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

Marco Marradi; Alberto Brandi; Armin de Meijere

doi:10.1055/s-2006-939687

LETTER

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

Marco Marradi^a,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;

Abstract

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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

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Referenzen

References and Notes

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.

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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.

<A NAME="RG01506ST-10A">10a</A> Baldwin SW. Wilson JD. Aubé J. J. Org. Chem. 1985, 50: 4432

<A NAME="RG01506ST-10B">10b</A> Aurich HG. Frenzen G. Gentes C. Chem. Ber. 1993, 126: 787

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.

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.

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.

<A NAME="RG01506ST-14">14</A> Cordero FM. Salvati M. Pisaneschi F. Brandi A. Eur. J. Org. Chem. 2004, 2205

<A NAME="RG01506ST-15A">15a</A> Brennan J. Richardson G. Stoodley RJ. J. Chem. Soc., Perkin Trans. 1 1983, 649

<A NAME="RG01506ST-15B">15b</A> Crackett PH. Pant CM. Stoodley RJ. J. Chem. Soc., Perkin Trans. 1 1984, 2785

<A NAME="RG01506ST-15C">15c</A> Sharma R. Stoodley RJ. Whiting A. J. Chem. Soc., Perkin Trans. 1 1987, 2361

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.

<A NAME="RG01506ST-17">17</A> For a review, see: Suckling CJ. Angew. Chem., Int. Ed. Engl. 1988, 27: 537 ; Angew. Chem. 1988, 100: 555

<A NAME="RG01506ST-18">18</A> 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:

<A NAME="RG01506ST-19A">19a</A> Salaün J. Baird MS. Curr. Med. Chem. 1995, 2: 511

<A NAME="RG01506ST-19B">19b</A> Salaün J. Top. Curr. Chem. 2000, 207: 1