O-, N-, or F-substituted 3-isopropylidene- and 3-isopropyl N-acyl azetidin-2-ones, lacking an ionizable moiety attached to the lactam nitrogen, have in vitro antibacterial activity, being particularly potent vs anaerobes. 3-Isopropylidenyl-(1) and 3-isopropyl (2) N-acyl azetidin-2-ones are novel synthetic monocyclic β-lactams exhibiting in vitro antibacterial activity vs anaerobes and Gram-positive aerobes.¹ A unique structural aspect differentiating azetidinones 1 and 2 from all other classes of β-lactam antibiotics is the lack of any negatively charged group (eg., CH₂CO₂⁻ or SO₃⁻) appended to the lactam nitrogen. Such anionic appendages are generally considered essential structural components, believed to play a role in attachment of substrate to the enzyme involved in bacterial cell wall biosynthesis.² A report that the related N-acyl 3-alkyl 1-acetoxy azetidin-2-ones inhibit human leukocyte elastase³ indicates a broadening interest in 3-alkyl N-acyl azetidinones. At the conceptual stage in our lead-finding program to examine the utility of N-1 activated 3-alkylidene azetidin-2-ones as potential antimicrobial agents, we required a template with a suitable synthetic handle, allowing for functionalization about the β-lactam. The ability to readily introduce a wide variety of side-chains or functionalities was a desirable feature, allowing us to maximize the chances of finding structural attributes which would enhance delivery to, or binding of, the β-lactam at the targeted transpeptidase active site.⁴ In this regard, the 3-(hydroxyisopropylidene)azetidin-2-ones 3Z and 3E were synthesized.⁵ Herein we report the synthesis and antibacterial activity of various heteroatom-substituted 3-isopropylidenyl- and 3-isopropyl N-acyl azetidin-2-ones, derived from these key intermediates.