Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.

A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.

Synthesis of 1,4,5 trisubstituted γ-lactams via a 3-component cascade reaction.

A three component one-pot cascade reaction was developed for the synthesis of 1,4,5-trisubstituted γ-lactams. The resulting scaffold can be modified independently at three positions, two of which are conveniently accessed by changing the components of the one-pot reaction. The phases of building block generation, scaffold synthesis and subsequent appendage modification were adapted to library production, which resulted in a screening library of 500 compounds.

Design, synthesis and decoration of molecular scaffolds for exploitation in the production of alkaloid-like libraries.

The design, synthesis and decoration of six small molecule libraries is described. Each library was inspired by structures embedded in the framework of specific alkaloid natural products. The development of optimised syntheses of the required molecular scaffolds is described, in which reactions including Pd-catalysed aminoarylation and diplolar cycloadditions have been exploited as key steps. The synthesis of selected exemplar screening compounds is also described. In five cases, libraries were subsequently nominated for production on the basis of the scope and limitations of the validation work, as well as predicted molecular properties. In total, the research has led to the successful synthesis of >2500 novel alkaloid-like compounds for addition to the screening collection (the Joint European Compound Library, JECL) of the European Lead Factory.

Synthesis and minisci reactions of organotrifluoroborato building blocks.

Copper-catalyzed borylation of a variety of organic halides with bis(pinacolato)diboron allows the preparation of diverse potassium organotrifluoroborates. The reactions are mild and general, providing access to a variety of interesting, boron-containing building blocks, including those containing piperidine, pyrrole, azetidine, tetrahydropyran, and oxetane substructures. Representative Minisci reactions are reported for select examples.

Suzuki-Miyaura cross-coupling of potassium dioxolanylethyltrifluoroborate and aryl/heteroaryl chlorides.

A robust and efficient protocol for the introduction of the dioxolanylethyl moiety onto various aryl and heteroaryl halides has been developed, providing cross-coupling yields up to 93%. Copper-catalyzed borylation of 2-(2-bromoethyl)-1,3-dioxolane with bis(pinacolato)diboron followed by treatment with potassium bifluoride provides the key organotrifluoroborate reagent.

Suzuki-Miyaura cross-coupling of potassium alkoxyethyltrifluoroborates: access to aryl/heteroarylethyloxy motifs.

The introduction of an alkoxyethyl moiety onto aromatic substructures has remained a long-standing challenge for synthetic organic chemists. The main reasons are the inherent instability of alkoxyethylmetallic species and the lack of general procedures to access them. A new method utilizing a cross-coupling strategy based on the exceptional properties of organotrifluoroborates has been developed, and the method allows an easy and efficient installation of this unit on a broad range of aryl and heteroaryl bromides.

Rapid and efficient access to secondary arylmethylamines.

Ammoniomethyl trifluoroborates are very powerful reagents that can be used to access biologically relevant aryl- and heteroaryl-methylamine motifs via Suzuki-Miyaura cross-couplings. Until now, this method was limited to the production of tertiary and primary amines. The synthesis of a large array of secondary ammoniomethyltrifluoroborates has been achieved through a one step nucleophilic substitution reaction on the potassium bromomethyltrifluoroborate. Smooth cross-coupling conditions have been designed, based on the use of an aminobiphenyl palladium precatalyst, to couple these trifluoroborates efficiently with aryl bromides. This strategy offers a new way to access biologically relevant motifs and allows, with the previously developed methods, access to all three classes of aminomethylarenes.

Synthesis and cross-coupling reactions of imidomethyltrifluoroborates with aryl chlorides.

Potassium imidomethyltrifluoroborate salts were efficiently synthesized. Potassium phthalimidomethyl-trifluoroborate was successfully used in Suzuki-Miyaura-like cross-coupling reactions with a variety of aryl chlorides.

Synthesis and cross-coupling of sulfonamidomethyltrifluoroborates.

Sulfonamidomethyltrifluoroborates were successfully synthesized and cross-coupled with a wide range of aryl and heteroaryl chlorides, allowing the construction of a sulfonamidomethyl aryl linkage through a new disconnection, thus offering a new way to access such structurally interesting motifs.

2-Phospha[3]ferrocenophanes with planar chirality: synthesis and use in enantioselective organocatalytic [3 + 2] cyclizations.

Planar chiral phosphines displaying a new ferrocenophane scaffold have been prepared via a stereoselective approach. The P-cyclohexyl substituted phosphine affords high levels of asymmetric induction in the organocatalytic [3 + 2] annulation reaction between allenes and electron-poor olefins.