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

Abstract

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 σC–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.

Poly-Amido-Saccharides (PASs): Functional Synthetic Carbohydrate Polymers Inspired by Nature

“…Finally, analysis of the reaction transition state reveals distinct mechanisms with respect to glycal conformation, with 4 H 5 conformers proceeding to products via a pseudo-stepwise mechanism (via an entropic intermediate; an intermediate not due to a local energy minimum, but rather requiring a rotation of the trichloroacetyl moiety of the isocyanate away from the glycal face) and 5 H 4 conformers successfully proceeding through a concerted, asynchronous mechanism. Dynamic analysis of these transition states, however, found negligible transmission (nearly 100% recrossing) of products to reactants in the former case, implying that the 5 H 4 concerted mechanism is the dominant reaction mechanism …”

“…Conceptually, glycals adopting a 5 H 4 conformation, unlike the 4 H 5 conformation, possess pyranose ring σ* C–O orbitals oriented at the 3′ and 6’ positions antiperiplanar to the allyloxocarbenium n−π system, allowing the hydroxyl protecting groups to influence negative hyperconjugation (shift in electron density from the ring π system or ring oxygen nonbonding orbital to neighboring σ* orbital) from the allyloxocarbenium system (Figure ). Additionally, the pseudoaxial protecting group orientation of 5 H 4 conformers explains the observed reaction stereoselectivity, as the bulky O -benzyl group on the β-face forces an α approach of the isocyanate toward the alkene . These results, in addition to informing the synthesis of new PAS monomers and preparation of additional polysaccharide mimetics, are relevant for protecting group choices in glycal chemistry.…”

“…Conversely, attempts to synthesize β-lactam monomers with tri- O -acetyl- d -glucal or tri- O -benzyl- d -glucuronal and chlorosulfonyl isocyanate led to no product formation even after 8 h of reaction. These observations, coupled with the poor understanding of the mechanism of the [2 + 2] cycloaddition reaction, motivated us to elucidate the factors influencing the kinetics of the reaction in order to synthesize a diverse PAS monomer library …”

“…Computationally determined minimum energy structures and QM DFT calculations show that protecting groups influence both glycal conformation and the frontier molecular orbital (HOMO) energy of the reactive double bond. Glycals protected with less bulky groups (e.g., methyl, acetyl) prefer the pseudoequatorial 4 H 5 orientation, while those with bulky groups (e.g., triisopropylsilyl) prefer the pseudoaxial 5 H 4 orientation . Simultaneously, the electron-withdrawing ability of protecting groups inversely correlates to both the calculated HOMO energy of the double bond and the logarithm of the reaction rate constant.…”

“…Indeed, the 3′-OH benzyl protecting group occupies the α face of both the predominant 4 H 5 (pseudoaxial) and less-prevalent 5 H 4 (pseudoequatorial) conformations of tri- O -benzyl- d -allal. We predicted that the reduced population of reactive 5 H 4 conformers (29% 5 H 4 ) would lead to a diminished cycloaddition rate in comparison to tri- O -benzyl- d -glucal (40% 5 H 4 ) . We synthesized the allal from d -allose by acetylation, glycosyl bromide synthesis, zinc-mediated reduction, deacetylation, and benzylation (Figure A).…”