Peptides, which are elongated of peptides chain of amino acids linked by amide bonds, are elementary components in living systems and regulate many biological processes. Since the solid-phase peptide synthesis was introduced by Merrifield in 1964, chemical synthesis of peptides using solid-phase system has emerged as a valuable method due to its ease of operation and rapid synthesis of desired peptides. However, despite of the effectiveness of the solid-phase approach, typical reaction requires excess amounts of coupling reagents, bases, and amino acids to achieve maximum conversion. And the ease of operation led to accumulate undesired segments together with target peptide because solid-phase system is generally carried out by coupling amino acids with N-terminal amino acid residue of peptides in a stepwise approach without any isolation and characterization at each step. To solve these issues, we focused on the development of catalytic liquid-phase synthesis, which has advantage of isolating the growing peptide chain from reaction solution after each coupling step. Although several liquid-phase methods have been developed, there is a still considerable room for the improvement of racemization, generality, and ligation reaction. In this view, we have developed a mild, practical, and efficient methods based on substrate-control by using boronic acid, niobium, and tantalum as catalysts. Our methods can be applied for a broad variety of amino acids to furnish the desired peptides in excellent yields without significant loss of stereochemical integrity. The developed straightforward approach overcome a lot of problem associated with peptide synthesis. This article describes our recent achievement based on catalytic substrate-controlled peptide synthesis.
Separation and extraction of nucleophilicity from Brønsted basicity are a fundamental interest in organometallic chemistry. This topic is especially important for realizing protecting group-minimum synthesis of multifunctional molecules, e.g. sugars and drug leads. Summarizing our recent achievements, here I showcase that copper(I)-conjugated carbon nucleophiles, such as allylcopper, allenylcopper, copper alkynides, and copper enolates, are uniquely functional under protic environments without being decomposed. The soft characteristics of copper(I)-conjugated carbon nucleophiles are crucial for this chemoselectivity. The concept of hard anion-conjugated soft metal complex catalysis (HASM) is the basis for the catalytic generation of the active nucleophiles from stable molecules. Introducing chiral ligands to the copper catalysts allows for the catalyst-controlled stereoselectivity. Combining those strengths of the copper(I) catalysis, we achieved anomeric C-C bond formation of unprotected sugars, short and stereodivergent synthesis of sialic acids, use of hydrocarbon eneynes in asymmetric synthesis, and asymmetric domino/iterative aldehyde aldol reactions for the synthesis of 1,3-polyols, which are the topics of this review.
Simultaneous control of multiple selectivity is a powerful means for constructing structurally discrete, functionalized building blocks, yet it has remained a challenging task in organic synthesis and catalysis. We have tackled this objective by taking advantage of the unique ability of P-spiro chiral tetraaminophosphonium ion to control transition-state structures of the target reaction. Namely, the use of its conjugate base, chiral iminophosphorane, as an organic base catalyst allowed for the rigorous control of not only enantioselectivity but also additional selectivity associated with other factors, such as geometry, regiochemistry, diastereomer formation, and reaction pathway, in various carbon-carbon bond-forming reactions. Theoretical investigation revealed key elements to achieve the multiple selectivity control, which would provide a basis for the development of related and more effective catalytic systems.
Enolization of carboxylic acid derivatives is the central science of fundamental carbonyl chemistry. The catalytic methods to activate carboxylic acid remained unexplored due to the intrinsic low acidity of α-protons, although enormous examples of catalytic activation (enolization) method for aldehydes, ketones, and ester derivatives have been reported. The innate Brønsted acidic carboxylic acid functionality also disrupts the deprotonation of α-protons. Therefore, more than two equivalents of a strong base such as lithium diisopropylamide are required for efficient enolization, which makes chemoselective enolization of carboxylic acid over more acidic carbonyls a formidable task. Furthermore, recent enolization methods were only applied to redox-neutral coupling using 2e- electrophiles and catalytic α-functionalization of carboxylic acids through a 1e- radical process, which could complement the chemoselectivity, and functional group tolerance restricted in the classical 2e- ion reaction, has never been achieved. Herein, we developed chemoselective catalytic activation of carboxylic acid equivalent, acylpyra-zole, and carboxylic acid for a 1e- radical process without external addition of stoichiometric amounts of Brønsted base. The present chemoselective catalysis could be applied to late-stage α-amination and oxidation, allowing for concise access to highly versatile unnatural α-amino acid and hydroxy acid derivatives. Moreover, chemoselective α-functionalization of less reactive carboxylic acids was achieved over innately more reactive carbonyl functionalities.
