New Oligocyclic β-Lactams and β-Amino Acid Derivatives by Intramolecular Cycloaddition of Bicyclopropylidenyl-Substituted Nitrones [1]

Abstract

Bicyclopropylidenylalkyl-substituted nitrones 6 and 7 undergo regio- and diastereoselective intramolecular cycloadditions to afford exclusively the ring-fused adducts 8 and 9, respectively. The thermal rearrangement of the cycloadducts 8 and 9 under acidic conditions (TFA) leads to the tricyclic β-lactams 12 and 14, respectively. Under the reaction conditions, 12 undergoes lactam-amide bond cleavage to yield the bicyclic N-trifluoroacetylated β-amino acid derivative 13.

Key words

1,3-dipolar cycloadditions - β-lactams - β-amino acids - small ring systems - heterocycles

References and Notes

• 1a

  For one of us (AdM) this is to count as Part 125 in the series ‘Cyclopropyl Building Blocks for Organic Synthesis’. For Part 124 see: Dalai, S.; Belov, V. N.; Nizamov, S.; Finsinger, D.; de Meijere, A. Eur. J. Org. Chem. 2006, in press.

• 1b Part 123: Revuelta J. Cicchi S. Faggi C. Kozhushkov SI. de Meijere A. Brandi A. J. Org. Chem.  2006,  71:  2417 
• For leading references on 1,3-dipolar cycloadditions engaging nitrones, see:
• 2a Tufariello JJ. In 1,3-Dipolar Cycloaddition Chemistry   Padwa A. John Wiley and Sons; New York: 1984. 
• 2b Confalone PN. Huie EM. Org. React.  1988,  36:  1 
• 2c Torssell KBG. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis   Feuer H. VCH Publishers; New York: 1988. 
• 2d Frederickson M. Tetrahedron  1997,  53:  403 
• 2e Gothelf KV. Jørgensen KA. Chem. Rev.  1998,  98:  863 
• 2f Jones RCF. Martin JN. In Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products   Padwa A. Pearson WH. John Wiley and Sons; New York: 2002. 
• 2g Koumbis AE. Gallos JK. Curr. Org. Chem.  2003,  7:  585-628  
• 2h Osborn HMI. Gemmell N. Harwood LM. J. Chem. Soc., Perkin Trans. 1  2002,  2419 
• 2i Merino P. In Science of Synthesis   Vol. 27:  Padwa A. Thieme; Stuttgart: 2004.  p.511-580  
• For recent reviews on alkylidenecyclopropanes, see:
• 3a Brandi A. Cicchi S. Cordero FM. Goti A. Chem. Rev.  2003,  103:  1213 
• 3b Cordero FM. De Sarlo F. Brandi A. Monatsh. Chem.  2004,  135:  649 
• 4a Cordero FM. Brandi A. Tetrahedron Lett.  1995,  36:  1343 
• 4b Estieu K. Paugam R. Ollivier J. Salaün J. Cordero FM. Goti A. Brandi A. J. Org. Chem.  1997,  62:  8276 
• 4c Ferrara M. Cordero FM. Goti A. Brandi A. Estieu K. Paugam R. Ollivier J. Salaün J. Eur. J. Org. Chem.  1999,  2725 
• 4d Pisaneschi F. Cordero FM. Goti A. Paugam R. Ollivier J. Brandi A. Salaün J. Tetrahedron: Asymmetry  2000,  11:  897 
• 5a Cordero FM. Pisaneschi F. Goti A. Ollivier J. Salaün J. Brandi A. J. Am. Chem. Soc.  2000,  122:  8075 
• 5b Paschetta V. Cordero FM. Paugam R. Ollivier J. Brandi A. Salaün J. Synlett  2001,  1233 
• 5c Cordero FM. Pisaneschi F. Salvati M. Paschetta V. Ollivier J. Salaün J. Brandi A. J. Org. Chem.  2003,  68:  3271 
• 6 Goti A. Anichini B. Brandi A. Kozhushkov SI. Gratkowski C. de Meijere A. J. Org. Chem.  1996,  61:  1665 
• 7a de Meijere A. Kozhushkov SI. Zefirov NS. Synthesis  1993,  681 
• 7b de Meijere A. Kozhushkov SI. Späth T. von Seebach M. Löhr S. Nüske H. Pohlmann T. Es-Sayed M. Bräse S. Pure Appl. Chem.  2000,  72:  1745 
• 8 Löhr S. Jacobi C. Johann A. Gottschalk G. de Meijere A. Eur. J. Org. Chem.  2000,  2979 
• 10a Baldwin SW. Wilson JD. Aubé J. J. Org. Chem.  1985,  50:  4432 
• 10b Aurich HG. Frenzen G. Gentes C. Chem. Ber.  1993,  126:  787 
• 14 Cordero FM. Salvati M. Pisaneschi F. Brandi A. Eur. J. Org. Chem.  2004,  2205 
• 15a Brennan J. Richardson G. Stoodley RJ. J. Chem. Soc., Perkin Trans. 1  1983,  649 
• 15b Crackett PH. Pant CM. Stoodley RJ. J. Chem. Soc., Perkin Trans. 1  1984,  2785 
• 15c Sharma R. Stoodley RJ. Whiting A. J. Chem. Soc., Perkin Trans. 1  1987,  2361 
• 17 For a review, see: Suckling CJ. Angew. Chem., Int. Ed. Engl.  1988,  27:  537 ; Angew. Chem.  1988,  100:  555 
• 18 For a recent review on β-amino acids containing cyclopropyl groups, see: Gnad F. Reiser O. Chem. Rev.  2003,  103:  1603 
• For the importance of cyclopropyl groups in naturally occurring and synthetic biologically active compounds, see:
• 19a Salaün J. Baird MS. Curr. Med. Chem.  1995,  2:  511 
• 19b Salaün J. Top. Curr. Chem.  2000,  207:  1 

