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

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<A NAME="RW11205ST-9">9</A>

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]⁺.

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<A NAME="RW11205ST-11">11</A>

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]].