Chiral Amino Acid Derivatives Research Articles

Second-Generation Chiral Amino Acid Derivatives Afford High Stereoselectivity and Stability in Aqueous RNA Acylation.

Activated acyl species have proven versatile in the esterification of 2'-OH groups in RNA, enabling structure mapping, caging, profiling, and labeling of the biopolymer. Nearly all reagents developed for this reaction have been achiral; however, a recent study reported that simple chiral amino acid acylimidazole derivatives could yield diastereoselective reactions at RNA 2'-OH in water, enabling up to 4:1 selectivity in screening. Here, we investigated the effect of steric bulk on the stereoselectivity of RNA reaction and on the stability of adducts with a library of 36 chiral acylimidazole scaffolds with increasing steric demand. The results document the highest stereoselectivity yet achieved in RNA acylation reactions, with as high as >99:1 diastereoselectivity at >70% conversion. Also notably, the bulky adducts were found to have markedly improved stability on RNA.

Cu-catalyzed asymmetric regiodivergent electrosynthesis and its application in the enantioselective total synthesis of (-)-fumimycin

Quaternary amino acids are one of the essential building blocks and precursors of medicinally important compounds. Various synthetic strategies towards their synthesis have been reported. On the other hand, developing core-structure-oriented cross-dehydrogenative coupling (CDC) reactions, is a largely unsolved problem. Herein, we describe a copper-catalyzed regiodivergent electrochemical CDC reaction of Schiff bases and commercially available hydroquinones to obtain three classes of chiral quaternary amino acid derivatives for the efficient assembly of complex scaffolds with excellent stereocontrol. The electrochemical anodic oxidation process with slow releasing of quinones serves as an internal syringe pump and provides high levels of reaction efficiency and enantiomeric control. The utility of this strategy is highlighted through the synthetic utility in the asymmetric total synthesis of (-)-fumimycin.

Sugar-Assisted Kinetic Resolutions in Metal/Chiral Amine Co-Catalyzed α-Allylations and [4+2] Cycloadditions: Highly Enantioselective Synthesis of Sugar and Chromane Derivatives.

Functionalized triose-, furanose and chromane-derivatives were synthesized by the titled reactions. The sugar-assisted kinetic resolution/C-C bond-forming cascade processes generate a functionalized sugar derivative with a quaternary stereocenter in a highly enantioselective fashion (up to >99 % ee) by using a simple combination of metal and chiral amine co-catalysts. Notably, the interplay between the chiral sugar substrate and the chiral amino acid derivative allowed for the construction of a functionalized sugar product with high enantioselectivity (up to 99 %) also when using a combination of racemic amine catalyst (0 % ee) and metal catalyst.

A Photoinduced Palladium-Catalyzed Cascade Reaction for the Synthesis of Chiral Piperidines with Chiral Amino Acid Derivatives and 1,3-Dienes

AbstractA photoinduced palladium-catalyzed cascade reaction involving remote C(sp3)–H functionalization and intramolecular Tsuji–Trost annulation is developed. The reaction is proposed to proceed through a sequence involving the amidyl radical generation, 1,5-HAT-mediated alkyl radical formation, and subsequent difunctionalization of 1,3-dienes. Without the use of exogeneous photosensitizers and external oxidants, the reaction provided an efficient approach to multi-substituted chiral piperidines in high yields, employing readily available chiral amino acid derivatives and 1,3-dienes as the substrates. In most cases, the syn/anti ratio of the product could be further improved by treatment with catalytic amount of iron salt.

Front Cover: Polystyrene‐Supported Aminocatalyst Derived from Diarylprolinol for Asymmetric α‐Amination of Aldehydes (Eur. J. Org. Chem. 21/2023)

The Front Cover illustrates the natural environment that needs to be protected by following the principles of 3Rs (Reduce, Reuse, and Recycle). The background of the picture shows our institute's riverfront, where a reusable polymer-supported aminocatalyst was developed for the sustainable synthesis of chiral amino acid derivatives. Cover design by Ms. Gayathri Chandrakumar. More information can be found in the Research Article by C. Appayee et al.

