Rational Tuning of the Reactivity of Three‐Membered Heterocycle Ring Openings via S_N2 Reactions

Abstract

The development of small molecule covalent inhibitors and probes continuously pushes the rapidly evolving field of chemical biology forward. A key element in these molecular tool compounds is the "electrophilic trap" that allows for a covalent linkage with the target enzyme. The reactivity of this entity needs to be well balanced to effectively trap the desired enzyme, while not being attacked by off-target nucleophiles. We here investigate the intrinsic reactivity of substrates containing a class of widely used electrophilic traps, the three-membered heterocycles with an N-(aziridine), P-(phosphirane), O-(epoxide) and S-atom (thiirane) as heteroatom. Using quantum chemical approaches, we studied the conformational flexibility and nucleophilic ring-opening reaction of a series of model substrates, in which these electrophilic traps are mounted on a cyclohexene scaffold (C6H10Y with Y = NH, PH, O, S). It is revealed that the activation energy of the ring-opening reaction does not necessarily follow the trend that is expected from C-Y leavinggroup bond strength, but steeply decreases from NH, to PH, to O, to S. We illustrate that the HOMONu-LUMOSubstrate interaction is an all-important factor for the observed reactivity. In addition, we show that the activation energy of aziridines and phosphiranes can be tuned far below that of the corresponding epoxides and thiiranes by the addition of proper electron-withdrawing ring substituents. Our results provide mechanistic insights to rationally tune the reactivity of this class of popular electrophilic traps and can guide the experimental design of covalent inhibitors and probes for enzymatic activity.

Masked cerulenin enables a dual-site selective protein crosslink

“…We selectively prepared intermediate 14 and its pure enantiomers (2R,3S,4R)-14 and (2S,3R,4S)-14. As shown in 24 While accurate for many epoxides, the additional a-keto and a-amido substituents further complicate the ability to provide effective calculations of the relative electrophilicity of the C2 and C3 positions in cerulenin, and these spheres represent suggestions. An electrostatic map of the cerulenin tautomers have been provided in ESI Fig.…”