炔酰胺类缩合剂研究进展

缩合剂是指用于促成羧酸与胺或者醇直接缩合构建酰胺键或酯键的一类试剂的总称.由于酰胺和酯的重要性,缩合剂的开发成为了学术界与工业界广泛关注的一个重要研究方向.多肽合成就是α-氨基酸在缩合剂的作用下反复形成酰胺键的过程,因此,缩合剂在多肽合成中发挥着至关重要的作用.当前多肽合成所使用的试剂和技术大多是20世纪50~80年代发展起来的,这些试剂和技术的天生弊端逐渐显现出来.比如传统多肽缩合剂过度活化α-氨基酸而诱发的外消旋化和其它副反应导致的副产物成为药物多肽生产过程中一个极为关切的问题.另外固相多肽合成的低原子经济性给可持续发展带来了极大的挑战.这些问题只能依靠原始创新的颠覆性技术和全新的缩合方法来解决.我们课题组致力于通过发展新试剂和新反应来解决多肽与蛋白质化学合成领域的难题.本文系统介绍了我们发展的一种结构全新的炔酰胺类缩合试剂及其在酰胺、酯、大环内酯、多肽、硫代多肽合成中的应用研究进展.     

Amidolithium and amidoaluminum catalyzed synthesis of substituted guanidines: an interplay of DFT modeling and experiment

The synthesis of substituted guanidines is of significant interest for their use as versatile ligands and for the synthesis of bioactive molecules. Lithium amides supported by tetramethylethylenediamine have recently been shown to catalyze the guanylation of amines with carbodiimide. In this report, density functional theory (DFT) calculations are used to provide insight into the mechanism of this transformation. The mechanism identified through our calculations is a carbodiimide insertion into the lithium-amide bond to form a lithium guanidinate, followed by a proton transfer from the amine. The proton transfer transition state requires the dissociation of one of the chelating nitrogen centers of the lithium guanidinate, proton abstraction from the amine, and bond formation between the lithium center and the amine nitrogen. On the basis of this mechanism, further calculations predicted that aluminum amides would also function as active catalysts for the guanylation of amines. We confirm this experimentally and report the development of aluminum amides as a new main group catalyst for the guanylation of a range of electron-poor amines with carbodiimide.     

Copper Catalyzed C−H Activation

Activation of C?H bonds and their application in cross coupling chemistry has received a wider interest in recent years. The conventional strategy in cross coupling reaction involves the pre‐functionalization step of coupling reactants such as organic halides, pseudo‐halides and organometallic reagents. The C?H activation facilitates a simple and straight forward approach devoid of pre‐functionalization step. This approach also addresses the environmental and economical issues involved in several chemical reactions. In this account, we have reported C?H bond activation of small organic molecules, for example, formamide C?H bond can be activated and coupled with β‐dicarbonyl or 2‐carbonyl substituted phenols under oxidative conditions to yield carbamates using inexpensive copper catalysts. Phenyl carbamates were successfully synthesized in moderate to good yields by cross dehydrogenative coupling (CDC) of phenols with formamides using copper catalysts in presence of a ligand. We have also prepared unsymmetrical urea derivatives by oxidative cross coupling of formamides with amines using copper catalysts. Synthesis of N,N‐dimethyl substituted amides, 5‐substituted‐γ‐lactams and α‐acyloxy ethers was carried out from carboxylic acids using recyclable CuO nanoparticles. Copper nanoparticles afforded N‐aryl‐γ‐amino‐γ‐lactams by oxidative coupling of aromatic amines with 2‐pyrrolidinone. Reusable transition metal HT‐derived oxide catalyst was used for the synthesis of N,N‐dimethyl substituted amides by the oxidative cross‐coupling of carboxylic acids and substituted benzaldehydes. Overview of our work in this area is summarized.     

Powerful amide synthesis from alcohols and amines under aerobic conditions catalyzed by gold or gold/iron, -nickel or -cobalt nanoparticles

Considering the importance of the development of powerful green catalysts and the omnipresence of amide bonds in natural and synthetic compounds, we report here on reactions between alcohols and amines for amide bond formation in which heterogeneous gold and gold/iron, -nickel, or -cobalt nanoparticles are used as catalysts and molecular oxygen is used as terminal oxidant. Two catalysts show excellent activity and selectivity, depending on the type of alcohols used. A wide variety of alcohols and amines, including aqueous ammonia and amino acids, can be used for the amide synthesis. Furthermore, the catalysts can be recovered and reused several times without loss of activity.     

