Three decades of selective product formation via Griesbaum co-ozonolysis: insight and advances (1995-2025)

The Griesbaum co-ozonolysis reaction was first described by Karl Griesbaum and his collaborators in the mid-1990s. Their pioneering work laid the foundation for synthesis of tetrasubstituted ozonides by the reaction of O-methyl oximes with carbonyl compounds in the presence of ozone. It has emerged as a powerful and selective alternative to conventional ozonolysis. This review highlights the unique advantages of the reaction, including its high selectivity, operational simplicity, mild conditions, and consistently good yields. Emphasis is placed on the distinctive features that make Griesbaum co-ozonolysis a preferred approach for constructing complex molecular frameworks, i.e., di-, tri- and tetrasubstituted ozonides, mainly spiro and dispiro-1,2,4-trioxolanes, triterpenoids and synthetic drug candidates. The reaction tolerates basic conditions, allowing for controlled functionalization, and has been applied in post-ozonolysis transformation and chemical sensor development. Importantly, it eliminates the need for tetrasubstituted alkenes, broadening accessibility to complex ozonides. A comprehensive survey of the literature from the past three decades is presented, focusing on the diverse range of products synthesized using this method. The review underscores the growing importance and synthetic utility of Griesbaum co-ozonolysis in modern synthetic, organic and medicinal chemistry.