Guidelines for β-Lactam Synthesis: Glycal Protecting Groups Dictate Stereoelectronics and [2+2] Cycloaddition...

The alkene-isocyanate cycloaddition method affords β-lactams from glycals with high regio- and stereoselectivity, but the factors that determine substrate reactivity are poorly understood. Thus, we synthesized a library of 17 electron-rich alkenes (glycals) with varied protecting groups to systematically elucidate the factors that influence their reactivity toward the electron-poor trichloroacetyl isocyanate. The experimentally determined reaction rates exponentially correlate with the computationally determined highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gap and natural bond orbital (NBO) valence energies. The electron-withdrawing ability of the protecting groups, but not bulk, impacts the electron density of the glycal allyloxocarbenium system when oriented pseudo-axially (i.e., stereoelectronics). In this conformation, ring σ_C-O* orbitals oriented antiperiplanar to the allyloxocarbenium system decrease glycal reactivity via negative hyperconjugation as protecting group electron withdrawal increases. Transition-state calculations reveal that protecting group stereoelectronics direct the reaction to proceed via an asynchronous one-step mechanism through a zwitterionic species. The combined experimental and computational findings, along with experimental validation on an unknown glycal, provide insight on the reaction mechanism and the role of distant protecting groups in glycal reactivity. Together, these studies will aid in the synthesis of new β-lactam antibiotics, β-lactamase inhibitors, and bicyclic carbohydrate-β-lactam monomers prepared by the alkene-isocyanate method.