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Peptides consisting of D-amino amides are highly represented among both biologically active natural products and non-natural small molecules used in therapeutic development. Chemical synthesis of D-amino amides most often involves approaches based on enzymatic resolution or fractional recrystallization of their diastereomeric amino acid salt precur...
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... In 2010, Johnston and coworkers pioneered the concept of umpolung amide synthesis (UmAS) via the oxidative coupling of α-bromo nitroalkanes with amines in the presence of N-iodosuccinimide and potassium carbonate 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). ...
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. In this work, 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.
... Therefore, the current interest in asymmetric synthesis of tailor-made AA is at an all-time high, providing structurally varied derivatives for comprehensive biological studies (Vogt and Brase 2007;Kukhar et al. 2009;Soloshonok and Sorochinsky 2010;Sorochinsky and Soloshonok 2010;Kim et al. 2011;Wang et al. 2011b; 1 3 and Sutherland 2016; Paek et al. 2016). Along with other research groups (Morrill et al. 2012;So et al. 2014;Metrano and Miller 2014;Schettini et al. 2014;Moozeh et al. 2015;Etxabe et al. 2015;Fanelli et al. 2015;Schwieter and Johnston 2015;Wangweerawong et al. 2016;Hutchby et al. 2016;Lin et al. 2016), we were involved in the development of general methods for preparation of various types of AAs, in particular, such as phosphorus Röschenthaler et al. 2012;Turcheniuk et al. 2012) and fluorine containing (Soloshonok et al. 1994(Soloshonok et al. , 1997aSoloshonok and Ono 1996;Bravo et al. 1998;Wang et al. 2011a;Drouet et al. 2014) sterically constrained (Soloshonok et al. , 2001bTang et al. 2000) and polyfunctional (Basiuk et al. 1992;Bravo et al. 1999;Yamada et al. 2006) derivatives of α-and β-AAs (Bravo et al. 1997;Shibata et al. 2012;Ding et al. 2013). One of the most prolific approaches has been the chemistry of Ni(II) complexes of AAs derived Schiff bases (Fig. 1). ...
This review article critically discusses examples of asymmetric synthesis of tailor-made α-amino acids via homologation of Ni(II) complexes of glycine and alanine Schiff bases, reported in the literature from 2013 through the end of 2016. Where it is possible, reaction mechanism and origin of the stereochemical outcome is discussed in detail. Special attention is given to various aspects of practicality and scalability of the reported methods. Among the most noticeable developments in this area are novel designs of axially chiral ligands, application of electro- and mechano-chemical (ball-milling) conditions, and development of dynamic kinetic resolution procedures.
... Johnston and co-workers studied the reactions of a wide range of N-Boc-α-amido sulfones (48) with bromonitromethane (49) [40]. They were interested in using Umpolung chemistry for peptide synthesis [41]. ...
... Up to now only α-aryl amides and α-oxyamides have been used with Umpolung chemistry. Although the aza-Henry reaction with bromonitromethane can in principle provide the necessary synthons, the reaction with alkyl imine electrophiles had not been successful prior to this report [40]. Now N-Boc-α-amido sulfones 47 bearing α-alkyl chains were reacted with bromonitromethane in the presence of Nbenzylquininium chloride (50), a phase-transfer agent used previously in aza-Henry chemistry with nitromethane [43]. ...
The formation of C-C and C-X bonds is a fundamental process in synthesis. In recent years organocatalysis has become a powerful tool to achieve these steps in a highly stereoselective manner and the nitro-Michael reaction was frequently used. From the functionalization of simple aldehydes, ketones or dicarbonyl compounds to the synthesis of privileged heterocyclic structures often found present in naturally occurring bioactive compounds and pharmaceuticals, several developments are being continuously documented. This review is focused on the period Jan 2014-Mar 2015 and it highlights the novel prospects for targetoriented synthesis, including many novel domino and cascade processes initiated by nitro- Michael reactions.
... nitroalkanes are relatively limited in substrate scope [7,8] In comparison, there are a wide variety of catalytic asymmetric methods that adopt nitromethane as a simple, cheap pronucleophile to add to both alkyl and aryl aldehydes, imines, enals, enones, and so forth. [9,10] Herein, our interest was to exploit these readily available primary nitroalkane substrates (Eqs. ...
... This premise was, however, given credence by the suggestion of N-iodo amine and a-amino nitroalkane intermediates being reported in a series of oxidative umpolung amide synthesis (UmAS) studies. [5][6][7] Herein, during the course of developing an atom-economical, direct amidation procedure of readily prepared chiral nitroalkanes, [9,10] we describe our independent findings and ultimately propose new mechanistic aspects that have general implications both in amine/halogen-based chemistry and in UmAS chemistry. ...
