An unexpected Mitsunobu reaction. A direct route to the 2,5-diazabicyclo[2.2.1]heptan-3-one skeleton as a γ-lactam mimic of β-lactam antibiotics

Hadfield, Peter S., Galt, Ronald H. B., Sawyer, Yvonne, Layland, Nicola J. and Page, Michael I. (1997) An unexpected Mitsunobu reaction. A direct route to the 2,5-diazabicyclo[2.2.1]heptan-3-one skeleton as a γ-lactam mimic of β-lactam antibiotics. Journal of the Chemical Society, Perkin Transactions 1 (4). pp. 503-509. ISSN 1472-7781

Abstract

Treatment of anilides of N-protected (2S,4R)-4-hydroxyproline, e.g. 1, with thioacetic acid under Mitsunobu conditions gives, unexpectedly, 2,5-diazabicyclo[2.2.1]heptan-3-ones, e.g. 2, the products of intramolecular cyclisation. However, the less acidic N-benzylamides of these proline derivatives, e.g. 7, are not sufficiently acidic and the hydrazido anion generated in the Mitsunobu reaction displaces the activated hydroxy group in an intermolecular reaction to give 8. The bicyclic -lactams are potential analogues of the -lactam antibiotics and suitable derivatives 9, 10, 11 and 12 are found to be competitive inhibitors of class A and C -lactamases, with Ki as low as 70 M

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