β-Lactams are the core structures of many antibiotics such as penicillin and its derivatives. Since their discovery in 1928, many β-lactam scaffolds were synthesized. However, there is a great demand for new β-lactam scaffolds because of the bacterial strains resistant to the existing drugs, and also of β-lactams application in non-antibacterial therapeutic areas such as antifungal, serine protease and cholesterol absorption inhibitors. We discovered a new approach to synthesize β-lactams with an exocyclic double bond through [2+2] cycloaddition reactions of Bestmann’s ylide with N-protected imines. Bestmann’s ylide is a phosphacumulene of formula, Ph3PCCO, which has been used as a linchpin reagent for the synthesis of important natural products with biological activity. It is also used in various cycloaddition reactions to synthesize heterocyclic compounds. Here we report a [2+2] cycloaddition reaction of Bestmann’s ylide with N-protected imines at 75 °C to form β-lactams with an exocyclic phosphonium ylide. In a one-pot reaction, the intermediately formed exocyclic ylides can be quenched with aldehydes to undergo a Wittig reaction with the formation of a range of β-lactams with an exocyclic double bond. The [2+2] cycloaddition reaction tolerates a variety of aromatic imines of different electronic properties. In addition, a wide variety of aldehydes can be utilized via Wittig reaction to form β-lactams with exocyclic double bonds in good to excellent yields.

Synthesis of N-protected β-lactams via [2+2] cycloaddition of Bestmann’s ylide with N-Cbz/Boc imines

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