Oxidative amide synthesis directly from alcohols with amines

Transition metal catalyzed oxidative amide synthesis directly from primary alcohols and amines is a highly atom economical transformation that evolves hydrogen gas as the only by-product. Several Ru-, Rh-based homogeneous and Ag-based heterogeneous catalysts have been developed for direct amide synthesis. Most of the developed catalysts showed excellent activity with sterically unhindered alcohols and amines; however, limited activity was observed with sterically hindered alcohols or amines, less basic aryl amines, and secondary amines. This account provides an overview of recent advances and challenges in direct amide synthesis.     

A New and Efficient Method for Synthesis of 5′‐Conjugates of Oligonucleotides through Amide‐Bond Formation on Solid Phase

An efficient method for synthesis of oligonucleotide 5′‐conjugates through amide‐bond formation on solid phase is described. Protected oligonucleotides containing a 5′‐carboxylic acid function were obtained by use of a novel non‐nucleosidic phosphoramidite building block, where the carboxylic acid moiety was protected by a 2‐chlorotrityl group. The protecting group is stable to the phosphoramidite coupling conditions used in solid‐phase oligonucleotide assembly, but is easily deprotected by mild acidic treatment. The protecting group may be removed also by ammonolysis. 5′‐Carboxylate‐modified oligonucleotides were efficiently conjugated on solid support under normal peptide‐coupling conditions to various amines or to the N‐termini of small peptides to yield products of high purity. The method is well‐suited in principle for the synthesis of peptide‐oligonucleotide conjugates containing an amide linkage between the 5′‐end of an oligonucleotide and the N‐terminus of a peptide.     

Nickel‐Catalyzed Synthesis of Dialkyl Ketones from the Coupling of N‐Alkyl Pyridinium Salts with Activated Carboxylic Acids

While ketones are among the most versatile functional groups, their synthesis remains reliant upon reactive and low‐abundance starting materials. In contrast, amide formation is the most‐used bond‐construction method in medicinal chemistry because the chemistry is reliable and draws upon large and diverse substrate pools. A new method for the synthesis of ketones is presented here that draws from the same substrates used for amide bond synthesis: amines and carboxylic acids. A nickel terpyridine catalyst couples N‐alkyl pyridinium salts with in situ formed carboxylic acid fluorides or 2‐pyridyl esters under reducing conditions (Mn metal). The reaction has a broad scope, as demonstrated by the synthesis of 35 different ketones bearing a wide variety of functional groups with an average yield of 60±16 %. This approach is capable of coupling diverse substrates, including pharmaceutical intermediates, to rapidly form complex ketones.     

Catalytic Nitrile Hydroboration: A Route to N,N‐Diborylamines and Uses Thereof

Catalytic reduction of nitriles is considered as an attractive and atom‐economical route to a diversity of synthetically valuable primary amines. Compared to other methods, dihydroboration approach has been developed relatively recently but has already attracted the attention of many research groups due to reasonably mild reaction conditions, selectivity control and the access to N,N‐diborylamines, which emerged as powerful reagents for C?N bond forming reactions. Early developments in catalytic dihydroboration of nitriles implied precious metal catalysts along with harsh conditions and prolonged reaction times, whereas recent advances mostly rely on base and main group metal catalytic systems with significantly improved profiles. This minireview aims to provide an overview of advances and challenges of dihydroboration of nitriles with d‐, f‐ and main group metal catalysts. Mechanistic features of different catalytic systems, functional group tolerance and scope of the methods are also presented. The synthetic utility of N,N‐diborylamies, beyond simple protodeborylation, is discussed in the aspect of N‐arylation, imine and amide synthesis.     

Role of surface-bound intermediates in the oxygen-assisted synthesis of amides by metallic silver and gold

A general mechanism for the oxygen-assisted synthesis of amides over metallic gold and silver surfaces has been derived from the study of acetaldehyde and dimethylamine in combination with previous work, allowing detailed comparison of the two surfaces' reactivities. Facile acetylation of dimethylamine by acetaldehyde occurs with high selectivity on oxygen-covered silver and gold (111) crystals via a common overall mechanism with different rate-limiting steps on the two metals. Adsorbed atomic oxygen activates the N-H bond of the amine leading to the formation of an adsorbed amide, which attacks the carbonyl carbon of the aldehyde, forming an adsorbed hemiaminal. Because aldehydes are known to form readily from partial oxidation of alcohols, our mechanism also provides insight into the related catalytic coupling of alcohols and amines. The hemiaminal β-H eliminates to form the coupled amide product. On silver, β-H elimination from the hemiaminal is rate-limiting, whereas on gold desorption of the amide is the slow step. Silver exhibits high selectivity for the coupling reaction for adsorbed oxygen concentrations between 0.01 and 0.1 monolayer, whereas gold exhibits selectivity more strongly dependent on oxygen coverage, approaching 100% at 0.03 monolayer. The selectivity trends and difference in rate-limiting steps are likely due to the influence of the relative stability of the adsorbed hydroxyl groups on the two surfaces. Low surface coverages of oxygen lead to the highest selectivity. This study provides a general framework for the oxygen-assisted coupling of alcohols and aldehydes with amines over gold- and silver-based catalysts in either the vapor or the liquid phase.     

