Torquoselective Mechanochemical Activation of the Staudinger Reaction To Form β-Lactams

Abstract

The Staudinger reaction yielding β-lactam rings via [2 + 2] cycloaddition is a torquoselective reaction where the stereochemistry of the product can be steered by suitable substituents. Although the mechanochemical ring-opening of β-lactams has been investigated recently, the force-assisted synthesis of this important functional four-ring motif remains unexplored. As it will be computationally demonstrated, mechanochemical activation greatly reduces the barrier of the rate-limiting ring-closure step while, at the same time, preserves its torquoselectivity. This finding strongly suggests that strained four-membered rings can be readily incorporated in chain molecules using sonication techniques that greatly enhance reactivity while conserving selectivity.

Polymer mechanochemistry-enabled pericyclic reactions

“…One of the most commonly occurring four-membered rings is the β-lactam scaffold and its activation by force via cycloelimination was investigated by Moore and Robb (Scheme 9a). 36,37 This motif dissociates into a ketene and an imine, i.e. the two reactants used for the synthesis of the β-lactam.…”

Sulfonamide‐β‐lactam Hybrids Incorporating the Piperazine Moiety as Potential Antiinflammatory Agent with Promising Antibacterial Activity

“…In the 1 H-NMR spectra, the observed coupling constants of the vicinal H-3 and H-4 protons of the β-lactam ring confirmed the cis stereochemistry of these new βlactam compounds. Based on our experimental results [59][60][61] and the literature data, [62][63][64] the plausible mechanism for the stereoselective formation of cis-β-lactam ring is shown in Scheme 3. In the first step of the reaction, the nucleophilic exo-attack of the imine (B) nitrogen to the ketene (A) results in zwitterionic intermediate (C), following direct conrotatory ring closure to yield cis β-lactam isomer (D).…”