Synthesis of β‐Lactams and β‐Homoprolines by Fragmentative Rearrangement of 5‐Spirocyclopropaneisoxazolidines Mediated by Acids

Abstract

Azetidinones and β‐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 β‐lactam and β‐homoproline derivatives not easily accessible through traditional processes. The serendipitous discovery made in our lab in 2000 involved the formation of a β‐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.

“Cyclopropylidene Effect” in the 1,3-Dipolar Cycloaddition of Nitrones to Alkylidene Cyclopropanes: A Computational Rationalization

“…The value of thermal rearrangement of 5-spirocyclopropane isoxazolidines 3 (Brandi-Guarna rearrangement, see Scheme ) , for the synthesis of monocyclic and polycyclic heterocycles containing a tetrahydropyridinone ring 4 has been largely proved in recent years. , The rearrangement is made possible by the presence in the molecule of a strained oxyspirocyclopropane moiety, where the oxygen is linked to a nitrogen with a bond that is easily cleaved under thermal activation. , Another important synthetic application of 5-spirocyclopropane isoxazolidines 3 is the synthesis of β-lactams 5 by thermal fragmentation under acidic conditions. − Isoxazolidines 3 find their origin in a 1,3-dipolar cycloaddition (1,3-DC) of nitrones 1 with methylenecyclopropane (MCP, 2 ). − …”