Oligonucleotides with 2'-O-carboxymethyl group: synthesis and 2'-conjugation via amide bond formation on solid phase

An efficient method for synthesis of oligonucleotide 2'-conjugates via amide bond formation on solid phase is described. Protected oligonucleotides containing a 2'-O-carboxymethyl group were obtained by use of a novel uridine 3'phosphoramidite, where the carboxylic acid moiety was introduced as its allyl ester. This protecting group is stable to the conditions used in solid-phase oligonucleotide assembly, but easily removed by Pd(0) and morpholine treatment. 2'-O-Carboxymethylated oligonucleotides were then efficiently conjugated on a solid support under normal peptide coupling conditions to various amines or to the N-termini of small peptides to give products of high purity in good yield. The method is well suited in principle for the preparation of peptide-oligonucleotide conjugates containing an amide linkage between the 2'-position of an oligonucleotide and the N-terminus of a peptide.     

Improved functional group compatibility in the palladium-catalyzed synthesis of aryl amines

[reaction: see text] The use of Pd2dba3 with bulky, electron-rich ligands 1 or 2 and LiN(TMS)2 as the base for the coupling of amines with aryl halides containing hydroxyl, amide, or enolizable keto groups is described. This protocol expands the utility of palladium-catalyzed C-N bond formation by allowing for the use of aryl halides containing these functional groups, obviating the need for protecting group manipulations.     

Analysis of amide bond formation with an alpha-hydroxy-beta-amino acid derivative, 3-amino-2-hydroxy-4-phenylbutanoic acid, as an acyl component: byproduction of homobislactone

In the synthesis of peptidomimetics containing alpha-hydroxy-beta-amino acid, the coupling of this N(beta)-protected beta-amino acid with amine components was generally performed without the protection of its alpha-hydroxyl group. However, the formation of dipeptides in low yield was often observed when sterically hindered amine components were used. Boc-Apns-OH [Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid, allophenylnorstatine] (6), which is one of such beta-amino acid derivatives, is intensively employed as a core structure in the development of HIV-1 protease inhibitors. There have been no precise studies, to date, that have examined amide bond formation with alpha-hydroxy-beta-amino acid derivatives as an acyl component. To determine the cause of this low-yield reaction, we studied the amide bond formation focusing on the activation step of N(beta)-protected alpha-hydroxy-beta-amino acid by using a model coupling reaction between 6 and H-Dmt-OR [Dmt: (R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid] (7). A significant amount of homobislactone 9 was formed through the activation of the carboxyl group of 6 to the benzotriazole-type active esters such as OBt and OAt. In addition, this homobislactone formation was markedly increased in the presence of a catalytic amount of a base, which exhibited good correlation with the low yield of the amide bond formation, suggesting that homobislactone formation is one major reason for the low yield of the amide bond formation. Moreover, homobislactones were also formed in other derivatives of the N(beta)-protected alpha-hydroxy-beta-amino acid, suggesting a common feature of this type of amino acids. The use of a strong activation method like EDC--HOAt without base addition enhanced amide bond formation, although a small amount of homobislactone may be formed during the coupling reaction.     

Photocatalytic Stille Cross-coupling on Gold/g-C3N4Nano-heterojunction

Heterogeneous catalysts have been developed for C-C coupling reactions, but stand low activity and always proceed under harsh conditions. Photocatalytic Stille cross-coupling reaction as a green catalytic method for C-C bond formation is of great interest for a wide range of scientists but still lacks stable and highly efficient catalysts. Herein, we have designed an Au nanoparticle-graphitic carbon nitride heterojunction as an outstanding photocatalyst for artificial photosynthesis in Stille cross-coupling reaction. The interface effect between metal and semiconductor makes electron rectify and prevents the recombination of electron-hole pairs. Moreover, the efficiency of Au nanoparticle catalysts could be adjusted by gold contents. Thus the turnover frequency(TOF) value reached the highest level of 788 h^-1 over the optimal heterojunction catalyst. Most importantly, the C-C bond formation reaction has been proved to be carried out well under visible light irradiation, indicating the low-cost organic synthesis process. Further analysis confirmed the stability and general application of our heterogeneous Au nano-heterojunction catalyst.     

