Sugar amino acids and related molecules: Some recent developments

To meet the growing demands for the development of new molecular entities for discovering new drugs and materials, organic chemists have started working on many new concepts that can help to assimilate knowledge-based structural diversities more efficiently than ever before. Emulating the basic principles followed by Nature to build its vast repertoire of biomolecules, organic chemists are developing many novel multifunctional building blocks and using them to create ‘nature-like’ and yet unnatural organic molecules. Sugar amino acids constitute an important class of such polyfunctional scaffolds where the carboxyl, amino and hydroxyl termini provide an excellent opportunity to organic chemists to create structural diversities akin to Nature’s molecular arsenal. In recent years, sugar amino acids have been used extensively in the area of peptidomimetic studies. Advances made in the area of combinatorial chemistry can provide the necessary technological support for rapid compilations of sugar amino acidbased libraries exploiting the diversities of their carbohydrate frameworks and well-developed solid-phase peptide synthesis methods. This perspective article chronicles some of the recent applications of various sugar amino acids, furan amino acids, pyrrole amino acids etc. and many other related building blocks in wide-ranging peptidomimetic studies     

Recent progress of sugar amino acids: Synthetic strategies and applications as glycomimetics and peptidomimetics

In order to meet the increasing demands for the development of large varieties of new molecules for discovering new drugs and materials, organic chemists are developing many novel multifunctional building blocks, which are assembled rationally to create ‘nature-like' and yet unnatural organic molecules with well-defined structures and useful properties. Sugar amino acids(SAAs), the carbohydrate derivatives bearing both amino and carboxylic acid functional groups, are important ones of these multifunctional building blocks, which can be used to create novel materials with potential applications as glycomimetics and peptidomimetics. This review will focus on recent synthetic strategies of SAAs and their applications in creating large number of structurally diverse glycomimetics and peptidomimetics.     

Synthesis of Nature‐Inspired Medium‐Sized Fused Heterocycles from Amino Acids

Herein, we describe the synthesis of molecular scaffolds consisting of medium‐sized fused heterocycles using amino acids, which are some of the most useful building blocks used by nature as well as chemists to create structural diversity. The acyclic precursors were assembled by using traditional Merrifield solid‐phase peptide synthesis, and cyclization was carried out through acid‐mediated tandem endocyclic N‐acyliminium ion formation, followed by nucleophilic addition with internal nucleophiles. The synthesis of molecular scaffolds consisting of seven‐, eight‐, and nine‐membered rings proceeded with full stereocontrol of the newly generated stereogenic center in most cases.     

Supramolecular Hydrogels Made of Basic Biological Building Blocks

As a consequence of the self‐assembly of small organic molecules in water, supramolecular hydrogels are evolving from serendipitous events during organic synthesis to become a new type of materials that hold promise for applications in biomedicine. In this Focus Review, we describe recent advances in the use of basic biological building blocks for creating molecules that act as hydrogelators and the potential applications of the corresponding hydrogels. After introducing the concept of supramolecular hydrogels and defining the scope of this review, we briefly describe the methods for making and characterizing supramolecular hydrogels. We then discuss representative hydrogelators according to the categories of their building blocks, such as amino acids, nucleobases, and saccharides, and highlight the applications of the hydrogels when necessary. Finally, we offer our perspective and outlook on this fast‐growing field at the interface of organic chemistry, materials, biology, and medicine. By providing a snapshot for chemists, engineers, and medical scientists, we hope that this Focus Review will contribute to the development of multidisciplinary research on supramolecular hydrogels for a wide range of applications in different fields.     

Calix [ 4 ] arene Polyaza Derivatives： Novel Effective Neutral Receptors for Cations and α-Amino Acids

IntroductionCalixarenes are one of the most important supra-molecular building blocks, which can be modified byintroducing different functional and/or structural groupsto create a specific interaction between the host and thetarget molecules, such as meta…     

Expanding the genetic code

Although chemists can synthesize virtually any small organic molecule, our ability to rationally manipulate the structures of proteins is quite limited, despite their involvement in virtually every life process. For most proteins, modifications are largely restricted to substitutions among the common 20 amino acids. Herein we describe recent advances that make it possible to add new building blocks to the genetic codes of both prokaryotic and eukaryotic organisms. Over 30 novel amino acids have been genetically encoded in response to unique triplet and quadruplet codons including fluorescent, photoreactive, and redox-active amino acids, glycosylated amino acids, and amino acids with keto, azido, acetylenic, and heavy-atom-containing side chains. By removing the limitations imposed by the existing 20 amino acid code, it should be possible to generate proteins and perhaps entire organisms with new or enhanced properties.     

