During the past decades, synthetic organic chemistry discovered that directing group assisted C–H activation is a key tool for the expedient and siteselective construction of C–C bonds. Among the v...

Bidentate Directing Groups: An Efficient Tool in C-H Bond Functionalization Chemistry for the Expedient Construction of C-C Bonds.

Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct incorporation of an additional mass or radioactive tag into an organic molecule with almost no changes in its chemical structure, physical properties, or biological activity. Using deuterium-labelled isotopologues to study the unique mass-spectrometric patterns generated from mixtures of biologically relevant molecules drastically simplifies analysis. Such methods are now providing unprecedented levels of insight in a wide and continuously growing range of applications in the life sciences and beyond. Tritium (3 H), in particular, has seen an increase in utilization, especially in pharmaceutical drug discovery. The efforts and costs associated with the synthesis of labelled compounds are more than compensated for by the enhanced molecular sensitivity during analysis and the high reliability of the data obtained. In this Review, advances in the application of hydrogen isotopes in the life sciences are described.

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Deuterium- and Tritium-Labelled Compounds: Applications in the Life Sciences

The use of deuteration in medicinal chemistry has exploded in the past years, and the FDA has recently approved the first deuterium-labeled drug. Precision deuteration goes beyond the pure and simple amelioration of the pharmacokinetic parameters of a drug and might provide an opportunity when facing problems in terms of metabolism-mediated toxicity, drug interactions, and low bioactivation. The use of deuterium is even broader, offering the opportunity to lower the degree of epimerization, reduce the dose of coadministered boosters, and discover compounds where deuterium is the basis for the mechanism of action. Nevertheless, designing, synthesizing, and developing a successful deuterated drug is far from straightforward, and the translation from concept to practice is often unpredictable. This Perspective provides an overview of the recent developments of deuteration, with a focus on deuterated clinical candidates, and highlights both opportunities and challenges of this strategy.

Applications of Deuterium in Medicinal Chemistry

Advances in the chemical synthesis of C-pyranosides/furanosides are summarized, covering the literature from 2000 to 2016. The majority of the methods take advantage of the construction of the glycosidic C—C bond. These C-glycosylation methods are categorized herein in terms of the glycosyl donor precursors, which are commonly used in O-glycoside synthesis and are easily accessible to nonspecialists. They include glycosyl halides, glycals, sugar acetates, sugar lactols, sugar lactones, 1,2-anhydro sugars, thioglycosides/sulfoxides/sulfones, selenoglycosides/telluroglycosides, methyl glycosides, and glycosyl imidates/phosphates. Mechanistically, C-glycosylation reactions can involve glycosyl electrophilic/cationic species, anionic species, radical species, or transition-metal complexes, which are discussed as subcategories under each type of sugar precursor. Moreover, intramolecular rearrangements, such as the Claisen rearrangement, Ramberg–Backlund rearrangement, and 1,2-Wittig rearrangement, which usuall...

Recent Advances in the Chemical Synthesis of C-Glycosides

Construction of sulfur-containing moieties in the total synthesis of natural products

Zinc-Mediated Decarboxylative Alkylation of Gem-difluoroalkenes

SGLT2 inhibitors deuterated at sites susceptible to oxidative metabolism were found to have a slightly longer tmax and half-life (t1/2), dose-dependent increase in urinary glucose excretion (UGE) in rats, and slightly superior effects on UGE in dogs while retaining similar in vitro inhibitory activities against hSGLT2. In particular, deuterated compound 41 has the potential to be a robust long-acting antidiabetic agent.

Design, synthesis, and biological evaluation of deuterated C-aryl glycoside as a potent and long-acting renal sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes.

Convenient methods were developed for copper-mediated oxidative C–H activation of aminoquinoline benzamides. The reaction conditions can be tuned to give either hydroxylation or dimerization compounds as the major products efficiently. Preliminary mechanistic studies suggested that different coordination states of copper may lead to different reaction outcomes.

Divergent copper-mediated dimerization and hydroxylation of benzamides involving C-H bond functionalization.

An efficient protocol was developed to access 3-fluoro-2-hydroxy-2-substituted benzo[b]furans with Selectfluor™ as the fluorinating reagent in MeCN and water. By utilizing SOCl2/Py as the dehydrating agent, the compounds above were readily converted to 3-fluorinated, 2-substituted benzo[b]furans in high yields.

Fluorination of 2-substituted benzo[b]furans with Selectfluor™

Dolastatin 10, an antineoplastic agent for cancer chemotherapy, is a linear peptide possessing N,N-dimethyl Val-OH, L-valine, (3R,4S,5S)-dolaisoleucine, (2R,3R,4S)-dolaproine and (S)-dolaphenine. Our efficient synthesis includes the following three key features: (1) SmI2-induced cross-coupling was employed to couple aldehyde 11 with (S)-N-tert-butanesulfinyl imine 12 to generate the required stereocenters of Dap (7); (2) asymmetric addition of chiral N-sulfinyl imine 10 provided a straightforward approach to the synthesis of the protected Doe ((S,S)-8); (3) a practical method to the key subunit Val-Dil (24a) has been established as an alternative synthetic route for the synthesis of this challenging chemical structure.

Xun Sun

Papers

Zinc-Mediated Decarboxylative Alkylation of Gem-difluoroalkenes

Design, synthesis, and biological evaluation of deuterated C-aryl glycoside as a potent and long-acting renal sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes.

Divergent copper-mediated dimerization and hydroxylation of benzamides involving C-H bond functionalization.

Fluorination of 2-substituted benzo[b]furans with Selectfluor™

A practical approach to asymmetric synthesis of dolastatin 10.