The inverted ketene synthon: a double umpolung approach to enantioselective β<sup>2,3</sup>-amino amide synthesis

Vishe, Mahesh; Johnston, Jeffrey N.

doi:10.1039/c8sc04330b

Cited by 14 publications

(6 citation statements)

References 104 publications

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“…N -Aryl amide 28 is a member of the globalagliatin-class of glucokinase activators for the treatment of diabetes . We envisioned an approach to 28 that involved the two key disconnections illustrated in Scheme , requiring chemistry that allows an inverted ketene synthon. , Friedel–Crafts acylation of 29 provided aryl ketone 31 , although the reaction was somewhat dependent on the age of the aluminum chloride used. Oxidation to the sulfone, and Wittig methylenation, delivered terminal alkene 32 .…”

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confidence: 99%

Preparation of N-Aryl Amides by Epimerization-Free Umpolung Amide Synthesis

2022

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Amide synthesis is one of the most widely practiced chemical reactions, owing to its use in drug development and peptide synthesis. Despite the importance of these applications, the attendant effort to eliminate waste associated with these protocols has met with limited success, and pernicious α-epimerization is most often minimized but not eliminated when targeting challenging amides (e.g., N-aryl amides). This effort has focused on what is essentially a single paradigm in amide formation wherein an electrophilic acyl donor reacts with a nucleophilic amine. Umpolung amide synthesis (UmAS) emerged from α-halo nitroalkane reactions with amines and has since been developed into a method for the synthesis of enantiopure amides using entirely catalytic, enantioselective synthesis. However, its inability to forge N-aryl amides has been a longstanding problem, one limiting its application more broadly in drug development where α-chiral N-aryl amides are increasingly common. We report here the reaction of αfluoronitroalkanes and N-aryl hydroxyl amines for the direct synthesis of N-aryl amides using a simple Brønsted base as the promoter. No other activating agents are required, and experiments guided by mechanistic hypotheses outline a mechanism based on the UmAS paradigm and confirm that the N-aryl amide, not the N-aryl hydroxamic acid, is the direct product. Ultimately, select chiral α-amino-N-aryl amides were prepared with complete conservation of enantioenrichment, in contrast to a parallel demonstration of their ability to epimerize using the conventional amide synthesis alternative.

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confidence: 99%

Preparation of N-Aryl Amides by Epimerization-Free Umpolung Amide Synthesis

2022

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“…[28] The Johnston group further expanded their UmAS concept to an extensive range of chiral nitroalkanes and amines. [29][30][31][32][33][34] Inspired by this body of work and our own amidation studies with the Hayashi group, [35] we herein show the synergistic combination of readily available chiral nitroalkanes with amines and elemental sulfur provides a direct and efficient method to form thioamides and thiopeptides in excellent yields (Fig. 1d).…”

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confidence: 61%

Nitroalkanes as Thioacyl Equivalents to Access Thioamides and Thiopeptides

Wang

Tang

et al. 2023

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Thioamides are an important, but a largely underexplored class of amide bioisostere in peptides. Replacement of oxoamide units with thioamides in peptide therapeutics is a valuable tactic to improve biological activity and resistance to enzymatic hydrolysis. This tactic, however, has been hampered by insufficient methods to introduce thioamide bonds into peptide or protein backbones in a site-specific and stereo-retentive fashion. Herein, we developed an efficient and mild thioacylation method to react nitroalkanes with amines directly in the presence of elemental sulfur and sodium sulfide to form a diverse range of thioamides in high yields. Notably, this convenient method can be employed for the controlled thioamide coupling of multifunctionalized peptides without epimerization of stereocenters, including the late stage thioacylation of advanced compounds of biological and medicinal interest. Experimental interrogation of postulated mechanisms currently supports the intermediacy of thioacyl species.

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“…The anthracene-derived chiral bisamidine 58 has been recently introduced as catalyst for the conjugate addition of nitroalkanes to nitroalkenes (Scheme 42). 88 The reaction is particularly effective with nitrostyrenes and affords with satisfactory syn diastereoselectivity the corresponding 1,3-dinitro derivatives. Catalyst 58 is used as triflimidic acid salt since the free base does not bring about significant levels of stereoselectivity in the formation of 1,3-dinitro derivatives, and this aspect stresses the bifunctional nature of the catalytic action provided.…”

Section: Amidines Guanidines and Related Catalystsmentioning

confidence: 97%

Catalysts’ evolution in the asymmetric conjugate addition of nitroalkanes to electron-poor alkenes

2022

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The inverted ketene synthon: a double umpolung approach to enantioselective β^2,3-amino amide synthesis

Abstract: A stereocontrolled route to β2,3-amino amides results from enantioselective nitroalkane-nitroalkene addition reactions and umpolung amide synthesis.

Cited by 14 publications

References 104 publications

Preparation of N-Aryl Amides by Epimerization-Free Umpolung Amide Synthesis

Preparation of N-Aryl Amides by Epimerization-Free Umpolung Amide Synthesis

Nitroalkanes as Thioacyl Equivalents to Access Thioamides and Thiopeptides

Catalysts’ evolution in the asymmetric conjugate addition of nitroalkanes to electron-poor alkenes

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The inverted ketene synthon: a double umpolung approach to enantioselective β2,3-amino amide synthesis

Abstract: A stereocontrolled route to β2,3-amino amides results from enantioselective nitroalkane-nitroalkene addition reactions and umpolung amide synthesis.

Cited by 14 publications

References 104 publications

Preparation of N-Aryl Amides by Epimerization-Free Umpolung Amide Synthesis

Preparation of N-Aryl Amides by Epimerization-Free Umpolung Amide Synthesis

Nitroalkanes as Thioacyl Equivalents to Access Thioamides and Thiopeptides

Catalysts’ evolution in the asymmetric conjugate addition of nitroalkanes to electron-poor alkenes

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The inverted ketene synthon: a double umpolung approach to enantioselective β^2,3-amino amide synthesis