Synthesis of highly substituted 1,2-diazetidin-3-ones, small ring scaffolds for drug discovery

Santos, Marilia S.; Nortcliffe, Andrew; Lewis, William; Bradshaw, Tracey D; Moody, Christopher J.

Abstract

1,2-Diazetidin-3-ones are readily accessible, small ring scaffolds that upon functionalization have the potential to produce diverse 3-dimensional structures for drug discovery. Thus treatment of diazo hydrazides, obtained from simple hydrazides and malonyl half ester derivatives, followed by diazo transfer, with catalytic amounts of rhodium (II) acetate dimer results in intramolecular carbenoid N–H insertion to give 1,2-diazetidin-3-ones. Although subsequent functionalization reactions could be hampered by the lability of the 4-membered ring, a wide range of new derivatives was available by deprotection at N-1, and subsequent amide or urea formation. The structures of four four-membered rings was confirmed by X-ray crystallography; the compounds showed modest growth inhibitory activity in mammary carcinoma cells.

Citation

Santos, M. S., Nortcliffe, A., Lewis, W., Bradshaw, T. D., & Moody, C. J. (in press). Synthesis of highly substituted 1,2-diazetidin-3-ones, small ring scaffolds for drug discovery. Chemistry - A European Journal, https://doi.org/10.1002/chem.201801309

• Journal Article Type: Article
• Acceptance Date: Mar 22, 2018
• Online Publication Date: Mar 31, 2018
• Deposit Date: Apr 19, 2018
• Publicly Available Date: Apr 1, 2019
• Journal: Chemistry - A European Journal
• Print ISSN: 0947-6539
• Electronic ISSN: 1521-3765
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1002/chem.201801309
• Public URL: https://nottingham-repository.worktribe.com/output/923177
• Publisher URL: https://onlinelibrary.wiley.com/doi/abs/10.1002/chem.201801309
• Additional Information: This is the peer reviewed version of the following article: Santos, Marilla S and Nortcliffe, Andrew and Lewis, William and Bradshaw, Tracey D and Moody, Christopher J (2018) Synthesis of highly substituted 1,2-diazetidin-3-ones, small ring scaffolds for drug discovery. Chemistry - a European Journal, doi:10.1002/chem.201801309, which has been published in final form at https://onlinelibrary.wiley.com/doi/abs/10.1002/chem.201801309. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
• Contract Date: Apr 19, 2018