For the construction of biaryl motifs, transition metal-catalyzed cross-coupling reactions have been established as a de facto standard. However, there still remains ample room for the development of new synthetic methodologies based on a completely different reaction mechanism which can provide a rapid access to unexplored biaryl compounds. To this end, we have developed metal-free coupling reaction of aryl sulfoxides with phenols based on sigmatropic rearrangement to afford 2-hydroxy-2’-sulfanylbiaryls. Our method was successfully applied to the syntheses of intriguing aromatic molecules including oligoarenes by iterative arylations, a series of enantioenriched dihetero  helicenes, and polyfluorobiaryls. The method has further extended beyond the coupling of aryl sulfoxides and phenols: Phenols can be replaced with anilines and aryl sulfoxides with aryliodane, which provides 2-amino-2’-sulfanylbiaryls and 2-hydroxy-2’-iodobiaryls, respectively.
C-H functionalization has had significant attention in organic synthesis to streamline chemical processes of functional molecules. Efforts in the last two decades have allowed a variety of transformations, that had conventionally been performed with pre-functionalized compounds, to directly convert unfunctionalized C-H bonds to functional groups. A majority of these transformations, however, can be performed at limited sites in organic molecules. In the case of metal-catalyzed C-H functionalization, reaction sites of C-H functionalization are often controlled by directing groups, which coordinate to metals to bring the catalyst centers close to C-H bonds being transformed. Directing groups are often specially designed for certain C-H functionalization reactions, and they need additional steps for installation and uninstallation in addition to the C-H functionalizations. Such strategies limit the overall utility and efficiency of synthetic schemes involving C-H functionalization. It is highly desired that one can control the site-selectivity of C-H functionalization not by directing groups but by catalysts with compounds bearing common functional groups. We have taken advantages of catalytic Lewis-pair formations to electronically activate substrates and control the site-selectivity of transition metal-catalyzed C-H functionalization. In this article, C-C and C-B bond-forming reactions through C-H activation by cooperative transition metal/Lewis acid catalysis are described. Common Lewis acid catalysts derived from Zn, B, and Al are demonstrated to be highly efficient co-catalysts for Ni- and Ir-catalyzed arene C-H functionalization. Steric repulsion between the Lewis acids and Ni or Ir catalysts allows para-selective C-H functionalization, whereas ligands bearing such Lewis acid moieties are shown to be effective to control meta-selective C-H functionalization.
This account deals with the unstoichiometric Suzuki-Miyaura polycondensation of excess dibromoarylene 5 with arylenediboronic acid (ester) 6 in the presence of t-Bu3PPd precatalyst 7 and CsF/18-crown-6 as a base. Since t-Bu3PPd(0), generated from 7 with the assistance of base, has a propensity for intramolecular catalyst transfer on the π-electron face of aromatics, successive reaction of 5 with 2 equivalents of 6 takes place through intramolecular catalyst transfer of t-Bu3PPd(0) on 5, affording high-molecular-weight polymer, even though an excess of 5 is used. High-molecular-weight poly(tetraalkoxy-substituted stilbene), polyphenylene, polyfluorene, poly-(thiophene-alt-phenylene), poly(fluorene-alt-benzthiadiazole), poly(phenylene-alt-benzothiadiazle), poly(cyclopentadithiophene-alt-benzothiadiazole), and polyphenylene containing C≡C, N=N, CH2, CO, N-Bu, O, SO2 in the backbone have been obtained under this unstoichiometric condition. The obtained polymers have a boronic acid (ester) moiety at both ends, which can be converted to other functional groups by means of Suzuki-Miyaura coupling reaction with another reagent, oxidation, bromination, and so on. In the synthesis of poly(tetraalkoxy-substituted stilbene), the abnormal unstoichiometric polycondensation, affording high-molecular-weight polymer with a boronic acid ester moiety at both ends, can be switched to normal unstoichiometric polycondensation, affording low-molecular-weight polymer with bromine at both ends, simply by the addition of unsubstituted stilbene, which promotes intermolecular catalyst transfer due to catalyst trapping. When at least one of the two monomers has a kinked structure, such as m-dibromophenylene or m-phenylenediboronic acid (ester), many kinds of cyclic polymers can be selectively obtained even under unstoichiometric conditions.
Generally aluminum-containing molecules have been considered as a Lewis acid because of the existence of a vacant p-orbital on the Al atom. In contrast, chemistry of nucleophilic aluminum anion has been rapidly growing in the last three years. Since the first discovery of Lewis-base-stabilized diaminoaluminum anion in 2018, a variety of aluminum-centered anion has been reported. Due to the lone pair electrons on the Al atom, these species exhibited Brønsted and Lewis basicity. On the other hand, such Al anion can also be considered as Al(I) species having low oxidation state, being capable to undergo oxidation reactions. This mini-review focuses on the chemistry of nucleophilic aluminum anions with inclusion of all reported examples in the last three years.
