Azo compounds (R─N═N─R′) are a foundational class of nitrogen-containing molecules. In contrast to the bench-stability of many azo derivatives, monomeric diboryl diazenes (R2BN═NBR2) have long eluded ...

ConspectusAlkynes are one of the most fundamental functional groups in organic synthesis due to the versatile chemistry of the triple bond, their unique rigid structure, and their use in bioconjugation. The introduction of alkynes onto organic molecules traditionally relies on nucleophilic activation, often requiring strong bases or metal catalysts. These conditions, however, restrict applications involving biomolecules such as peptides and proteins due to functional group incompatibility. To address this limitation, our group developed an “umpolung” approach, utilizing hypervalent iodine compounds to create electrophilic alkyne transfer reagents such as benziodoxol(on)es (Bx(X)s) and benziodazolones (BZs). The high reactivity of EBx/X/Z reagents enables efficient alkyne transfer to various nucleophilic residues in peptides and proteins under different reaction conditions, providing a versatile tool for biomolecule modification.In this Account, we highlight the residue-selective alkynylation and alkenylation of peptides enabled by the development of novel EBx/X/Z reagents with a focus on progress since 2021. This includes the following: (1) Selective residue modification: We have made significant progress in the residue-selective alkynylation and alkenylation of peptides and proteins. Building on our initial work with Cys-selective alkynylation, we enhanced reactivity and solubility by introducing a sulfonate group on the benziodoxolone arene core, facilitating lipophilic alkynylation in an aqueous environment. Furthermore, we developed perfluoroaryl-modified BZ reagents to achieve sequential Cys-Cys cross-linking and used them for antibody cross-linking with superior reactivity compared to that of conventional methods. Additionally, we expanded the reactivity beyond Cys to achieve Tyr-selective conjugation. All of these achievements underscored the tunability of EBx/X/Z reagents through strategic substituent modification on the iodine core. (2) Peptide stapling and macrocyclization: We designed EBx(X) reagents featuring an additional reactive site on the alkyne moiety, enabling Cys-Cys and Cys-Lys stapling in peptides. This approach enhanced their α-helicity and potential as PPI inhibitors with improved binding affinity to the MDM2 protein. For sequences lacking Cys, we incorporated the whole EBx(X) core onto Lys residues via an activated ester on the alkyne, forming peptide-EBx(X) conjugates. These conjugates facilitated the formation of rigid, functional peptide macrocycles using C-terminal or Trp-selective alkynylation. The utility of these macrocyclizations was demonstrated by achieving improved binding affinity to the KEAP1 protein and by generating fluorescent cyclic peptides suitable for live-cell imaging without additional fluorophores. (3) Broadening applicability with EBx-containing amino acids: We prepared EBx amino acids compatible with both solid-phase peptide synthesis (SPPS) and solution-phase synthesis (SPS), allowing us to apply our cyclization strategies to construct a diverse library of cyclic peptides.

Full or associate professor at the Department of Physical Chemistry

We report on the discovery of “hidden” heterogeneous catalysis in the hydrogenation of nitrous oxide while assessing the catalytic activity of a rhodium(i) hydride complex supported by a nominally rob...

Expanding the boundaries of synthetic tractability ─ of what molecules can be synthesized and isolated ─ is an eternal challenge for synthetic chemists. The development of new synthetic methods and strategies enables the properties and potential functions of novel molecular targets to be experimentally evaluated. In the context of catalysis, predictable synthetic strategies are often available to access kinetically persistent intermediates such as catalyst resting states. In contrast, synthesis and characterization of the reactive intermediates are often not possible due to the fleeting lifetimes of these species. In crystallo photochemistry combines single-crystal matrix isolation with cryogenic photochemistry to enable reactive intermediates to be synthesized under conditions in which they are persistent and can be (crystallographically) characterized. This Outlook highlights key achievements of in crystallo photochemistry as well as discusses opportunities and challenges that confront realization of the potential of in crystallo synthesis to redefine the boundaries of synthetic tractability.

Under the Pd(II)/Pd(IV) catalytic cycle, the cyclization of pent-4-en-1-amine derivatives typically yields either pyrrolidines or piperidines depending on the N-protecting group. We report herein an unprecedented Pd(II)-catalyzed oxidative domino process that converts readily accessible N-protected 2-(2-amidoethyl)-1-methylenecyclobutane derivatives to 1-fluoro-2-azabicyclo[3.2.1]octanes. This transformation constructs three chemical bonds under mild conditions [Pd(hfacac)2 (5.0 mol %), Selectfluor (2.0 equiv), MeCN, 60 °C, 10 min] through a domino sequence involving 5-exo-trig amidopalladation/Pd(II)–oxidation/chemoselective dyotropic rearrangement/C–F bond-forming reductive elimination. Notably, the cyclization mode remains independent of the N-protecting group under these conditions. Furthermore, diverse functional groups can be introduced at the bridgehead position of a bicyclic compound via an apparent anti-Bredt bridgehead iminium intermediate.