Concise, Divergent β-Lactam-based Route to Indolizidine and Quinolizidine Derivatives via Sequential Regio- and Stereocontrolled Intramolecular Nitrone-alkene Cycloadditions
Benito Alcaide*, Carmen Pardo, Elena Sáez Departamento de Química Orgánica I. Facultad de Química, Universidad Complutense, 28040-Madrid, Spain Fax: +34(91)3944103; e-Mail: alcaideb@quim.ucm.es;
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Publication History
Received
10 September 2001 Publication Date: 01 February 2007 (online)
A novel, concise, divergent methodology to both indolizidine and quinolizidine systems based on the sequential regio- and stereocontrolled intramolecular nitrone-alkene cycloaddition (INAC) reactions of 2-azetidinone-tethered alkenylaldehydes is reported.
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-β-methylthienamycin. A notable feature of such processes is their propensity for the predominant formation of the fused bicyclic systems as opposed to the bridged systems. See, for example:
Related nitrones derived from α-amino and α-hydroxy acids behave almost identically in terms of their stereoselectivities. The stereocenter at the α-position effectively controls the formation of the new contiguous stereocenters. See, for example:
12aChiacchio U.
Casuscelli F.
Corsaro A.
Librando V.
Rescifina A.
Romeo R.
Romeo G.
Tetrahedron
1995,
51:
5689
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 µL, 0.72 mmol) in dichloromethane (0.2 mL) was added dropwise to a stirred solution of oxalyl chloride (3.1 µL, 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 µL, 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. [α]D +33.4 (c 0.8, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 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): δ = 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): ν 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 compound (+)-1b was obtained as a colorless oil. [α]D = +1.9 (c 3.1, CHCl3). 1H NMR (300 MHz, C6D6): δ = 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): δ = 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: C, 66.15; H, 7.90; N, 12.10).
Synthesis of Indolizidine (+)-2 from alcohol(-)-12. A solution of alcohol (-)-12 (55 mg, 0.17 mmol) in CH2Cl2 (0.3 mL) was added dropwise to a stirred solution of DMP (103 mg, 0.24 mmoles) in CH2Cl2 (0.5 mL). The reaction mixture was stirred at r.t. for 90 min and then NaOH (10%, 1.2 mL) was added. The organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure to give aldehyde 13, which was used without further purification. N-methyl-hydroxylamine (19 mg, 0.22 mmol) and triethylamine (6.2 µL, 0.44 mmol) was added to a stirred solution of aldehyde 13 (49 mg, 0.15 mmol) 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 eluting with EtOAc-MeOH mixtures gave compound 2 (26 mg, 45%) as a pale yellow oil. Selected data: [α]D +2 (c 1.4, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.97 (1 H, t, J = 8.4 Hz), 2.20 (2 H, m), 2.28 (3 H, s), 2.65 (3 H, s), 2.83 (1 H, dd, J = 4.6, 2.2 Hz), 2.94 (2 H, m), 3.18 (1 H, m), 3.39 (1 H, t, J = 8.4 Hz), 3.57 (4 H, m), 3.97 (1 H, dd, J = 9.0, 6.6 Hz), 4.07 (1 H, dd, J = 7.6, 5.0 Hz), 4.45 (1 H, d, J = 12.4 Hz), 4.72 (1 H, d, J = 12.4 Hz), 7.31 (5 H, m). 13C NMR (75 MHz, acetone-d6): δ = 139.5, 129.2, 129.1, 128.4, 73.0, 72.8, 72.3, 69.2, 69.0, 68.9, 67.5, 61.6, 54.2, 45.7, 45.1, 43.6, 42.0. MS (CI): m/z = 346(1) [MH+], 345(1) [M+], 314(100), 177(47), 91(90). (Anal. Calcd for C19H27N3O3: C, 66.06; H, 7.88; N, 12.16. Found: C, 66.05; H, 7.86; N, 12.19).
Compounds 1a and 1b showed only one methylene carbon resonance at δ (C) 69.4 and 68.8 (DEPT), respectively, attributables to one endocyclic oxygen substituted methylene carbon. In addition, both of them displayed a methylene carbon resonance at δ (C) 28.2 and 27.2 (DEPT), respectively, corresponding to their former bridged structural moieties. Compound 2 showed two methylene carbon resonances at δ (C) 69.0 and 69.2 (DEPT) attributable to two endocyclic oxygen substituted methylene carbons as expected for its all fused structure.