... (3)). In short, all attempts to prepare, infer, or observe the anticipated N-iodo amines, [5][6][7] were not confirmed in our hands. Instead, we interpret our NMR data to show that amines like allylamine and a-methyl benzyl amine form a complex readily with NIS and precipitate, and these precipitates behave chemically as sources of electrophilic iodine and nucleophilic amine. ...
The formation of amides and peptides often necessitates powerful yet mild reagent systems. The reagents used, however, are often expensive and highly elaborate. New atom-economical and practical methods that achieve such goals are highly desirable. Ideally, the methods should start with substrates that are readily available in both chiral and non-chiral forms and utilize cheap reagents that are compatible with a wide variety of functional groups, steric encumbrance, and epimerizable stereocenters. A direct oxidative method was developed to form amide and peptide bonds between amines and primary nitroalkanes simply by using I2 and K2CO3 under O2. Contrary to expectations, a 1:1 halogen-bonded complex forms between the iodonium source and the amine, which reacts with nitronates to form a-iodo nitroalkanes as precursors to the amides.
... nitroalkanes are relatively limited in substrate scope. [7,8] In comparison, there are aw ide variety of catalytic asymmetric methods that adopt nitromethane as as imple,c heap pronucleophile to add to both alkyl and aryl aldehydes,i mines, enals,e nones,a nd so forth. [9,10] Herein, our interest was to exploit these readily available primary nitroalkane substrates (Eqs. ...
... These would be similarly oxidized with oxygen to afford peroxy adducts bearing amine groups and eventually trans-form into amides.A tt his juncture,a mong other mechanistic concerns,i tw as not certain whether the formation and reaction of N-iodo amines could be achieved in situ and thereby generate the requisite a-amino nitroalkane intermediates.T his premise was,h owever,g iven credence by the suggestion of N-iodo amine and a-amino nitroalkane intermediates being reported in as eries of oxidative umpolung amide synthesis (UmAS) studies. [5][6][7] Herein, during the course of developing an atom-economical, direct amidation procedure of readily prepared chiral nitroalkanes, [9,10] we describe our independent findings and ultimately propose new mechanistic aspects that have general implications both in amine/halogen-based chemistry and in UmAS chemistry. ...
... (3)). In short, all attempts to prepare,i nfer, or observe the anticipated N-iodo amines, [5][6][7] were not confirmed in our hands.I nstead, we interpret our NMR data to show that amines like allylamine and a-methyl benzyl amine form acomplex readily with NIS and precipitate,a nd these precipitates behave chemically as sources of electrophilic iodine and nucleophilic amine.F or ...
The formation of amides and peptides often necessitates powerful yet mild reagent systems. The reagents used, however, are often expensive and highly elaborate. New atom-economical and practical methods that achieve such goals are highly desirable. Ideally, the methods should start with substrates that are readily available in both chiral and non-chiral forms and utilize cheap reagents that are compatible with a wide variety of functional groups, steric encumberance, and epimerizable stereocenters. A direct oxidative method was developed to form amide and peptide bonds between amines and primary nitroalkanes simply by using I2 and K2CO3 under O2. Contrary to expectations, a 1:1 halogen-bonded complex forms between the iodonium source and the amine, which reacts with nitronates to form α-iodo nitroalkanes as precursors to the amides.
... nitroalkanes are relatively limited in substrate scope. [7,8] In comparison, there are aw ide variety of catalytic asymmetric methods that adopt nitromethane as as imple,c heap pronucleophile to add to both alkyl and aryl aldehydes,i mines, enals,e nones,a nd so forth. [9,10] Herein, our interest was to exploit these readily available primary nitroalkane substrates (Eqs. ...
... These would be similarly oxidized with oxygen to afford peroxy adducts bearing amine groups and eventually trans-form into amides.A tt his juncture,a mong other mechanistic concerns,i tw as not certain whether the formation and reaction of N-iodo amines could be achieved in situ and thereby generate the requisite a-amino nitroalkane intermediates.T his premise was,h owever,g iven credence by the suggestion of N-iodo amine and a-amino nitroalkane intermediates being reported in as eries of oxidative umpolung amide synthesis (UmAS) studies. [5][6][7] Herein, during the course of developing an atom-economical, direct amidation procedure of readily prepared chiral nitroalkanes, [9,10] we describe our independent findings and ultimately propose new mechanistic aspects that have general implications both in amine/halogen-based chemistry and in UmAS chemistry. ...