Gram‐Scale Synthesis of Chain‐Deuterated Sphingosine and Its Derivatization to Produce Ceramide, Sphinganine and Sphingosine‐1‐phosphate

AbstractSphingosine plays crucial roles in various cellular functions. Deuterated molecules are widely used as the important tools to explore the structure, property, and function of biochemical materials. We here report a gram‐scale synthesis of sphingosines with different deuterated chains. The synthesis started from different protiated fatty acids, which underwent hydrothermal platinum‐catalyzed hydrogen/deuterium (H/D) exchange to produce the deuterated chains with different length. The Horner–Wadsworth–Emmons (HWE) coupling of a chiral amino acid derivative with the deuterated chains generated the unsaturated ketone precursors. The following stereoselective reduction via cyclic Felkin–Anh transition led to the desired anti‐amino alcohol geometry. This efficient protocol enabled the gram‐scale synthesis of the chain‐deuterated sphingosines. The subsequent synthesis of the chain‐deuterated derivatives, i. e. ceramide, sphinganine and sphingosine‐1‐phosphate, is also described. Their deuterium content was simultaneously characterized by 1H NMR and high‐resolution mass spectrum (HRMS).

Locally Rotated Chiral Molecular Tiara with Reversible CPL Emissions

AbstractChiroptical materials capable of emitting circularly polarized luminescence (CPL) have been gaining intensive interest for their wide applications in fields of materials. In this work, a locally rotated molecular tiara Py5P5, in which five bulky pyrene units locate at one rim of Py5P5, and five small methoxy groups at the other, is designed. The planar chiral skeleton of Py5P5 can make five pyrene units being ordered in asymmetrical manner to arise the CPL emission from pyrene excimer, and the small methoxy groups rim in the other can ensure the interconversion between pR‐ and pS‐conformers of Py5P5 freely via local rotation. Thus, both left‐handed and right‐handed CPL may emit from pyrene units of Py5P5 stacked in the asymmetrical order with a high |glum| up to 1.28 × 10−3 under the induction of chiral amino acid derivatives. It is the first observation that both right‐handed and left‐handed CPL from pyrene excimer can be arisen from a single molecule by adding the simple chiral guests.

Design of Photoredox-Catalyzed Giese-Type Reaction for the Synthesis of Chiral Quaternary α-Aryl Amino Acid Derivatives via Clayden Rearrangement.

Chiral quaternary α-aryl amino acids are biologically valued but synthetically challenging building blocks. Herein, we report a strategy for the synthesis of molecular architectures by unifying a photoredox catalytic asymmetric Giese-type reaction and Clayden rearrangement. A new class of chiral Karady-Beckwith dehydroalanines is designed and serves as a versatile handle for the photoredox-mediated highly stereoselective Giese-type reaction with feedstock carboxylic acids and tertiary amines. Subsequent Clayden rearrangement delivers chiral quaternary α-aryl amino acid derivatives with high stereoselectivity. The versatile approach offers a reliable source for the assembly of highly demanding chiral building blocks.

Phosphine oxide directing-group-enabled atroposelective C–H bond acyloxylation via an eight-membered palladacycle intermediate

Herein, we report the first atroposelective C(sp2)–H bond acyloxylation enabled by a phosphine oxide directing group. Uniquely, this transformation is shown to proceed through an eight-membered palladacycle intermediate, as opposed to the kinetically and thermodynamically favored five-membered palladacycle intermediate. Additionally, l-pGlu-OH, a cheap and abundant chiral amino acid derivative, was identified as the best chiral ligand to promote this atroposelective remote CH functionalization reaction.

Asymmetric Ruthenium-Catalyzed Hydroalkylation of Racemic Allylic Alcohols for the Synthesis of Chiral Amino Acid Derivatives.