Expanding the Genetic Code

Although chemists can synthesize virtually any small organic molecule, our ability to rationally manipulate the structures of proteins is quite limited, despite their involvement in virtually every life process. For most proteins, modifications are largely restricted to substitutions among the common 20 amino acids. Herein we describe recent advances that make it possible to add new building blocks to the genetic codes of both prokaryotic and eukaryotic organisms. Over 30 novel amino acids have been genetically encoded in response to unique triplet and quadruplet codons including fluorescent, photoreactive, and redox‐active amino acids, glycosylated amino acids, and amino acids with keto, azido, acetylenic, and heavy‐atom‐containing side chains. By removing the limitations imposed by the existing 20 amino acid code, it should be possible to generate proteins and perhaps entire organisms with new or enhanced properties.     

Differently Glycosidated 2‐Amino‐2‐deoxy‐d‐glucopyranosiduronic Acids as Building Blocks in Peptide Synthesis

Seven differently glycosidated sugar amino acids (SSAs) derived from glucosamine have been prepared. Following standard solution‐phase peptide‐coupling procedures, the glycosidated 2‐amino‐2‐deoxy‐D ‐glucopyranosiduronic acids were condensed with natural amino acids to furnish useful heterodi‐ and ‐trimeric building blocks to be used in peptide synthesis. Combinations of these building blocks yielded hetero‐oligomeric peptides with two sugar amino acid units in different distances to each other. These were prepared to evaluate the influence of glycosidic side chains on the peptide backbone. Conformations of selected examples were examined by means of ROESY spectroscopy in combination with molecular dynamics (MD) simulations and circular‐dichroism (CD) studies.     

From amino acids to heteroaromatics--thiopeptide antibiotics, nature's heterocyclic peptides

Amino acids, the building blocks of proteins, also serve as precursors to a wide range of other naturally occurring substances including alkaloids, antibiotics, and, the subject of this Review, heterocyclic peptides. Simple alpha-amino acids are converted into complex arrays of heteroaromatic rings that display interesting and potent biological activity. The thiopeptide antibiotics, with their complex molecular architectures, are wonderful examples. In this Review we show how organic chemists have developed innovative methods for the synthesis of the heterocyclic ring systems, including routes inspired by the likely biosynthetic processes, and successfully assembled such building blocks into the final target molecule by application of orthogonal protecting groups and coupling methodologies.     

Calix[4]arene Polyaza Derivatives: Novel Effective Neutral Receptors for Cations and (a)-Amino Acids

Introduction Calixarenes are one of the most important supramolecular building blocks, which can be modified by introducing different functional and/or structrual groups to create a specific interaction between the host and the target molecules, such as metal cations and small organic molecules[1,2]. In particular, the recognition of amino acids is an interesting theme in biomimetic chemistry[3].     

Facile access to α,β-dehydroalanine and α,β-dehydroamino butyric acid derivatives from DL-serines and threonines

Not only α,β-dehydroamino acids are important constituents for a number of bioactive peptides in nature, but also they are important building blocks for a variety of synthetic amino acids in organic synthesis. Methods to prepare dehydroamino acids have been reported extensively in the literature; however, efficient and convenient protocols are still required. Here we have developed a convenient method to prepare dehydroalanine (ΔAla) and dehydroamino butyric acid (ΔAbu) derivatives derived from DL-serines and DL-threonines, respectively. 4-Toluenesulfonyl chloride (TsCl) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were employed in this procedure, which carried out activation of hydroxyl group and β-elimination in one pot. Because it is convenient and easy to handle, this method will attract the attention of synthetic chemists.     

Novel ester linked glycosyl amino acids: convenient building blocks for the synthesis of glycopeptide libraries

The completely orthogonally protected aspartic acid derivative FmocAsp(OBn)O^tBu is readily synthesized on a large scale. Deprotection of the β-carboxylic acid allows coupling to various sugar derivatives via free hydroxyl groups to produce novel glycosyl amino acids. Subsequent deprotection of either the α-acid or nitrogen is achieved cleanly to allow elaboration into an oligopeptide, whilst selective deprotection of PMB protected sugar hydroxyls is also readily achievable. Such novel glycosyl amino acid building blocks may be useful for the combinatorial synthesis of novel glycopeptide libraries.     

Covalent organic frameworks

Covalent organic frameworks (COFs) are a class of crystalline porous polymers that allow the atomically precise integration of organic units to create predesigned skeletons and nanopores. They have recently emerged as a new molecular platform for designing promising organic materials for gas storage, catalysis, and optoelectronic applications. The reversibility of dynamic covalent reactions, diversity of building blocks, and geometry retention are three key factors involved in the reticular design and synthesis of COFs. This tutorial review describes the basic design concepts, the recent synthetic advancements and structural studies, and the frontiers of functional exploration.     

Organoselenium Chemistry in Stereoselective Reactions

Selenium-based methods have developed rapidly over the past few years asnd organoselenium chemistry has become a very useful tool in the hands of synthetic chemists. The different reactivity of selenium-containing compounds in contrast to the sulfur analogues has led to versatile and new synthetic methods in organic chemistry. Various functionalities can be selectively introduced into complex molecules under very mild reaction conditions. In this review, the principles of organoselenium chemistry are traced back to their origins and are highlighted with respect to stereoselective synthesis. The unique properties of selenium allow the development of new and highly selective transformations, which can be employed subsequently in new routes for the synthesis of versatile chiral building blocks and for natural product synthesis.     