... (3)). In short, all attempts to prepare,i nfer, or observe the anticipated N-iodo amines, [5][6][7] were not confirmed in our hands.I nstead, we interpret our NMR data to show that amines like allylamine and a-methyl benzyl amine form acomplex readily with NIS and precipitate,a nd these precipitates behave chemically as sources of electrophilic iodine and nucleophilic amine.F or ...
The formation of amides and peptides often necessitates powerful yet mild reagent systems. The reagents used, however, are often expensive and highly elaborate. New atom-economical and practical methods that achieve such goals are highly desirable. Ideally, the methods should start with substrates that are readily available in both chiral and non-chiral forms and utilize cheap reagents that are compatible with a wide variety of functional groups, steric encumberance, and epimerizable stereocenters. A direct oxidative method was developed to form amide and peptide bonds between amines and primary nitroalkanes simply by using I2 and K2CO3 under O2. Contrary to expectations, a 1:1 halogen-bonded complex forms between the iodonium source and the amine, which reacts with nitronates to form α-iodo nitroalkanes as precursors to the amides.
... Johnston and co-workers studied the reactions of a wide range of N-Boc-α-amido sulfones (48) with bromonitromethane (49) [49]. They were interested in using Umpolung chemistry for peptide synthesis [50]. ...
... Up to now only α-aryl amides and α-oxyamides have been used with Umpolung chemistry. Although the aza-Henry reaction with bromonitromethane can in principle provide the necessary synthons, the reaction with alkyl imine electrophiles had not been successful prior to this report [49]. Now N-Boc-α-amido sulfones 47 bearing α-alkyl chains were reacted with bromonitromethane in the presence of Nbenzylquininium chloride (50), a phase-transfer agent used previously in aza-Henry chemistry with nitromethane [53]. ...
Background: The organocatalytic asymmetric aza-Henry (nitro-Mannich) reaction is a powerful tool for the synthesis of enantiopure compounds containing a 1,2-arrangement of stereogenic nitrogen-bearing carbon centers. The products are useful synthetic intermediates which may be easily transformed into a variety of useful substances, with applications in medicine, agriculture and even as ligands or organocatalysts for asymmetric synthesis. Given the usefulness of this reaction and the large body of information published, this review aims to provide readers with an up-to-date account of the latest developments in the field. Methods: The research published on the organocatalytic aza-Henry reaction during approximately the last two years is reviewed. The last comprehensive review dedicated exclusively to this subject was published in March 2013. Results: The main developments which took place during this period were the design of novel catalysts which broadened the scope of the reaction, including some anchored to solid supports, novel activating groups and access to novel targets up to now inaccessible via this route: non-symmetric cis-stilbene diamines, chiral α-amino-β-nitroesters, α-amino-β-nitrophosphonates and functionalized isatin-derived ketimines to name a few. Umpolung chemistry was used to afford peptides bearing aliphatic side chains and it even became possible to carry out asymmetric aza-Henry reactions in the presence of water. The development of new multi-component reactions and domino processes which provided nitrogen heterocycles bearing multiple chiral centers with very high degrees of stereoselectivity continued to be an important addition to the chemist’s repertoire. Conclusion: The developments achieved during this period continue to show the enormous potential of asymmetric organocatalysis and should inspire further work in this area.
Organocatalytic asymmetric synthesis has evolved over the years and continues to attract the interest of many researchers worldwide. Enantiopure noncanonical amino acids (ncAAs) are valuable building blocks in organic synthesis, medicinal chemistry, and chemical biology. They are employed in the elaboration of peptides and proteins with enhanced activities and/or improved properties compared to their natural counterparts, as chiral catalysts, in chiral ligand design, and as chiral building blocks for asymmetric syntheses of complex molecules, including natural products. The linkage of ncAA synthesis and enantioselective organocatalysis, the subject of this perspective, tries to imitate the natural biosynthetic process. Herein, we present contemporary and earlier developments in the field of organocatalytic activation of simple feedstock materials, providing potential ncAAs with diverse side chains, unique three-dimensional structures, and a high degree of functionality. These asymmetric organocatalytic strategies, useful for forging a wide range of C–C, C–H, and C–N bonds and/or combinations thereof, vary from classical name reactions, such as Ugi, Strecker, and Mannich reactions, to the most advanced concepts such as deracemisation, transamination, and carbene N–H insertion. Concurrently, we present some interesting mechanistic studies/models, providing information on the chirality transfer process. Finally, this perspective highlights, through the diversity of the amino acids (AAs) not selected by nature for protein incorporation, the most generic modes of activation, induction, and reactivity commonly used, such as chiral enamine, hydrogen bonding, Brønsted acids/bases, and phase-transfer organocatalysis, reflecting their increasingly important role in organic and applied chemistry.