Academically and industrially, the catalytic activation of neutral small molecules followed by the formation of C-C bonds is a highly important method to increase the complexity and/or value of simple starting materials. Traditionally, transition-metal catalysts have been used for this purpose, and these are still considered superior to catalysts based on main-group elements. However, catalytic transformation reactions of neutral small organic molecules in the absence of a transition-metal catalyst remain largely unknown, although such “transition-metal-free” catalytic systems would be highly desirable in order to avoid the use of precious metals. Herein, we will reported the isolation of the stable digermyne with a Ge-Ge triple bond, and demonstrated its high susceptibility to [2+2+2]cycloadditions in the presence of two molecules of alkynes to afford the corresponding 1,2-digermabenzenes. We have since discovered that the reaction of the digermyne with three equivalents of an arylacetylene exclusively affords the corresponding 1,2,4-triarylbenzene derivatives. Finally, we were able to demonstrate that a substoichiometric amount of the digermyne promotes the regioselective cyclotrimerization of several arylacetylenes in high yield. Our results demonstrate that bespoke main-group-element compounds can catalytically activate small neutral organic molecules and induce the formation of C-C bonds. The development of such main-group-element catalysts should represent a highly attractive addition to the toolkit of catalytic coupling reactions, and hopefully improve catalytic efficiency and selectivity under concomitant reduction of the consumption of precious-metal resources.
The development of “selective” reaction catalysts has considerable research interest in synthesizing fine chemicals and bioactive compounds. We have developed four types of solid-state heterogeneous palladium catalysts immobilized on cellulose particles (CLP), monolithic cellulose (CLM), and monolithic silica particles (SM), 5% Pd/CLP, 5% Pd/CLM, 5% Pd/SM, and 0.25% Pd/SM(sc) [sc: supercritical], for chemoselective hydrogenation under batch and continuous-flow reaction conditions. These four catalysts indicate novel chemoselectivity toward hydrogenations based on the structure of supports and immobilization methods, even using the same techniques or materials. 5% Pd/CLM, 5% Pd/SM, and 0.25% Pd/SM(sc)-packed catalyst cartridges for continuous-flow hydrogenation were also developed as efficiently utilizing the monolithic structure of the solid-state catalysts. The continuous-flow system using such catalysts could achieve high productivities of the hydrogenated products. Furthermore, the tertiary amine-functionalized basic anion exchange resin WA30, as a solid-state organocatalyst, catalyzed synthesis of site-selectively deuterium-labeled β-nitroalcohols have been developed under both batch and continuous-flow conditions. The WA30-catalyzed deuteration of nitromethane in deuterium oxide and the subsequent nitroaldol reaction proceeded to provide the bis-deuterium-labeled β-nitroalcohols in high yields and high deuterium contents. The WA30-packed catalyst cartridge can be applied in continuous synthesis for at least 72 h without degradation of the catalyst activity.
Organic synthesis is an essential technology to create functional materials such as pharmaceuticals, plastics and electronics materials, and has enriched our lives. Recently chemicals having more complicated structure have been required to realize sophisticated materials. Chemoselective reaction is one of the most important tools for synthesizing such complicated compounds and is achieved by optimizing reaction conditions, using appropriate reagents, utilizing difference of reaction rate and so on. When we utilize the difference of reaction rate, chemoselectivity was sometimes not enough in macro batch system because a volume of reaction system is large and heat and mass transfers are not efficient. On the other hand, microreactors have small reaction space and heat and mass transfer become more efficient. Thus better chemoselectivity according to reaction kinetics can be accomplished. In this review, we explained the reason why heat and mass transfer were more efficient in microreactor than in macro batch system. Then, examples of chemoselective reactions using microreactors were introduced. Finally, one-flow and multi-step reactions by integrating of microreactors were also introduced.
In recent years, solvent-less mechanochemical organic reactions using ball milling have come to the forefront of organic synthesis as cleaner and sustainable synthetic alternatives to conventional solution-based approaches. Apart from the environmental benefits, mechanochemical approaches potentially enable access to novel chemical space that has reactivities and selectivities different from those of conventional solution-based reactions. In this context, we have focused on the development of new solid-state organic transformations using mechanochemistry. We recently succeeded in developing broadly applicable solid-state palladium-catalyzed cross-coupling reactions under mechanochemical conditions. The key finding of these studies is that alkene additives can cat as dispersants for the palladium-based catalyst and also as stabilizer for the active monomeric palladium(0) species, thus facilitating these challenging solid-state bond forming reactions. In addition, we have discovered a conceptually new redox system, in which electrons are transferred from distorted piezoelectric materials in the solid-state to trigger organic transformations. This ‘mechanoredox’ system represents a unique solid-state approach that is complementary to photoredox reactions in solution.