Synthesis of Dicarba-closo-dodecaborane-1-carboxamides

Abstract

Amide bond formation is one of the most important chemical reactions. In peptide and organic chemistry, the application of amide coupling reagents is a routine strategy, but surprisingly not in carborane chemistry. Thus, we now report a fast, safe, and robust protocol to couple amines to m- and p-dicarba-closo-dodecaborane-1-carboxylic acids. The procedure comprises the activation of carboxylic acid with the coupling reagent (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)(dimethylamino)morpholinocarbenium hexafluorophosphate, extraction of the product using the hydrophobic nature of the cluster, and a straightforward chromatographic purification. The protocol allows access to a variety of carborane-organic hybrid molecules suitable for application in multiple areas.

Borinostats: solid-phase synthesis of carborane-capped histone deacetylase inhibitors with a tailor-made selectivity profile

“…As benzoic acid analogues of ortho -carborane prove problematic in amide couplings, we chose the meta isomer, closo -1,7-dicarbadodecaborane ( meta - 1 ), for our second cap group scaffold. 44 The respective carboxylic acid 4 was obtained following a slightly modified literature procedure of Kasar and co-workers. 46 Monolithiation of meta - 1 and subsequent treatment with gaseous CO 2 afforded 4 in quantitative yield ( Scheme 1 ).…”

“…The syntheses proceeded flawlessly for carborane analogues of benzoic and phenylacetic acid without cluster degradation and intermittent isolation (and detection problems associated with carboranes). 44 These carborane derivatives were employed as bioisosteres in HDACi drug design to precisely steer the selectivity of the HDACis between pan inhibition and highly selective HDAC6 inhibition with only minor adjustments to the inhibitor structure. In reference to the successful FDA-approved HDACi vorinostat, we termed the best-in-category cluster compounds borinostat A ( 9d ) and borinostat B ( 8c ).…”

Comprehensive exploration of chemical space using trisubstituted carboranes

“…The Kumada–Tamao–Corriu cross coupling between 21 and trimethylsilylacetylene was performed under reaction conditions similar to those described in Scheme 2 to give 9,10-bis(trimethylsilyletynyl)- m -carborane 23 in 94% yield. After introducing a carboxylic acid into the C1-position of 23 , the resulting carboxylic acid was subjected to amidation reactions with benzyl amine or isobutyl amine using COMU 52 to afford compounds 24a and 24b in 41% and 48% yields over two steps, respectively. After removal of the TMS group, the Hüsgen cycloaddition reaction was carried out to obtain compounds IVa – d in 29–82% yields over the two steps.…”

OxymaPure Coupling Reagents: Beyond Solid-Phase Peptide Synthesis

“…In 2017, Scholz and Wingen reported promising results using COMU for the synthesis of a carborane. 47 Amide bond formation in carboranes is unlike that in peptides and organic compounds, and only moderate yields are obtained with other traditional methods (Scheme 9).…”