[18F]Difluorocarbene for Positron Emission Tomography

The advent of total-body Positron Emission Tomography (PET) has vastly broadened the range of research and clinical applications of this powerful molecular imaging technology1. Such possibilities have accelerated progress in 18F-radiochemistry with numerous methods available to 18F-label (hetero)arenes and alkanes2. However, access to 18F-difluoromethylated molecules in high molar activity (Am) is largely an unsolved problem, despite the indispensability of the difluoromethyl group for pharmaceutical drug discovery3. We report herein a general solution by introducing carbene chemistry to the field of nuclear imaging with a [18F]difluorocarbene reagent capable of a myriad of 18F-difluoromethylation processes. In contrast to the tens of known difluorocarbene reagents, this 18F-reagent is carefully designed for facile accessibility, high molar activity and versatility. The issue of Am is solved using an assay examining the likelihood of isotopic dilution upon variation of the electronics of the difluorocarbene precursor. Versatility is demonstrated with multiple [18F]difluorocarbene based reactions including O–H, S–H and N–H insertions, and cross-couplings that harness the reactivity of ubiquitous functional groups such as (thio)phenols, N-heteroarenes, and aryl boronic acids that are easy to install. Impact is illustrated with the labelling of highly complex and functionalised biologically relevant molecules and radiotracers

Protocol for clickable photoaffinity labeling and quantitative chemical proteomics

Summary: Here, we describe a protocol for a photoaffinity labeling probe strategy for target deconvolution in live cells. We made a chemical probe by incorporation of a photoreactive group to covalently cross-link with adjacent amino acid residues upon UV irradiation. Click chemistry-based enrichment captures labeled proteins for proteomic analysis. Here, we detail specifics for finding targets of LXRβ, but the protocol has potential for application to other targets.For complete details on the use and execution of this protocol, please refer to Seneviratne et al. (2020)

Total Synthesis of (±)-Bisabosqual A

The synthesis of the novel squalene synthase inhibitor, bisabosqual A, was completed in 14 steps (longest linear sequence) from commercially available starting materials. The doubly convergent route employs a tandem 5-exo, 6-exo radical cyclization as the key step. This reaction assembles the fully functionalized tetracyclic core and introduces three stereogenic centers. Other effective transformations are the regioselective deoxygenation of an advanced enone intermediate and the chemo- and diastereoselective addition of trimethylaluminum to a ketone in the presence of esters

Total Synthesis of (±)-Bisabosqual A

The synthesis of the novel squalene synthase inhibitor, bisabosqual A, was completed in 14 steps (longest linear sequence) from commercially available starting materials. The doubly convergent route employs a tandem 5-exo, 6-exo radical cyclization as the key step. This reaction assembles the fully functionalized tetracyclic core and introduces three stereogenic centers. Other effective transformations are the regioselective deoxygenation of an advanced enone intermediate and the chemo- and diastereoselective addition of trimethylaluminum to a ketone in the presence of esters

Total Synthesis of (±)-Bisabosqual A

The synthesis of the novel squalene synthase inhibitor, bisabosqual A, was completed in 14 steps (longest linear sequence) from commercially available starting materials. The doubly convergent route employs a tandem 5-exo, 6-exo radical cyclization as the key step. This reaction assembles the fully functionalized tetracyclic core and introduces three stereogenic centers. Other effective transformations are the regioselective deoxygenation of an advanced enone intermediate and the chemo- and diastereoselective addition of trimethylaluminum to a ketone in the presence of esters

Divergent Synthesis of Monosubstituted and Unsymmetrical 3,6- Disubstituted Tetrazines from Carboxylic Ester Precursors

As tetrazines are important tools to the field of bioorthogonal chemistry, there is a need for new approaches to synthesize unsymmetrical and 3-monosubstituted tetrazines. Described here is a general, one-pot method for converting (3methyloxetan-3-yl)methyl carboxylic esters into 3thiomethyltetrazines. These versatile intermediates were applied as a platform for the synthesis of unsymmetrical tetrazines via Pdcatalyzed cross-coupling and in the first example of catalytic thioether reduction to access monosubstituted tetrazines. The method enables the development of new tetrazines possessing a favorable combination of kinetics, small size and hydrophilicity. The chemistry was applied to a broad range of aliphatic and aromatic ester precursors and to the synthesis of heterocycles including BODIPY fluorophores and biotin. In addition, a series of tetrazine probes for monoacylglycerol lipase (MAGL) were synthesized and the most reactive one was applied in labeling of endogenous MAGL in live cells<br /

Synthesis of Pyridopyrazine-1,6-diones from 6‑Hydroxypicolinic Acids via a One-Pot Coupling/Cyclization Reaction

A facile one-pot synthesis of 3,4-dihydro-1<i>H</i>-pyrido[1,2-<i>a</i>]pyrazine-1,6(2<i>H</i>)-diones (pyridopyrazine-1,6-diones) has been developed which employs a sequential coupling/cyclization reaction of 6-hydroxypicolinic acids and β-hydroxylamines. The transformation proceeds in good yield under mild conditions using <i>O</i>-(7-aza-1<i>H</i>-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) to both carry out the amide formation and activate the hydroxyl group for intramolecular alkylation

Synthesis of Pyridopyrazine-1,6-diones from 6‑Hydroxypicolinic Acids via a One-Pot Coupling/Cyclization Reaction

A facile one-pot synthesis of 3,4-dihydro-1<i>H</i>-pyrido[1,2-<i>a</i>]pyrazine-1,6(2<i>H</i>)-diones (pyridopyrazine-1,6-diones) has been developed which employs a sequential coupling/cyclization reaction of 6-hydroxypicolinic acids and β-hydroxylamines. The transformation proceeds in good yield under mild conditions using <i>O</i>-(7-aza-1<i>H</i>-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) to both carry out the amide formation and activate the hydroxyl group for intramolecular alkylation

Synthesis of Pyridopyrazine-1,6-diones from 6‑Hydroxypicolinic Acids via a One-Pot Coupling/Cyclization Reaction

A facile one-pot synthesis of 3,4-dihydro-1<i>H</i>-pyrido[1,2-<i>a</i>]pyrazine-1,6(2<i>H</i>)-diones (pyridopyrazine-1,6-diones) has been developed which employs a sequential coupling/cyclization reaction of 6-hydroxypicolinic acids and β-hydroxylamines. The transformation proceeds in good yield under mild conditions using <i>O</i>-(7-aza-1<i>H</i>-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) to both carry out the amide formation and activate the hydroxyl group for intramolecular alkylation