A CuH‐catalyzed enantioselective hydroamidation reaction of vinylarenes has been developed using readily accessible 1,4,2‐dioxazol‐5‐ones as electrophilic amidating reagents. This method provides a ...straightforward and efficient approach to synthesize chiral amides in good yields with high levels of enantiopurity under mild conditions. Moreover, this transformation tolerates substrates bearing a broad range of functional groups.
Born to be mild: A CuH‐catalyzed enantioselective hydroamidation reaction of vinylarenes was developed using readily accessible 1,4,2‐dioxazol‐5‐ones as electrophilic amidating reagents. This method provides straightforward and efficient access to chiral amides in good yields with high levels of enantiopurity under mild conditions. Moreover, the transformation exhibits broad functional‐group tolerance.
We report the catalytic stereocontrolled synthesis of dinucleotides. We have demonstrated, for the first time to our knowledge, that chiral phosphoric acid (CPA) catalysts control the formation of ...stereogenic phosphorous centers during phosphoramidite transfer. Unprecedented levels of diastereodivergence have also been demonstrated, enabling access to either phosphite diastereomer. Two different CPA scaffolds have proven to be essential for achieving stereodivergence: peptide-embedded phosphothreonine-derived CPAs, which reinforce and amplify the inherent substrate preference, and C2-symmetric BINOL-derived CPAs, which completely overturn this stereochemical preference. The presently reported catalytic method does not require stoichiometric activators or chiral auxiliaries and enables asymmetric catalysis with readily available phosphoramidites. The method was applied to the stereocontrolled synthesis of diastereomeric dinucleotides as well as cyclic dinucleotides, which are of broad interest in immuno-oncology as agonists of the stimulator of interferon genes (STING) pathway.
Oxindoles with adjacent tetrasubstituted stereocenters were obtained in high yields and stereoselectivities by organocatalyzed conjugate addition reactions of monothiomalonates (MTMs) to ...isatin‐derived N‐Cbz ketimines. The method requires only a low catalyst loading (2 mol %) and proceeds under mild reaction conditions. Both enantiomers are accessible in good yields and excellent stereoselectivities by using either Takemoto’s catalyst or a cinchona alkaloid derivative. The synthetic methodology allowed establishment of a straightforward route to derivatives of the gastrin/cholecystokinin‐B receptor antagonist AG‐041R.
Crowd around: Oxindoles with adjacent fully substituted stereogenic centers were formed by mild organocatalytic addition reactions with high diastereo‐ and enantioselectivities. The synthetic versatility of the products with orthogonally addressable functional moieties was showcased in the synthesis of derivatives of the bioactive oxindole AG‐041R.
Herein, we report a practical two‐step synthetic route to α‐arylpyrrolidines through Suzuki–Miyaura cross‐coupling and enantioselective copper‐catalyzed intramolecular hydroamination reactions. The ...excellent stereoselectivity and broad scope for the transformation of substrates with pharmaceutically relevant heteroarenes render this method a practical and versatile approach for pyrrolidine synthesis. Additionally, this intramolecular hydroamination strategy facilitates the asymmetric synthesis of tetrahydroisoquinolines and medium‐ring dibenzo‐fused nitrogen heterocycles.
An enantioselective copper‐catalyzed intramolecular hydroamination reaction can be used jointly with the Suzuki–Miyaura cross‐coupling to yield a diverse array of α‐arylpyrrolidine scaffolds that contain pharmaceutically relevant heteroarenes with excellent enantiomeric purity under mild conditions. Furthermore, this intramolecular hydroamination strategy is applicable to the asymmetric syntheses of six‐ to nine‐membered benzo‐fused nitrogen heterocycles.
Chemoselective Acylation of Nucleosides Tang, Yu; Grange, Rebecca L.; Engl, Oliver D. ...
Chemistry : a European journal,
September 16, 2022, Volume:
28, Issue:
52
Journal Article
Peer reviewed
Open access
Acylated nucleoside analogues play an important role in medicinal chemistry and are extremely useful precursors to various other nucleoside analogues. However, chemoselective acylation of nucleosides ...usually requires several protection and deprotection steps due to the competing nucleophilicity of hydroxy and amino groups. In contrast, direct protecting‐group‐free chemoselective acylation of nucleosides is a preferred strategy due to lower cost and fewer overall synthetic steps. Herein, a simple and efficient chemoselective acylation of nucleosides and nucleotides under mild reaction conditions, giving either O‐ or N‐acylated products respectively with excellent chemoselectivity is reported.
Chemoselective functionalization of oxygen atoms versus nitrogen atoms in bifunctional and polyfunctional molecules is a long‐standing challenge in both fundamental chemistry and in complex molecule synthesis. Different conditions that allow high selectivity in the derivatization of complex nucleosides that contain both O‐ and N‐based functionalities are described. Particularly intriguing cases are also presented, in which the reactivity of the O‐ and N‐based functionalities is quite context dependent, exhibiting reactivity that blurs conventional considerations, yet where selectivity may also be observed.
A straightforward stereodivergent route to dihydrocoumarins and dihydroquinolinones based on cinchona alkaloid catalyzed addition reactions of monothiomalonates (MTMs) to functionalized nitroolefins ...followed by deprotection and chemoselective cyclization has been developed. The synthesis proceeds under mild conditions and yields heterocycles with adjacent quaternary and tertiary stereogenic centers in very high yields and stereoselectivities. Moreover, full control over the relative and absolute configuration is achieved by the use of (pseudo)enantiomeric catalysts and the difference in reactivity of thioester versus oxoester moieties.
α‐Fluorinated β‐amino thioesters were obtained in high yields and stereoselectivities by organocatalyzed addition reactions of α‐fluorinated monothiomalonates (F‐MTMs) to N‐Cbz‐ and N‐Boc‐protected ...imines. The transformation requires catalyst loadings of only 1 mol % and proceeds under mild reaction conditions. The obtained addition products were readily used for coupling‐reagent‐free peptide synthesis in solution and on solid phase. The α‐fluoro‐β‐(carb)amido moiety showed distinct conformational preferences, as determined by crystal structure and NMR spectroscopic analysis.
Get rid of the middleman: A broad range of α‐fluorinated β‐amino thioesters were formed with high diastereo‐ and enantioselectivity in the presence of 1 mol % of a cinchona‐alkaloid–squaramide catalyst (see scheme; PG=protecting group). The resulting preactivated fluorinated β‐amino acids were readily incorporated into α,β‐peptides without the need for coupling reagents and had a defined conformation that was retained within the peptides.
Monothiomalonates (MTMs) are surrogates of thioester enolates that allow for stereoselective C–C bond formations under mild conditions and thereby afford access to synthetically versatile thioester ...derivatives. Here we present a straightforward synthetic route to MTMs that proceeds through nucleophilic ring‐opening of Meldrum's acid derivatives followed by O‐alkylation of the resulting malonic acid half thioesters with alkyl triflates or acetimidates as electrophiles. The method affords MTMs in overall yields of 34 – 92% and allows for variations of the oxo‐ and thioester moieties as well as the substituent at the C(α) position.
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