9

Typical Procedure for the Synthesis of Isoxazolidine 8.
A 0.5 M solution of the alcohol 4 (300 mg, 2.17 mmol) in anhyd CH₂Cl₂ (4.3 mL) was added at 25 °C under a nitrogen atmosphere to a suspension of PCC (754 mg, 3.26 mmol) in anhyd CH₂Cl₂ (3.3 mL). The mixture was stirred at 25 °C for 3 h, and then Et₂O (4.5 mL) was added. The mixture containing the desired aldehyde was directly filtered through Celite^®, the dark filter cake was washed with Et₂O (22 mL) into a flask containing activated molecular sieves 3 Å (1.7 g), N-methylhydroxylamine hydrochloride (217 mg, 2.60 mmol) and Et₃N (360 µL, 2.60 mmol) in Et₂O (10 mL). The resulting mixture was stirred at 25 °C for 48 h, then filtered through Celite^®, and finally the solvents were evaporated. The crude product was purified by flash column chromatography to afford 8 (207 mg, 58%) as a colorless oil.
Analytical Data for Compound 8.
R _f = 0.27 (eluent CH₂Cl₂-MeOH, 100:1). IR (neat): 3077, 3051, 3028, 2986, 2952, 2865, 1458 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.11 (bd, 1 H, J = 5.6 Hz), 2.71 (s, 3 H), 2.26-2.13 (m, 1 H), 1.78 (br dd, 1 H, J = 14.3, 9.3 Hz), 1.69 (ddd, 1 H, J = 10.0, 8.7, 1.9 Hz), 1.51-1.39 (m, 1 H), 1.18 (dt, 1 H, J = 8.1, 5.0 Hz), 0.97-0.82 (m, 2 H), 0.57-0.43 (m, 3 H), 0.22-0.14 (m, 1 H). ¹³C NMR (75.5 MHz, CDCl₃): δ = 76.3 (d), 64.0 (s), 44.5 (q), 43.8 (s), 26.6 (t, 2 C), 22.3 (d), 10.2 (t), 8.8 (t), 6.7 (t). MS (EI): m/z (rel. int.) = 165 (17) [M⁺], 136 (3), 108 (16), 79 (100). Anal. Calcd for C₁₀H₁₅NO (165.23): C, 72.69; H, 9.15; N, 8.48. Found: C, 72.67; H, 8.95; N, 8.13.

11

Analytical Data for Compound 9.
R _f = 0.43 (eluent CH₂Cl₂-MeOH, 100:1). IR (neat): 3081, 3057, 2990, 2931, 2855, 1457 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 2.79 (s, 3 H), 2.71 (dd, 1 H, J = 9.9, 6.1 Hz), 1.76-1.70 (m, 2 H), 1.69-1.62 (m, 1 H), 1.57-1.52 (m, 1 H), 1.19-1.11 (m, 1 H), 0.97-0.91 (m, 1 H), 0.88 (dt, 1 H, J = 11.4, 6.8 Hz), 0.79 (ddd, 1 H, J = 11.4, 6.8, 5.8 Hz), 0.67 (dt, 1 H, J = 9.4, 5.9 Hz), 0.49 (dd, 1 H, J = 9.4, 5.0 Hz), 0.38 (ddd, 1 H, J = 10.5, 6.8, 5.8 Hz), 0.36-0.34 (m, 1 H), 0.26 (dt, 1 H, J = 10.5, 6.8 Hz). ¹³C NMR (75.5 MHz, CDCl₃): δ = 70.5 (d), 65.8 (s), 44.7 (q), 30.2 (s), 27.1 (t), 22.5 (t), 16.7 (t), 14.2 (d), 12.2 (t), 9.5 (t), 6.1 (t). MS (EI): m/z (rel. int.) = 179 (14) [M⁺], 150 (13), 123 (23), 94 (71), 79 (100). Anal. Calcd for C₁₁H₁₇NO (179.26): C, 73.70; H, 9.56; N, 7.81. Found: C, 73.51; H, 9.27; N, 7.65.

