Asymmetric Synthesis of Functionalized Azetidines through Intramolecular Michael Additions

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.

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

References

1 For a recent review on applications of aziridines, see: Zwanenburg B. ten Holte P. Top. Curr. Chem.  2001,  216:  96 

2a Jacobsen EN. In Comprehensive Asymmetric Catalysis   Vol 2:  Jacobsen EN. Pfaltz A. Yamamoto H. Springer-Verlag; Berlin: 1999.  p.607-618  

2b For recent examples see: Loncaric C. Wulff WD. Org. Lett.  2001,  23:  3675 

2c Guthikonda K. Du Bois J. J. Am. Chem. Soc.  2002,  124:  13672 

3 Ojima I. Zhao M. Yamato T. Nakahashi K. J. Org. Chem.  1991,  56:  5263 

4 Marinetti A. Hubert P. Genêt JP. Eur. J. Org. Chem.  2000,  1815 

5 Barluenga J. Fernandez-Mari F. Viado AL. Aguilar E. Olano B. J. Org. Chem.  1996,  61:  5659 

6 Kozikowski AP. Tückmantel W. Liao Y. Manev H. Ikonomovic S. Wrobleski JT. J. Med. Chem.  1993,  36:  2706 

7a Guanti G. Riva R. Tetrahedron: Asymmetry  1995,  12:  2921 

7b Hermsen PJ. Cremers JGO. Thijs L. Zwanenburg B. Tetrahedron Lett.  2001,  42:  4243 

8a Behnen W. Mehler T. Martens J. Tetrahedron: Asymmetry  1993,  4:  1413 

8b Shi M. Jiang JK. Tetrahedron: Asymmetry  1999,  10:  1673 

8c Wilken J. Erny S. Wassman S. Martens J. Tetrahedron: Asymmetry  2000,  11:  2143 

8d

See ref. 7b.

8e Yamaguchi M. Shiraishi T. Hirama M. J. Org. Chem.  1996,  61:  3520 

8f Starmans WAJ. Thijs L. Zwanenburg B. Tetrahedron  1998,  54:  629 

8g Couty F. Prim D. Tetrahedron: Asymmetry  2002,  13:  2619 

9a Agami C. Couty F. Evano G. Tetrahedron: Asymmetry  2002,  13:  297 

9b Agami C. Couty F. Rabasso N. Tetrahedron Lett.  2002,  43:  4633 

10 To the best of our knowledge, intramolecular Michael additions leading to four-membered rings were not previously reported. Intramolecular Michael additions involving metallated amino nitrile have been little reported. For a recent example leading to a pyrrolidine ring see: Yokoshima S. Tokuyama H. Fukuyama T. Angew. Chem.  2000,  112:  4239 

11a Jurczak J. Golebiowski A. Chem. Rev.  1989,  89:  149 

11b Reetz M. Chem. Rev.  1999,  99:  1121 

12 Ireland RE. Norbeck DW. J. Org. Chem.  1985,  50:  2198 

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.

14 Kingsbury CA. Soriano DS. Podraza KF. Cromwell NH. J. Heterocycl. Chem.  1982,  19:  82 

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.

16 Enders D. Shilvock JP. Chem. Soc. Rev.  2000,  29:  359 

17

All new compounds gave satisfactory spectral and analytical data. Selected data: Compound 6. Oil, R_f = 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: R_f = 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.