Synlett

This study explores the merged cycloaddition/cycloreversion of a 1,4-oxazinone substrate and conjugated bisalkyne precursors. Good regioselectivity in the Diels–Alder operation is observed and pyridines bearing 3-alkynyl functionality are afforded following cycloreversion and extrusion of CO2. Examples with both symmetric and nonsymmetric bisalkyne substrates are included.

We report the photocatalytic functionalization of terminal alkenes to vicinal dichlorides by using visible light and FeCl3 as a catalyst, LiCl as a chloride source, and air as an oxidant. The transformation is proposed to be initiated by ligand-to-metal charge-transfer bond homolysis of a Fe–Cl bond, giving a highly reactive chloride radical able to initiate the functionalization of olefins. The process shows high chemoselectivity and broad functional-group tolerance with yields of up to 94% under mild conditions.

An efficient protocol was developed for the N-arylation of 1,2,4-triazole by using substituted aryl bromides catalyzed by CuCl under ligand-free conditions. This method afforded the products in good to excellent yields (up to 88%) under the optimized conditions.

The different topics and synthetic approaches in an isotope chemistry laboratory of a pharma company are described. Besides the challenges in the synthesis of long-lived isotopes such as 3H or 14C, short-lived isotopes such as 68Ga and stable isotopes such as 15N, 13C or 2H approaches for the isotopic labeling are also demonstrated. Furthermore, method development with emphasis on collaborations with academic groups to tackle the future challenges are discussed.1 Introduction2 Isotopic Labeling with Hydrogen Isotopes Deuterium (2H, D) and Tritium (3H, T)2.1 Deuterium Labeling for MS Standards2.1.1 Labeled Nitrosamines – The Hunt to Quantify Hazardous Impurities2.1.2 Deuterated Drugs, an Approach To Improve Existing Drugs or To Find Opportunities in Drug Discovery2.2 Tritium-Labeling Methods – The Fast Approach to Radioactively Labeled Compounds2.2.1 Hydrogen Isotope Exchange by Iridium Catalysis2.2.2 Ruthenium-Catalyzed HIE2.2.3 Nanoparticles as Catalysts in HIE2.2.4 Photoredox-Catalyzed HIE2.2.5 HIE via Classical Radical Mechanism2.2.6 Beyond HIE – Halogen–Tritium Exchange3 Challenges in 14C-Synthesis Projects4 Short-Lived Isotopes – The Need for Speed5 Beyond Isotope Science – Late-Stage Functionalization5.1 Examples of Late-Stage Functionalization for Peptides5.2 Examples of Catalyst-Controlled Late-Stage Functionalization6 Conclusion

The synthesis of biomimetic thioesters for enzymatic studies of ketoreductase (KR) domains from polyketide synthases is described. A TBS-protected dihydroxyalkene fragment was synthesised by a sequence involving a Nagao acetate aldol reaction, a Mukaiyama propionate aldol reaction, and a methylene Wittig olefination. Fragment coupling to N-acetylcysteamine (SNAC) (E)-3-hydroxyhex-4-enethioates by an olefin cross-metathesis (OCM) and subsequent deprotection gave the potential KR product stereoisomers. An analogous OCM with a SNAC (E)-3-ketohex-4-enethioate did not give the desired KR precursor, but the reaction could successfully be replaced by a Horner–Wadsworth–Emmons olefination between a SNAC 3-ketothioester phosphonate and a TBS-protected dihydroxy aldehyde. After deprotection, an intramolecular cyclisation was observed that needs to be considered as a spontaneous side reactivity in the enzymatic assays.

Molecules with a π-system that can be mapped onto a Möbius strip may display Möbius aromaticity. Such molecules are difficult to synthesize because they have a twisted structure. Recently, we combined chiral [6]helicene and fluorescent [7]cycloparaphenylene, and synthesized the first helicene para-phenylene ([6,7]HPP) carbon nanohoop. We have demonstrated that this design strategy ultimately provides a Möbius topology of the molecular π-electron system and, therefore, offers the potential to study Möbius aromaticity experimentally. In addition, the synthesized nanohoop exists as a mixture of conformers in solution. Some of the conformers possess a different orientability of their π-systems, i.e., they differ in their topology. As a result, the recorded circularly polarized luminescence of isolated enantiomers displays both left- and right-handedness of the emitted light, each emanating from a conformer with a different π-system topology. Therefore, [6,7]HPP provided the first experimental evidence of such topological bistability in carbon nanohoops.

Acetal substitution reactions can proceed by a number of mechanisms, but oxocarbenium ion intermediates are involved in many of these reactions. Our research has focused on understanding the conformational preferences, structures, and reactions of these intermediates. This account summarizes our observations that electrostatic effects play a significant role in defining the preferred conformations, and that torsional effects determine how those intermediates react. Neighboring-group effects are not as straightforward as they might seem, considering that oxocarbenium ion intermediates are in equilibrium with structures that involve stabilization by a nearby substituent.1 Introduction2 Unexpected Stereoselectivities3 Determining Conformational Preferences of Oxocarbenium Ions4 Structures of Carbocations by NMR Spectroscopy and X-ray Crystallography5 Stereoelectronic Models for Reactions Involving Other Oxocarbenium Ions6 Stereoselectivity and Reactivity: When They Correlate, When They Do Not7 Neighboring–Group Participation Is Not as Simple as It Seems8 What Is True for Carbocations Is True for Carbonyl Compounds9 Stereoelectronic and Torsional Effects in Reactions of Enolates10 Summary of Expected Selectivities for Reactions of Cyclic Acetals11 Conclusion

Bioorthogonal reactions hold significant promise for applications in chemical biology. Despite their potential, nitriles have often been overlooked as reactive functional groups for selective bioconjugation. The condensation reaction between cyanopyridines and 1,2-aminothiols stands out as a particularly favorable nitrile modification strategy that proceeds under biocompatible conditions. Cyanopyridines can be seamlessly incorporated into peptides and proteins through both chemical and biotechnological approaches. Similarly, the selective integration of 1,2-aminothiols into peptides and proteins is achievable, leveraging the uniquely reactive N-terminal cysteine functional group.1 Introduction2 The Biocompatible Condensation Reaction3 Peptide Macrocyclisation4 Orthogonality to Cysteine5 Combination with Genetic Encoding6 Conclusion

A silver-promoted nucleophilic radiofluorination of α-bromoamides has been developed for the radiosynthesis of α-[18F]fluoroamides. The reaction conditions are straightforward and compatible with primary, secondary, and tertiary α-bromoamides. Furthermore, the methodology has been successfully applied to the synthesis of bioactive radiotracers with good radiochemical conversion (RCC) and radiochemical yield (RCY).

Glycans control various biological processes, depending on their structures. Particularly, core fucose, formed by α1,6-fucosyltransferase (FUT8), has a substantial influence on multiple biological processes. In this study, we investigated the development of FUT8 inhibitors with structural elements encompassing both the glycosyl donor (GDP-fucose) and acceptor (N-glycan) of FUT8. To efficiently optimize the structure of FUT8 inhibitors, we employed a strategy involving fragmentation of the target structure, followed by a structure optimization using a diversity-oriented synthesis approach. This study proposes an efficient strategy to accelerate the structural optimization of middle molecules.