Layered hydroxide hybrid nanostructures: a route to multifunctionality

Today, seeking new materials for tailor-made applications and new devices leads to explore the potential offered by various kinds of functional building blocks. Hence, it concerns not only solid-state chemists, physicists or materials engineers, but also the area of (supra)molecular chemistry, and biochemistry as well. This is especially clear in the field of hybrid multifunctional materials. Indeed, their design requires investigating new concepts derived from principles developed in these different disciplines. The aim of this critical review is to present the last achievements concerning transition metal hydroxide hybrids, their synthesis, flexibility and functional properties. They often provide nice model systems for understanding the correlation between structure and physical properties brought by the molecular moieties grafted onto the metal hydroxide basis layers. The contribution of the atomic scale modelling to the electronic structure calculations and structural optimization is also reported (216 references).     

Asymmetric Eschenmoser-Claisen rearrangement for anti-beta-substituted gamma,delta-unsaturated amino acids

Optically active anti-beta-substituted gamma,delta-unsaturated amino acids are important synthetic building blocks in organic synthesis and for peptidomimetics. A novel asymmetric Eschenmoser-Claisen rearrangement with use of a C2-symmetric chiral auxiliary was developed to generate this type of amino acid. Excellent diastereoselectivities and high enantioselectivities (87-93% ee) were obtained after the chiral auxiliary was removed via iodolactonization/zinc reduction.     

Adding a Functional Handle to Nature′s Building Blocks: The Asymmetric Synthesis of β‐Hydroxy‐α‐Amino Acids

β‐Hydroxy‐α‐amino acids are not only used by synthetic chemists but are also found in natural products, many of which show anti‐microbial or anti‐cancer properties. Over the past 30 years, chemists have searched for many asymmetric routes to these useful building blocks. Initial attempts to synthesize these compounds utilized chiral auxiliaries and the reactions of glycine equivalents with aldehydes to form two stereocenters in one step. Other methods with the formation of specific intermediates or that were aimed at a specific amino acid have also been investigated. Asymmetric hydrogenation by dynamic kinetic resolution has emerged as a high‐yielding method for the synthesis of an array of modified amino acids with good stereoselectivity. More recently, amino‐acid functionalization and multicomponent reactions have increased the atom economy and simplified many long and difficult routes. In this Focus Review, many of the elegant syntheses of these compounds are explored. The applications of β‐hydroxy‐α‐amino acids in natural‐product synthesis are also mentioned.     

Amphoteric α-boryl aldehydes

A new class of stable molecules, α-boryl aldehydes, has been prepared from oxiranyl N-methyliminodiacetyl boronates by a 1,2-boryl migration with concomitant epoxide scission. A range of boryl imines, alkenes, alcohols, acids, enol ethers, enamides, and other functionalized boronic acid derivatives that are difficult or impossible to prepare using established protocols can be accessed from α-boryl aldehydes. The chemoselective transformations of these building blocks, including the facile synthesis of functionalized unnatural amino acids from silyloxy and amido vinyl boronates, attest to the potential of α-boryl aldehydes in chemical synthesis.     

Solid-phase synthesis of new S-glycoamino acid building blocks

Efficient synthesis of unprotected S-glycoamino acid building blocks in the solid phase by coupling a sugar 1-thiolate with iodine activated fluoren-9-ylmethoxycarbonyl (Fmoc) protected amino acids.     

HFIP-Promoted de Novo Synthesis of Biologically Relevant Nonnatural α-Arylated Amino Esters and Dipeptide Mimetics

Amino acids are fundamental building blocks, which have been extensively used in drug design and organic synthesis. However, nonnatural amino acids are relatively less studied. In this work, the authors report the first HFIP-promoted de novo synthesis of nonnatural α-arylated amino esters and dipeptide mimetics (27 examples, up to 99 % yield) from readily available amines, ethyl glyoxylate and electron-rich arenes under mild conditions, in which one C−C bond, one C−N bond and one chiral center were established simultaneously. The reaction was also performed on a gram scale, giving compound 4 a in 96 % yield. In addition, this protocol was successfully applied to the late-stage elaboration of drug molecules, such as tranylcypromine (TCP or PCPA) and troxipide. Interestingly, compound 4 h inactivated histone lysine specific demethylase 1 (LSD1) potently with an IC₅₀ value of 0.296 μm . To the best of our knowledge, compound 4 h is the first LSD1 inhibitor derived from nonnatural α-arylated amino esters, and therefore could be used as a hit compound for the development of new LSD1 inhibitors. The synthesized nonnatural α-arylated amino esters and dipeptide mimetics as unique building blocks may have potential synthetic utilities.