Desulfitative transformations

As described above, two new Cu-catalyzed desulfitative transformations have been discovered that can be used for the construction of peptidyl ketones from peptidic thiol esters and boronic acids. Under aerobic reaction conditions, S -acylthiosalicylamides are effective and efficient, although 2 equiv of the boronic acid are mechanistically required (Scheme 23.6). In comparison, 5 -acyl-2-mercaptoaryloximes function as MT mimics and can produce peptidyl ketones under anaerobic reaction conditions from only a single equivalent of boronic acid. The latter reaction is also efficient and general, but in its current design, it is only catalytically effective at elevated temperatures (>90 C). 

For biological applications the metal-catalyzed desulfitative transformations must be made effective in pure water or in aqueous biological buffers as the reaction solvent. This will require the development of substrates that are not only water soluble, but that also retain their effectiveness in desulfitative reactions with boronic acids in both the aerobic and anaerobic reaction systems (Fig. 23.7) [54]. 

Finally, current efforts in defining water-soluble reactants for both the aerobic and anaerobic reaction systems will guide the use of the new catalytic desulfitative transformations in advanced ketobioconjugations as represented in Fig. 23.8 [54]. 

Of the native carbon-heteroatom bonds that are biologically relevant (C-O, C-N, C-S), the C-S bond is particularly polarizable, and it therefore has the potential to engage in highly selective transformations catalyzed by thiophilic metals in the presence of C-O- and C-N-based functional groups. As a consequence, given its inherent chemoselectivity, the desulfitative catalysis could also play an important role in highly selective bioconjugative reactions where a biomolecule is coupled to another biomolecule, to a probe or therapeutic molecule, or to a nanomaterial (dot, tube, particle, etc.) or surface [7]. 

All first-generation palladium-catalyzed desulfitative couplings of thioorganics and boronic acids highlighted in Fig. 23.4 require the use of stoichiometric quantities of a copper(l) carboxylate cofactor. This requirement is implicit in the mechanism of the transformation (Scheme 23.3). 

An efficient method for palladium(II) catalytic desulfitative conjugate addition of arylsulfinic acids with a, -unsaturated carbonyl compound has been developed. Experimental evidences for the key reacting intermediates including aryl Pd(II) sulfinic intermediate, aryl Pd(II), and C=0-Pd complexes were provided. The mechanism of the dehydrosulfenylation of 2-arylsulfinyl esters for furnishing enoates has been determined to be a homolytic process. The interception of the radical intermediate using a nitroxyl radical and mass spectrometry techniques were useful for identification of the intermediates involved in the dehydrosulfenylation of 2-arylsulfinyl esters. These data indicated that a radical-mediated process is operative. Tetrabutylammonium iodide has been found to promote deselenylation reaction of ) -chloro- and -oxyselenides to afford alkenes efficiently with formation of selenenyl iodides. A catalytic version of the transformation has also been developed. 

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