12

The fusion between the cyclopropane and the cyclohexane rings must be cis as a consequence of the way in which the nitrone functionality approaches the double bond during the cycloaddition (see Figure [1] ), thus the term cis-fused for the isoxazolidines 8 and 9 refers to the fusion between the two larger rings.

13

Analytical Data for Compound 13.
Two rotamers in a ratio of 1.6:1; R _f = 0.37 (eluent CH₂Cl₂-MeOH-CH₃CO₂H, 20:1:0.1); mp 131 °C. IR (KBr): 3052, 2998, 2967, 2891, 1684, 1459 cm^-1. ¹H NMR (300 MHz, CDCl₃, 50 °C): δ = 5.16 and 4.64 (0.62 H and 0.38 H, br s and d with J = 6.2 Hz), 3.01 and 2.91 (1.85 H and 1.15 H, each s), 2.39 (dt, 1 H, J = 8.1, 5.0 Hz), 2.19-2.04 (m, 1 H), 2.00-1.63 (m, 3 H), 1.54-1.42 (m, 1 H), 0.88-0.83 (m, 1 H), the signal of the COOH proton could not be assigned. ¹³C NMR (75.5 MHz, CDCl₃, 50 °C): δ = 177.2 and 176.8 (each s), 157.1 and 156.9 (each q with J _C,F = 35.5 Hz), 116.9 and 116.7 (each q with J _C,F = 288.4 Hz), 57.5 and ca. 56.8-55.4 (qd with J _C,F = 4.1 Hz and broad signal), 32.0 and 31.7 (each s), 30.6 and 29.5 (each q), 30.2 (d), 30.1 and 29.0 (each t), 26.2 and 25.8 (each t), 19.4 and 19.3 (each t). ¹⁹F NMR (282 MHz, CDCl₃, 50 °C): δ = -67.6 and -70.0 (1.15 and 1.85 F, each s, together NCOCF ₃). MS (EI): m/z (rel. int.) = 251 (81) [M⁺], 206 (59), 154 (82), 196 (42), 136 (42), 124 (50), 79 (100). Anal. Calcd for C₁₀H₁₂F₃NO₃ (251.20): C, 47.81; H, 4.81; N, 5.58. Found: C, 47.98; H, 4.61; N, 5.76.

16

Typical Procedure for the Synthesis of β-Lactam 14.
To a 0.02 M solution of the isoxazolidine 9 (60 mg, 0.33 mmol) in MeCN was added TFA (51 µL, 0.66 mmol), and the mixture was heated under reflux for 15 min. The solvent was evaporated, and the crude product was purified by flash column chromatography to afford 14 (33 mg, 66%) as a colorless oil.
Analytical Data for Compound 14.
R _f = 0.23 (eluent CH₂Cl₂-MeOH, 50:1). IR (neat): 3063, 2991, 2930, 2857, 1750, 1450, 1382 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.47 (dd, 1 H, J = 9.0, 5.9 Hz), 2.87 (s, 3 H), 1.93 (dtd, 1 H, J = 12.5, 5.9, 2.0 Hz), 1.81-1.65 (m, 2 H), 1.65-1.51 (m, 2 H), 1.33 (dd, 1 H, J = 9.3, 6.2 Hz), 1.11-0.99 (m, 1 H), 0.94-0.83 (m, 1 H), 0.79 (t, 1 H, J = 6.2 Hz). ¹³C NMR (75.5 MHz, CDCl₃): δ = 172.3 (s), 55.6 (d), 35.0 (s), 27.3 (t and q, 2 C), 23.0 (t), 17.8 (t), 14.7 (d), 11.6 (t). MS (EI): m/z (rel. int.) = 151 (22) [M⁺], 123 (29), 94 (20), 79 (100), 77 (16), 42 (16). Anal. Calcd for C₉H₁₃NO (151.21): C, 71.49; H, 8.67; N, 9.26. Found: C, 71.27; H, 8.65; N, 9.09.