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Synlett 2003(5): 0726-0728
DOI: 10.1055/s-2003-38353
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Asymmetric Synthesis of Functionalized Azetidines through Intramolecular Michael Additions

Abel Carlin-Sinclaira, François Couty*a, Nicolas Rabassoa,b
a SIRCOB, UMR 8086, Université de Versailles, 45, Avenue des Etats-Unis, 78035, Versailles Cedex, France
e-Mail: couty@chimie.uvsq.fr;
b Laboratoire de Synthèse Asymétrique, UMR 7611, Université Pierre et Marie Curie, 4 Place Jussieu, 75005 Paris, France
Further Information

Publication History

Received 13 December 2002
Publication Date:
28 March 2003 (online)

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Abstract

Enantiopure 2-cyano azetidines were prepared in good yields from β-amino alcohols. This synthesis is based on two important steps: (i) Wittig olefination of a transient amino aldehyde derived from a N-cyanomethylated β-amino alcohol and (ii) a 4-exo-tet ring closure through the intramolecular Michael addition of a lithiated α-amino nitrile. The former step is stereoselective. The thus produced functionalized azetidines were transformed into conformationnally constrained analogues of glutamic acid.

Key words

Michael additions - amino acids - nitrogen heterocycles - ring closure - asymmetric synthesis

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13

HPLC was performed using a WELK 0-1 column of 250 mm length and of 4 mm diameter. The flow rate was 1mL/mn and the pressure 39kg/cm2. (Heptane-iso-propanol = 95/5 + 0.5% of acetic acid). Using these conditions, tr for 6 was 23.85 min and 22.00 min for ent-6.

15

Compound 9 crystallized in the space group P21 21 21 (Orthorhombic crystal system) with a = 5.558(2) Å, b = 17.627(5) Å, c = 19.730(4) Å, and d calcd = 1.15 g/cm3. The intensity data were mesured on a Enraf-Nonius CAD4 diffractometer (Mo radiation). There were 1988 independent reflexions of which 1118 were considered observed. Final discrepancy indices were R = 0.0757 and wR = 0.0880. Crystallographic data have been deposited (number 199691) at the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK.

17

All new compounds gave satisfactory spectral and analytical data. Selected data: Compound 6. Oil, Rf = 0.47 (Et2O-cyclohexane = 1/1). [α] d 25 = -15.8 (c 0.5, CHCl3). IR(neat): 2980, 2925, 2863, 2238, 1726, 1491, 1450 cm-1. 1H NMR (250 MHz): δ = 1.02 (d, J = 5.9 Hz, 3 H, Me), 1.19 (t, J = 7.1 Hz, 3 H, Me), 2.42 (d, J = 3.1 Hz, 1 H, CHHCO), 2.45 (d, J = 0.9 Hz, 1 H, CHHCO), 2.52-2.67 (m, 1 H, CHCH2), 2.90 (qd, J = 6.0, 7.5 Hz, 1 H, CHMe), 3.35 (d, J = 7.4 Hz, 1 H, CHCN), 3.64 (AB syst., 2 H, J = 12.9 Hz, CH 2Ph), 4.08 (q, J = 7.4 Hz, 2 H, CH 2O), 7.19-7.27 (m, 5 H, Ar). 13C NMR (62.9 MHz): δ = 14.3 (Me), 20.6 (Me), 36.7 (CH2CH), 41.0 (CHCH2), 54.3 (CHCN), 60.8 and 61.2 (CH2), 65.8 (CHMe), 119.0 (CN), 128.0, 128.6, 129.4 (CH Ar), 135.7 (Cq Ar), 170.6 (C=O). Anal. Calcd For C16H20N2O2: C, 70.56; H, 7.40; N, 10.29. Found: C, 70.54; H, 7.51; N, 10.24. Compound 17: Rf = 0.25 (EtOH-NH3-H2O = 9/3/1). [α] d 25 = +9.5 (c 0.2, H2O). 1H NMR (200 MHz, D2O): 1.51 (d, J = 7.0 Hz, 3 H, Me), 2.38-2.91 (m, 3 H, CHCH 2), 4.21 (quint., J = 8.8 Hz, 1 H, CHMe), 4.33 (d, J = 8.6 Hz, 1 H, CHCOOH). 13C NMR (75.5 MHz): δ = 21.3 (Me), 43.6 (CH2CH), 45.3 (CHCH2), 62.4 and 63.0 (CH), 176.3 and 181.5 (C=O). MS (CI, CH4): m/z (%) = 174 (22) [MH+] 173 (55), 156 (100), 130 (26), 128 (35). HRMS: Anal. Calcd For C7H12NO4 [MH+]: 174.0766. Found: 174.0764.