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Abstract Computational methods for predicting product ratios in dynamically controlled reactions with shallow intermediates or bifurcating pathways after an ambimodal transition state are reviewed and benchmarked. The range of methods includes molecular dynamics simulations, machine learning-based models and recent advancements in correlational methods, all of which rely on quantum mechanical computations. Together, these approaches form a computational toolbox that enhances the efficiency and effectiveness of exploring reaction selectivity influenced by dynamic effects. 

Manipulation of polar functional groups to extend the druggability and developability space is an important approach in the current field of drug discovery. Here, we report an editing method that enables the direct insertion of anthranilyl units into inert amides to form versatile oligoamides and cyclic peptides under exceptionally mild reaction conditions. We showcase a diverse array of pharmaceuticals, natural products, and bioactive molecules involving the mentioned scaffold insertion. The synthesis of the secondary metabolites from marine-derived fungi, the expedited construction of bioactive molecules, and the assembly of functionalized peptide macrocycles through iterative insertions highlight the synthetic utility of this method. Computational tools and experimental measurements indicate that a hydrogen bond network formed by reacting and catalytic amide enables the insertion of the anthranilyl unit into a C─N bond. 

Abstract 2641 presented at 2025 ASBMB meeting 

Abstract The chemiluminescent light‐emission pathway of phenoxy‐1,2‐dioxetane luminophores attracts growing interest within the scientific community. Dioxetane probes undergoing rapid flash‐type chemiexcitation exhibit higher detection sensitivity than those with a slow glow‐type chemiexcitation rate. We discovered that dioxetanes fused to non‐strained six‐member rings, with hetero atoms or inductive electron‐withdrawing groups, present both accelerated chemiexcitation rates and elevated chemical stability compared to dioxetanes fused to four‐member strained rings. DFT computational simulations supported the chemiexcitation acceleration observed by spiro‐fused six‐member rings with inductive electron‐withdrawing groups of dioxetanes. Specifically, a spiro‐dioxetane with a six‐member sulfone ring exhibited a chemiexcitation rate 293‐fold faster than that of spiro‐adamantyl‐dioxetane. A turn‐ON dioxetane probe for the detection of the enzyme β‐galactosidase, containing the six‐member sulfone unit, exhibited a S/N value of 108 in LB cell growth medium. This probe demonstrated a substantial increase in detection sensitivity towardsE. colibacterial cells expressing β‐galactosidase, with an LOD value that is 44‐fold more sensitive than that obtained by the adamantyl counterpart. The accelerated chemiexcitation and the elevated chemical stability presented by dioxetane containing a spiro‐fused six‐member ring with a sulfone inductive electron‐withdrawing group, make it an ideal candidate for designing efficient turn‐on chemiluminescent probes with exceptionally high detection sensitivity.