Enantioselective Synthesis of β-Lactams Using a Chiral Auxiliary

Abstract

An efficient and enantioselective synthesis of trans-β-lactams from carboximide 1 and imines 2 using a chiral auxiliary under the classical Reformatsky reaction conditions is described. An enolate-imine mechanism has been proposed for this reaction.

β-lactams - imines - Reformatsky reaction - enantio­selectivity

References and Notes

1 Gilman H. Speeter M. J. Am. Chem. Soc.  1943,  65:  2255 

2a Singh GS. Tetrahedron  2003,  59:  7631 

2b Enantioselective Synthesis of β-Amino Acids   2nd ed.:  Juaristi E. Soloshonok VA. Wiley-VCH; Hoboken: 2005. 

3a Magriotis PA. Angew. Chem. Int. Ed.  2001,  40:  4377 

3b Ojima I. Delaloge F. Chem. Soc. Rev.  1997,  26:  377 

3c Ojima I. Acc. Chem. Res.  1995,  28:  383 

3d Chemistry and Biology of β-Lactam Antibiotics   Vol. 1-3:  Morin RB. Gorman M. Academic Press; New York: 1982. 

3e Dürckheimer W. Blumbach J. Latrell R. Scheunemann KH. Angew. Chem., Int. Ed. Engl.  1985,  24:  180 

3f Nagahara T. Kametani T. Heterocycles  1987,  25:  729 

3g The Chemistry of β-Lactams   Page MI. Chapman and Hall; London: 1992. 

4a Alcaide B. Almendros P. Curr. Med. Chem.  2004,  11:  1921 

4b Deshmukh ARAS. Bhawal BM. Krishnaswamy D. Govande VV. Shinkre BA. Jayanthi A. Curr. Med. Chem.  2004,  11:  1889 

4c Alcaide B. Almendros P. Synlett  2002,  381 

4d Palomo C. Aizpurua JM. Ganboa I. Oiarbide M. Synlett  2001,  1813 

4e Alcaide B. Almendros P. Chem. Soc. Rev.  2001,  30:  226 

5a Hart DJ. Ha DC. Chem. Rev.  1989,  89:  1447 

5b Chen L. Zhao G. Ding Y. Tetrahedron Lett.  2003,  44:  2611 

6a France S. Weatherwax A. Taggi AE. Lectka T. Acc. Chem. Res.  2004,  37:  592 

6b Tomioka K. Fujieda H. Hayashi S. Hussein MA. Kambara T. Nomura Y. Kanai M. Koga K. Chem. Commun.  1999,  715 

7 Jian SZ. Ma C. Wang YG. Synthesis  2005,  725 

8 Seki M. Miyake T. Izukawa T. Ohmizu H. Synthesis  1997,  47 

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Typical Procedure for the Synthesis of β-Lactams 3.
A mixture of carboximide 1 (1.0 mmol), imine 2 (1.2 mmol) and zinc dust (3 mmol) in THF (5 mL) was refluxed for 10-20 min, cooled to r.t., poured into H₂O (5 mL), and then extracted with CH₂Cl₂ (3 × 5 mL). The combined extracts were washed with brine, dried over anhyd Na₂SO₄, and evaporated in vacuo. The residue was chromatographed through a silica gel column with hexane-EtOAc to give pure β-lactams 3 and chiral auxiliary 4.
(3 S ,4 R )-4-(4-Chlorophenyl)-3-methyl-1-phenylazetidin-2-one ( 3a): ¹H NMR (500 MHz, CDCl₃): δ = 1.51 (d, J = 7.4 Hz, 3 H), 3.16 (dq, J = 2.4, 7.4 Hz, 1 H, H-3), 4.61 (d, J = 2.4 Hz, 1 H, H-4), 7.06 (m, 1 H) 7.26-7.43 (m, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 13.35, 55.56, 62.97, 117.21, 123.99, 126.07, 128.69, 129.28, 129.38, 138.08, 138.20, 168.63. ESI-MS: m/z = 238 [M + H]⁺.
(3 S ,4 S , E )-3-Ethyl-1-phenyl-4-styrylazetidin-2-one ( 3j): ¹H NMR (500 MHz, CDCl₃): δ = 1.09 (t, J = 7.4 Hz, 3 H), 1.83 (m, 1 H), 1.94 (m, 1 H), 3.06 (m, 1 H, H-3), 4.33 (dd, J = 1.9, 8.4 Hz, 1 H, H-4), 6.30 (dd, J = 8.4, 15.9 Hz, 1 H), 6.78 (d, J = 15.9 Hz, 1 H), 7.03-7.50 (m, 10 H). ¹³C NMR (125 MHz, CDCl₃): δ = 11.63, 21.85, 59.21, 60.04, 117.03, 123.93, 126.83, 127.67, 128.53, 128.95, 129.28, 133.84, 136.02, 138.56, 167.61. ESI-MS: m/z = 278 [M + H]⁺, 300 [M + Na]⁺, 577 [2 M + Na]⁺.

10 Cainelli G. Panunzio M. Bandini E. Martelli G. Spunta G. Tetrahedron  1996,  52:  1685 

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CCDC 273640 contains the supplementary crystallographic data (excluding structure factors) for compound 3b. These data can be obtained free of charge via http://www.ccdc. cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; or [e-mail]].