d,
J = 14.4 Hz), 3.45 (1 H, dd, J = 8.9, 6.8 Hz), 3.50 (1 H, t,
J = 2.2 Hz), 3.74 (1 H, dd, J = 8.6, 6.8 Hz), 3.81 (1 H, dd,
J = 14.4, 4.1 Hz), 4.10 (1 H, s broad), 4.30 (1 H, t, J = 8.8
Hz), 4.48 (1 H, d, J = 11.9 Hz), 4.61 (1 H, dd, J = 5.0, 4.1
Hz), 4.71 (1 H, d, J = 11.9 Hz), 7.32 (2 H, m), 7.44 (3 H, m).
13C NMR (75 MHz, CDCl3): = 169.6, 136.9, 128.6, 128.3,
128.1, 76.3, 72.5, 71.5, 69.4, 66.1, 65.4, 60.2, 50.8, 48.2,
46.2, 43.9, 28.2. IR (CHCl3): 1655 cm–1. MS (CI): m/z =
360(1) [MH+], 205(11), 112(19), 91(100). (Anal. Calcd for
C19H25N3O4: C, 63.49; H, 7.01; N, 11.69. Found: C, 63.55;
H, 7.07; N, 11.75). Quinolizidinone (+)-1b: From 50 mg
(0.16 mmol) of compound (–)-9b, 31 mg (58%) of
(10) Selected data for compound 5: Colorless oil. [ ]D +80 (c 2.4,
CHCl3). 1H NMR (200 MHz, CDCl3): = 2.2 (1 H, s broad),
2.45 (3 H, s), 2.65 (1 H, dd, J = 10.9, 5.7 Hz), 3.24 (4 H, m),
3.57 (1 H, dd, J = 9.0, 2.9 Hz), 3.78 (3 H, s), 4.06 (2 H, m),
4.38 (1 H, d, J = 11.5 Hz), 4.81 (1 H, d, J = 11.5 Hz), 7.31 (5
H, m). 13C NMR (200 MHz, CDCl3): = 171.5, 137.0, 128.5,
128.4, 128.1, 78.0, 75.8, 72.7, 70.3. 52.6, 52.0, 48.7, 43.7.
(Anal. Calcd for C16H22N2O4: C, 62.73; H, 7.24; N, 9.14.
Found: C, 62.65; H, 7.14; N, 9.26).
(11) INAC reactions of aliphatic 2-substituted 5-hexenyl and 5-
heptenyl nitrones have been successfully used for the
synthesis of key monocyclic intermediates of 1- -
methylthienamycin. A notable feature of such processes is
their propensity for the predominant formation of the fused
compound (+)-1b was obtained as a colorless oil.
[ ]D = +1.9 (c 3.1, CHCl3). 1H NMR (300 MHz, C6D6):
=
1.89 (1 H, m), 2.44 (3 H, m), 2.56 (3 H, s), 2.63 (3 H, s), 2.65
(1 H, dd, J = 5.4, 1.9 Hz), 2.76 (3 H, m), 2.98 (1 H, d, J = 4.4
Hz), 3.09 (1 H, d, J = 2.0 Hz), 3.29 (1 H, t, J = 2.0 Hz), 3.37
(1 H, d, J = 7.5 Hz), 3.75 (1 H, dd, J = 7.5, 5.6 Hz), 4.18 (1
H, d, J = 11.9 Hz), 4.37 (1 H, t, J = 5.6 Hz), 4.52 (1 H, d,
J = 11.9 Hz), 7.35 (2 H, m), 7.49 (3 H, m). 13C NMR (75
MHz, C6D6): = 140.0, 128.5, 128.0, 127.9, 76.5, 74.1, 72.2,
68.8, 67.6, 66.0, 65.8, 60.8, 54.2, 46.3, 44.8, 41.5, 27.2. MS
(CI): m/z = 346(1) [MH+], 207(49), 204(50), 91(100). (Anal.
Calcd for C19H27N3O3: C, 66.06; H, 7.88; N, 12.16. Found:
Synlett 2002, No. 1, 85–88 ISSN 0936-5214 © Thieme Stuttgart · New York