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[Image: see text] RNA polymerase I (Pol I) transcribes ribosomal DNA (rDNA) into the 47S ribosomal RNA (rRNA) precursor. Further processing produces the 28S, 5.8S, and 18S rRNAs that are assembled into mature ribosomes. Many cancers exhibit higher Pol I transcriptional activity, reflecting a need for increased ribosome biogenesis and protein synthesis and making the inhibition of this process an attractive therapeutic strategy. Lead molecule BMH-21 (1) has been established as a Pol I inhibitor by affecting the destruction of RPA194, the Pol I large catalytic subunit. A previous structure–activity relationship (SAR) study uncovered key pharmacophores, but activity was constrained within a tight chemical space. This work details further SAR efforts that have yielded new scaffolds and improved off-target activity while retaining the desired RPA194 degradation potency. Pharmacokinetic profiling was obtained and provides a starting point for further optimization. New compounds present additional opportunities for the development of Pol I inhibitory cancer therapies.

International audience; The intermolecular rhodium(II)-catalyzed C(sp 3)-H amination of enamides gives access to new 4-aminopiperidine derivatives that are useful building blocks in medicinal chemistry. This efficient transformation proceeds at room temperature with complete regio- and chemoselectivity in favor of the allylic C(sp 3)-H bond, and has a broad functional group tolerance. In addition, the matched combination of the chiral complex Rh2(S-nta)4 [nta = (S)-N-1,8-naphthoylalanine] with an optically pure (S)-sulfonimidamide allows the isolation of allylic amines with excellent stereocontrol.

This article describes the reaction of ynamides with metallanitrenes generated in the presence of an iodine(III) oxidant. N-(Boc)-Ynamides are converted to oxazolones via a cyclization reaction. The reaction is mediated by a catalytic dirhodium-bound nitrene species that first behaves as a Lewis acid. The oxazolones can be converted in a one pot manner to functionalized oxazolidinones following a regio- and stereoselective oxyamination reaction with the same nitrene reagent generated in stoichiometric amounts.

A novel regio- and diastereoselective iron-catalyzed intermolecular oxyazidation of enamides using various azidobenziodoxolone (ABX) derivatives is presented. A variety of α-N3 amino derivatives and of α-N3 piperidines were synthesized in good yields and under mild reaction conditions. The reaction involves a radical process using cheap FeCl2 as the initiator.

Direct C(3) alkenylation of non-aromatic enamides through palladium(II)-catalyzed Fujiwara–Moritani cross-coupling was developed. The reaction scope includes a range of cyclic enamides as well as activated alkenes. The utility of this methodology is illustrated by the synthesis of octa- or tetrahydroquinoline cores obtained from conjugated enamides via Diels–Alder cycloaddition.

The first example of an Fe(II)-catalyzed trifluoromethylation of enamides, e.g. (I), (IV), (VI), (VIII), and (X), using Togni′s reagent (II) as electrophilic CF3 source is reported.