Concise, Divergent β-Lactam-based Route to Indolizidine and Quinolizidine Derivatives via Sequential Regio- and Stereocontrolled Intramolecular Nitrone-alkene Cycloadditions

Abstract

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.

β-lactams - indolizidines - quinolizidines - aza-sugars - nitrone-alkene cycloaddition - asymmetric synthesis

References

See, for example:

1a Asano N. Nash RJ. Molynuex RJ. Fleet GWJ. Tetrahedron: Asymmetry  2000,  11:  1645 

1b Stuetz AE. In Iminosugars as Glycosidase Inhibitors, Nojirimycin and Beyond   Wiley-VCH; Weinheim: 1999. 

1c Vlietinck AJ. De Bruyne T. Apers S. Pieters LA. Planta Med.  1998,  64:  97 

1d Howard AS. Michael JP. In The Alkaloids   Vol. 28:  Brosi A. Academic Press; Orlando: 1986.  p.183 

1e Format for theses: Goering BK. Ph. D. Dissertation   Cornell University; Cornell: 1995. 

For reviews, see:

2a Ojima I. Adv. Asym. Synth.  1995,  1:  95 

2b Palomo C. Aizpurua JM. Ganboa I. Oiarbide M. Amino-acids  1999,  16:  321 

2c Ojima I. Delaloge F. Chem. Soc. Rev.  1997,  26:  377 

2d Manhas MS. Wagle DR. Chiang J. Bose AK. Heterocycles  1988,  27:  1755 

3 Alcaide B. Almendros P. Alonso JM. Aly MF. Torres MR. 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 

5a Alcaide B. Alonso JM. Aly MF. Sáez E. Martínez-Alcázar MP. Hernández-Cano F. Tetrahedron Lett.  1999,  40:  5391 

5b Alcaide B. Sáez E. Tetrahedron Lett.  2000,  41:  1647 

For reviews, see:

6a Tufariello JJ. In 1,3-Dipolar Cycloaddition Chemistry   Vol. 2:  Padwa A. John Wiley and Sons; New York: 1984.  Chap. 9. p.83 

6b Wade PA. In Comprehensive Organic Synthesis   Vol. 4:  Trost BM. Fleming I. Semmelhack ME. Pergamon Press; Oxford: 1991.  Chap. 4.10. p.1111 

6c Frederickson M. Tetrahedron  1997,  53:  403 

6d Gothelf KV. Jorgensen KA. Chem. Rev.  1998,  98:  863 

For the synthesis of bicyclic alkaloid systems involving 1,3-dipolar cycloadditions, see:

7a Broggini G. Zecchi G. Synthesis  1999,  905 ; and references cited therein

7b El Nemr A. Tetrahedron  2000,  56:  8579 

For very recent selected examples, see: Indolizidines:

8a Klitzke CF. Pilli RA. Tetrahedron Lett.  2001,  42:  5605 

8b Groaning MD. Meyers AI. Chem. Commun.  2000,  1027 

8c Pourashraf M. Delair P. Rasmusen MO. Greene AE. J. Org. Chem.  2000,  65:  6966 

Quinolizidines:

9a Gebarowski P. Sas W. Chem. Commun.  2001,  915 

9b Ledoux S. Marchalant E. Célérier J.-P. Lhommet G. Tetrahedron Lett.  2001,  42:  5397 

10

Selected data for compound 5: Colorless oil. [α]_D +80 (c 2.4, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 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): δ = 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).

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:

11a Kang SH. Kim WJ. Synlett  1991,  520 

11b Kang SH. Lee HS. Tetrahedron Lett.  1995,  36:  6713 

11c Junk ME. Vu BT. J. Org. Chem.  1996,  61:  4427 

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:

12a Chiacchio U. Casuscelli F. Corsaro A. Librando V. Rescifina A. Romeo R. Romeo G. Tetrahedron  1995,  51:  5689 

12b Shing TKM. Zhong Y.-L. Mak TCW. Wang R. Xue F. J. Org. Chem.  1998,  63:  414 . (See also ref.⁶)

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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).

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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.

15

Selected NOE effects and stereochemistry of compounds 1 and 2 (Figure [1] ).

Figure 1