A Physical Organic Approach to Tuning Reagents for Selective and Stable Methionine Bioconjugation.

We report a data-driven, physical organic approach to the development of new methionine-selective bioconjugation reagents with tunable adduct stabilities. Statistical modeling of structural features described by intrinsic physical organic parameters was applied to the development of a predictive model and to gain insight into features driving the stability of adducts formed from the chemoselective coupling of oxaziridine and methionine thioether partners through Redox Activated Chemical Tagging (ReACT). From these analyses, a correlation between sulfimide stabilities and sulfimide ν (C═O) stretching frequencies was revealed. We exploited the rational gains in adduct stability exposed by this analysis to achieve the design and synthesis of a bis-oxaziridine reagent for peptide stapling. Indeed, we observed that a macrocyclic peptide formed by ReACT stapling at methionine exhibited improved uptake into live cells compared to an unstapled congener, highlighting the potential utility of this unique chemical tool for thioether modification. This work provides a template for the broader use of data-driven approaches to bioconjugation chemistry and other chemical biology applications.

Amphiphilic π-Allyliridium C,O-Benzoates Enable Regio- and Enantioselective Amination of Branched Allylic Acetates Bearing Linear Alkyl Groups.

The first examples of amphiphilic reactivity in the context of enantioselective catalysis are described. Commercially available π-allyliridium C,O-benzoates, which are stable to air, water and SiO2 chromatography, and are well-known to catalyze allyl acetate-mediated carbonyl allylation, are now shown to catalyze highly chemo-, regio- and enantioselective substitutions of branched allylic acetates bearing linear alkyl groups with primary amines.

Generation and reactivity of unsymmetrical strained heterocyclic allenes.

Strained cyclic allenes are short-lived intermediates that confine a functional group with a preferred linear geometry, an allene, into a small ring, inducing strain-driven reactivity. Nitrogen-containing variants, or azacyclic allenes, have proved valuable for the assembly of complex nitrogen-containing compounds. Whereas 3,4-azacyclic allenes, which bear a symmetrical core, have been the focus of multiple studies, their unsymmetrical 2,3-azacyclic counterparts have remained underexplored. In the present study, we report density functional theory studies investigating the structure of such unsymmetrical azacyclic allenes and experimental efforts to access and engage them in strain-promoted cycloadditions under mild conditions. Control experiments support either concerted or stepwise diradical mechanisms for these reactions, depending on the type of cycloaddition examined. Moreover, we generate the corresponding 2,3-oxacyclic allene and demonstrate its reactivity in cycloadditions and a metal-catalysed process. Given the scaffolds accessed, coupled with the observed selectivity trends, these results are expected to encourage the application of unsymmetrical heterocyclic allenes for the synthesis of heterocycles that bear a high fraction of sp3-hybridized atoms.

Merging Metals and Strained Intermediates.

Strained intermediates such as cyclic alkynes and allenes are most commonly utilized in nucleophilic additions and cycloadditions, but have seen increased use in a third area of reactivity: metal-mediated transformations. The merger of strained intermediates and metal catalysis has enabled rapid access to complex, polycyclic systems. Following a discussion of relevant landmark studies involving metals and strained intermediates, this article highlights recent advances in transition metal-mediated transformations from our laboratory. Specifically, this includes the use of arynes in the synthesis of decorated organometallic complexes, and the utilization of cyclic allenes to access enantioenriched heterocycles. Moreover, the broad applicability of such transformations, and exciting future areas of research are discussed.