Download PDF
Synlett 2006(7): 1125-1127  
DOI: 10.1055/s-2006-939687
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Marco Marradia,b, Alberto Brandi*b, Armin de Meijere*a
a Institut für Organische und Biomolekulare Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany
Fax: +49(551)399475; e-Mail: Armin.deMeijere@chemie.uni-goettingen.de;
b Dipartimento di Chimica Organica ‘Ugo Schiff’, Università di Firenze, via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax: +39(055)4573572; e-Mail: alberto.brandi@unifi.it;
Further Information

Publication History

Received 23 January 2006
Publication Date:
24 April 2006 (online)

    Permissions and Reprints All articles of this category

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