Bioorthogonal cleavage reactions are gaining popularity in chemically inducible prodrug activation and in the control of biomolecular functions. Despite similar applications, these reactions were developed and optimized on different substrates and under different experimental conditions. Reported herein is a side‐by‐side comparison of palladium‐, ruthenium‐ and tetrazine‐triggered release reactions, which aims at comparing the reaction kinetics, efficiency and overall advantages and limitations of the methods. In addition, we disclose the possibility of mutual combination of the cleavage reactions. Finally, we compare the efficiency of the bioorthogonal deprotections in cellular experiments, which revealed that among the three methods investigated, the palladium‐ and the tetrazine‐promoted reaction can be used for efficient prodrug activation, but only the tetrazine‐triggered reactions proceed efficiently inside cells.
Access to unprotected (hetero)aryl pseudo-C-glucosides via a mild Pd-catalysed Hiyama cross-coupling reaction of protecting-group-free 1-diisopropylsilyl-d-glucal with various (hetero)aryl halides has been developed. In addition, selected unprotected pseudo-C-glucosides were stereoselectively converted into the corresponding αand β-C-gluco-sides, as well as 2-deoxy-β-C-glucosides. This methodology was applied to the efficient and high-yielding synthesis of dapagliflozin, a medicament used to treat type 2 diabetes mellitus. Finally, the versatility of our methodology was proved by the synthesis of other analogues of dapagliflozin.
This work represents another step in the effort to use glycals (1,2unsaturated derivatives of carbohydrates) as donor synthons for transition metal-catalyzed arylation reactions. We have employed a novel 1-silyl derivative of d-glucal, which was obtained as ab enchstable solid and could therefore be used conveniently.F or its preparation, we have used at ransient protection with MOP groups, which we developed previously,a nd therefore we could access the key synthon in its unprotected form. Ta king advantage of this, we have carried out ar ange of Hiyama arylation reactions without the need for protection. We have also spectroscopically confirmed the role of the silyl hydride derivative as am asked silanol and its hydrolytic activation, which is ak ey mechanistic step for transmetalation of the glycal moiety to palladium. Moreover,w eh ave used this strategy to develop av ery short synthesis of Dapagliflozin, an important commercial drug.
A silyl hydride derivative of d‐glucal was used conveniently as a bench‐stable precursor for the construction of C‐glycosidic bond. After activation by fluoride‐mediated dehydrogenative hydrolysis, an intermediate silanol species was used for Hiyama arylation. Various aryl and heteroaryl C‐glycosides, C‐glycopeptides, as well as both a‐ and b‐isomers of Dapagliflozin could be constructed rapidly and without the need for protecting groups. The cover image was designed by Tomáš Belloň at IOCB Prague. More information can be found in the Full Paper by K. Parkan et al. (DOI: 10.1002/chem.202101052).
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