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

Peter S. Hadfield, Ron H.B. Galt, Yvonne Sawyer, Nicola J. Layland, Michael I. Page

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 γ-lactams are potential analogues of the β-lactam antibiotics and suitable derivatives 9, 10,11 and 12 are found to be competitive inhibitors of class A and C β-lactamases, with Ki as low as 70 μM.

Original languageEnglish
Pages (from-to)503-509
Number of pages7
JournalJournal of the Chemical Society - Perkin Transactions 1
Issue number4
DOIs
Publication statusPublished - 21 Feb 1997

Fingerprint

Lactams
Anilides
Anti-Bacterial Agents
Derivatives
Cyclization
Hydroxyproline
Proline
Anions
thioacetic acid

Cite this

@article{1332af5376be4a7b92e2621e2dddf6d2,
title = "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",
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 γ-lactams are potential analogues of the β-lactam antibiotics and suitable derivatives 9, 10,11 and 12 are found to be competitive inhibitors of class A and C β-lactamases, with Ki as low as 70 μM.",
author = "Hadfield, {Peter S.} and Galt, {Ron H.B.} and Yvonne Sawyer and Layland, {Nicola J.} and Page, {Michael I.}",
year = "1997",
month = "2",
day = "21",
doi = "10.1039/a604564b",
language = "English",
pages = "503--509",
journal = "Journal of the Chemical Society, Perkin Transactions 2",
issn = "0300-922X",
publisher = "Chemical Society",
number = "4",

}

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, Ron H.B.; Sawyer, Yvonne; Layland, Nicola J.; Page, Michael I.

In: Journal of the Chemical Society - Perkin Transactions 1, No. 4, 21.02.1997, p. 503-509.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Hadfield, Peter S.

AU - Galt, Ron H.B.

AU - Sawyer, Yvonne

AU - Layland, Nicola J.

AU - Page, Michael I.

PY - 1997/2/21

Y1 - 1997/2/21

N2 - 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 γ-lactams are potential analogues of the β-lactam antibiotics and suitable derivatives 9, 10,11 and 12 are found to be competitive inhibitors of class A and C β-lactamases, with Ki as low as 70 μM.

AB - 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 γ-lactams are potential analogues of the β-lactam antibiotics and suitable derivatives 9, 10,11 and 12 are found to be competitive inhibitors of class A and C β-lactamases, with Ki as low as 70 μM.

UR - http://www.scopus.com/inward/record.url?scp=33748658255&partnerID=8YFLogxK

U2 - 10.1039/a604564b

DO - 10.1039/a604564b

M3 - Article

SP - 503

EP - 509

JO - Journal of the Chemical Society, Perkin Transactions 2

JF - Journal of the Chemical Society, Perkin Transactions 2

SN - 0300-922X

IS - 4

ER -