Brett

Photoaffinity probes were designed to target cyclin‐dependent kinases (CDKs), which can be regarded as the timekeepers of cellular processes. As reported by J. T. Bush and co‐workers in their Research Article (DOI: https://doi.org/10.1002/anie.20190632110.1002/anie.201906321), these probes competitively enrich CDKs from cell lysates, and a biochemical photoaffinity displacement assay was developed to measure compound potency. The seesaw represents the balance of competition between the photoaffinity probe and competitor compound.

Selectivity snapshots with PALs: Photoaffinity probes were designed to target the cyclin‐dependent kinase family, and found to competitively enrich CDKs from cell lysates. Subsequently, a biochemical photoaffinity displacement assay was developed to measure compound potency.

Abstract

The CDK family plays a crucial role in the control of the cell cycle. Dysregulation and mutation of the CDKs has been implicated in cancer and the CDKs have been investigated extensively as potential therapeutic targets. Selective inhibition of specific isoforms of the CDKs is crucial to achieve therapeutic effect while minimising toxicity. We present a group of photoaffinity probes designed to bind to the family of CDKs. The site of crosslinking of the optimised probe, as well as its ability to enrich members of the CDK family from cell lysates, was investigated. In a proof of concept study, we subsequently developed a photoaffinity probe‐based competition assay to profile CDK inhibitors. We anticipate that this approach will be widely applicable to the study of small molecule binding to protein families of interest.

A novel protocol for the efficient activation of the Beckmann rearrangement utilizing the readily available sulfuryl fluoride (SO₂F₂ gas) is reported. The substrate scope of this methodology has been demonstrated by 37 examples with good to nearly quantitative isolated yields in a short time. A tentative mechanism was proposed involving formation and elimination of sulfonyl ester.

A novel, mild and practical protocol for the efficient activation of the Beckmann rearrangement utilizing the readily available and economical sulfuryl fluoride (SO₂F₂ gas) has been developed. The substrate scope of the operationally simple methodology has been demonstrated by 37 examples with good to nearly quantitative isolated yields (over 90 % yield in most cases) in a short time, including B(OH)₂, COOH, NH₂, and OH substituted substrates. A tentative mechanism was proposed involving formation and elimination of key intermediate, sulfonyl ester.

Nature Chemistry, Published online: 10 June 2019; doi:10.1038/s41557-019-0278-x

Modulating particular ubiquitin chains using binding molecules is challenging given the diversity of chain lengths and linkages found in vivo. Now, tight binding modulators that are specific to K48-linked ubiquitin chains have been found by combining protein synthesis and screening of macrocyclic peptide ligands.

Recent developments in experimental and computational chemistry have identified a rapidly growing class of nucleophilic aromatic substitutions that proceed by concerted (cSNAr),1,2 rather than classical two‐step, SNAr mechanisms. Whereas traditional SNAr reactions require substantial activation of the aromatic ring by electron‐withdrawing substituents, such activating groups are not mandatory in the concerted pathways. At this crucial stage of growth in understanding of these reactions, our aim is to review the current state of knowledge on CSNAr reactions. [The review includes many types of substrates and nucleophiles; it specifically excludes transition metal‐related processes that might involve concerted substitutions on arenes].

Concerted or stepwise? A class of nucleophilic aromatic substitutions has been developed that proceed by concerted (cS_NAr) rather than classical, two‐step, S_NAr mechanisms. Whereas traditional S_NAr reactions require substantial activation of the aromatic ring by electron‐withdrawing substituents, such activating groups are not mandatory in the concerted pathways.

Abstract

Recent developments in experimental and computational chemistry have identified a rapidly growing class of nucleophilic aromatic substitutions that proceed by concerted (cS_NAr) rather than classical, two‐step, S_NAr mechanisms. Whereas traditional S_NAr reactions require substantial activation of the aromatic ring by electron‐withdrawing substituents, such activating groups are not mandatory in the concerted pathways.

Arylboronate complexes formed from alkylboronic esters and phenyllithium were found to undergo facile single‐electron oxidation to form alkyl radicals. The novel use of these complexes as radical precursors enabled the development of a photoredox‐catalyzed cyclobutane synthesis proceeding through a radical‐polar crossover mechanism.

Abstract

Photoredox‐catalyzed methylcyclobutanations of alkylboronic esters are described. The reactions proceed through single‐electron transfer induced deboronative radical addition to an electron‐deficient alkene followed by single‐electron reduction and polar 4‐exo‐tet cyclization with a pendant alkyl halide. Key to the success of the methodology was the use of easily oxidizable arylboronate complexes. Structurally diverse cyclobutanes are shown to be conveniently prepared from readily available alkylboronic esters and a range of haloalkyl alkenes. The mild reactions display excellent functional group tolerance, and the radical addition‐polar cyclization cascade also enables the synthesis of 3‐, 5‐, 6‐, and 7‐membered rings.

Copper to the rescue: A general method for the synthesis of propargylic sulfones featuring quaternary stereocenters has been developed. The method relies on a copper‐catalyzed sulfonylation of propargylic cyclic carbonates using sodium sulfinates. It provides the first example of such a transition‐metal‐catalyzed enantioselective propargylic substitution reaction with sulfur‐centered nucleophiles and gives access to functionalized tertiary sulfones.

Abstract

Tertiary propargylic sulfones are of significant importance in organic synthesis and medicinal chemistry, but to date no general asymmetric synthesis approach has been developed. We disclose a versatile copper‐catalyzed sulfonylation of propargylic cyclic carbonates using sodium sulfinates that allows the construction of propargylic sulfones featuring elusive quaternary stereocenters. This method provides the first successful example of such an enantioselective propargylic sulfonylation, features high asymmetric induction, wide functional group tolerance, and scalability, and enables attractive product diversification.

S_NAr stands corrected

S_NAr stands corrected, Published online: 20 September 2018; doi:10.1038/s41557-018-0138-0

Dynamic covalent chemistry combines the error-correcting behaviour of supramolecular chemistry with the robustness of covalent bonding, but relies on a somewhat limited set of reactions. Now, the classic nucleophilic aromatic substitution (SNAr) reaction has been shown to be reversible and self-correcting.