Synthesis of beta-lactams and beta-homoprolines by fragmentative rearrangement of 5-spirocyclopropane-isoxazolidines mediated by acids

Azetidinones and beta-amino acids serve as useful building blocks in synthetic organic chemistry and their structural motifs are often found in biologically active compounds. Due to the importance of these compounds, several synthetic strategies have been developed and availability of new synthetic approaches is highly desirable. In this account, we describe the development of an original method that allows the preparation of beta-lactam and beta-homoproline derivatives not easily accessible through traditional processes. The serendipitous discovery made in our lab in 2000 involved the formation of a -lactam by heating a mixture of an alkylidenecyclopropane tethered to a formyl group with N-methylhydroxylamine hydrochloride. Investigation of the process resulted in disclosing an alternative synthetic method of azetidinones based on an acid induced fragmentative rearrangement of cycloadducts of nitrones with suitable methylenecyclopropane derivatives. Herein, the scope of this process is reviewed. In addition, both experimental and computational studies of the mechanism for this peculiar fragmentative rearrangement are presented.