Nickel-Catalyzed Synthesis of Dialkyl Ketones from the Coupling of N-Alkyl Pyridinium Salts with Activated Carboxylic Acids

While ketones are among the most versatile functional groups, their synthesis remains reliant upon reactive and low-abundance starting materials. In contrast, amide formation is the most-used bond-construction method in medicinal chemistry because the chemistry is reliable and draws upon large and diverse substrate pools. A new method for the synthesis of ketones is presented here that draws from the same substrates used for amide bond synthesis: amines and carboxylic acids. A nickel terpyridine catalyst couples N-alkyl pyridinium salts with in situ formed carboxylic acid fluorides or 2-pyridyl esters under reducing conditions (Mn metal). The reaction has a broad scope, as demonstrated by the synthesis of 35 different ketones bearing a wide variety of functional groups with an average yield of 60±16 %. This approach is capable of coupling diverse substrates, including pharmaceutical intermediates, to rapidly form complex ketones.     

Recent Advances in the Metal‐Catalyzed Activation of Amide Bonds

The amide functional group is commonly found in peptides, proteins, pharmaceutical compounds, natural products, and polymers. The synthesis of amides is typically performed by using classical approaches that involve the reaction between a carboxylic acid and an amine in the presence of an activator. Amides are thought to be an inert functional group, because they are unsusceptible to nucleophile attack, owing to their low electrophilicity. The reason for this resistance is clear: the resonance stability of the amide bond. However, transition metal catalysis can circumvent this stability by selectively rupturing the N?C bond of the amide, thereby facilitating further cross‐coupling or other reactions. In this Focus Review, we discuss the recent advances in this area and present a summary of methods that have been developed for activating the amide N?C bond by using precious and non‐precious metals.     

Direct amide formation from unactivated carboxylic acids and amines

The direct coupling of unactivated carboxylic acids with amines can be performed in toluene 110 °C in the absence of catalyst. The use of simple zirconium catalysts at 5 mol% loading gave amide formation in as little as 4 h.     

Synthesis and applications of a novel polymer-supported EEDQ reagent

A simple synthetic protocol for a novel polymer-supported EEDQ reagent is reported. This reagent promotes solution-phase amide bond formation without any additives or base, as well as the selective coupling of aliphatic amines with acids in the presence of aromatic amines.     

Transformation of a [4+6] Salicylbisimine Cage to Chemically Robust Amide Cages

In recent years, interest in shape‐persistent organic cage compounds has steadily increased, not least because dynamic covalent bond formation enables such structures to be made in high to excellent yields. One often used type of dynamic bond formation is the generation of an imine bond from an aldehyde and an amine. Although the reversibility of the imine bond formation is advantageous for high yields, it is disadvantageous for the chemical stability of the compounds. Amide bonds are, in contrast to imine bonds much more robust. Shape‐persistent amide cages have so far been made by irreversible amide bond formations in multiple steps, very often accompanied by low yields. Here, we present an approach to shape‐persistent amide cages by exploiting a high‐yielding reversible cage formation in the first step, and a Pinnick oxidation as a key step to access the amide cages in just three steps. These chemically robust amide cages can be further transformed by bromination or nitration to allow post‐functionalization in high yields. The impact of the substituents on the gas sorption behavior was also investigated.     

Transition‐metal‐catalyzed aminations and aziridinations of C?H and CC bonds with iminoiodinanes

Catalytic insertion or addition of a metal‐imido/nitrene species, generated from reaction of a transition‐metal catalyst with iminoiodanes, to C? H and C?C bonds offers a convenient and atom economical method for the synthesis of nitrogen‐containing compounds. Following this groundbreaking discovery during the second half of the last century, the field has received an immense amount of attention with a myriad of impressive metal‐mediated methods for the synthesis of amines and aziridines having been developed. This review will cover the significant progress made in improving the efficiency, versatility and stereocontrol of this important reaction. This will include the various iminoiodanes, their in situ formation, and metal catalysts that could be employed and new ligands, both chiral and non‐chiral, which have been designed, as well as the application of this functional group transformation to natural product synthesis and the preparation of bioactive compounds of current therapeutic interest. DOI 10.1002/tcr.201100018     

Expanding the utility of proteases in synthesis: broadening the substrate acceptance in non-coded amide bond formation using chemically modified mutants of subtilisin

The strategy of combined site directed mutagenesis and chemical modification creates chemically modified mutants (CMMs) with greatly broadened substrate specificities. We have previously reported that the CMMs of subtilisin Bacillus lentus (SBL) are efficient catalysts for the coupling of both l- and d-amino acids. We now report that these powerful catalysts also allow amide bond formation between a variety of non-coded carboxylic acids, including β-alanine and β-amino homologues of phenylalanine, with both l- and d-amino acid nucleophiles. As a guide to enzyme efficiency, a hydrolysis assay indicating pH change has been employed. CMMs selected by this screen furnished higher yields of coupling products compared to the wild-type enzyme (WT). Furthermore, both WT and CMM enzymes allow highly stereoselective aminolysis of a meso diester with an amino acid amine. These results highlight the utility of CMMs in the efficient formation of non-coded amides as potential peptide isosteres.