The asymmetric hydroalkylation of racemic allylic alcohols has been developed for the synthesis of chiral amino acid derivatives with two remote chiral centers by borrowing hydrogen catalysis. The stereoselectivities are controlled by a single chiral Ru catalyst via a dynamic kinetic asymmetric transformation process and an interesting diastereoselectivity amplification process of the product. The method could be used for the synthesis of several types of biologically important molecules, including stereodivergent synthesis of chiral pyrrolidine derivatives.

Asymmetric Ruthenium‐Catalyzed Hydroalkylation of Racemic Allylic Alcohols for the Synthesis of Chiral Amino Acid Derivatives

AbstractThe asymmetric hydroalkylation of racemic allylic alcohols has been developed for the synthesis of chiral amino acid derivatives with two remote chiral centers by borrowing hydrogen catalysis. The stereoselectivities are controlled by a single chiral Ru catalyst via a dynamic kinetic asymmetric transformation process and an interesting diastereoselectivity amplification process of the product. The method could be used for the synthesis of several types of biologically important molecules, including stereodivergent synthesis of chiral pyrrolidine derivatives.

Chiral Bicyclic Imidazole-Catalyzed Direct Enantioselective C -Acetylation of Indolones

Chiral Bicyclic Imidazole-Catalyzed Direct Enantioselective <i>C</i> -Acetylation of Indolones

Construction of a quaternary stereogenic center by asymmetric hydroformylation: a straightforward method to prepare chiral α-quaternary amino acids.

The construction of chiral quaternary carbon stereocenters has been a long-standing challenge in organic chemistry. Particularly, α-quaternary amino acids that are of high importance in biochemistry still lack a straightforward synthetic method. We here reported a hydroformylation approach to access chiral quaternary stereogenic centers, which has been a long-standing challenge in transition metal catalysis. α,β-Unsaturated carboxylic acid derivatives undergo hydroformylation with a rhodium catalyst to generate an α-quaternary stereocenter under mild conditions. By using this method, a variety of chiral α-quaternary amino acids could be synthesized with satisfactory enantioselectivity. In-depth investigation revealed that the regioselectivity is dramatically influenced by the electronic properties of the substituents attached to the target C Created by potrace 1.16, written by Peter Selinger 2001-2019 ]]> C bond. By applying NMR and DFT analyses, the chiral environment of a rhodium/Yanphos complex was depicted, based on which a substrate-catalyst interaction model was proposed.

Copper-catalyzed asymmetric propargylic substitution with salicylaldehyde-derived imine esters.

Copper-catalyzed asymmetric propargylic substitution with salicylaldehyde-derived imine esters and propargylic carbonates has been successfully realized, generating a wide range of chiral amino acid derivatives containing propargylic groups with excellent results (up to 95% yield and 94% ee). The ortho-hydroxy group of the salicylaldehyde-derived imine esters is crucial to increase the reactivity and stabilize the azomethine ylide, which may be due to the formation of an intramolecular hydrogen bond between the hydroxyl group and the imine group. A series of synthetic transformations were carried out to access other important chiral compounds, which displayed the synthetic versatility.

Iridium-catalyzed asymmetric double allylic alkylation of azlactone: efficient access to chiral α-amino acid derivatives.

An unprecedented Ir-catalyzed enantioselective double allylic alkylation of less bulky cyclic imine glycinate (azlactone) was rationally designed and developed, providing various bisallylated chiral amino acid derivatives. Control experiments revealed that this transformation proceeds in a sequential manner featuring quasi-dynamic kinetic resolution of the initially-formed monoallylation intermediates.

Expanding the Protecting Group Scope for the Carbonyl Olefin Metathesis Approach to 2,5-Dihydropyrroles.

Chiral pyrrolidine derivatives are important building blocks for natural product synthesis. Carbonyl olefin metathesis has recently emerged as a powerful tool for the construction of such building blocks from chiral amino acid derivatives. Here, we demonstrate that the supramolecular resorcinarene catalyst enables access to chiral 2,5-dihydropyrroles under Brønsted acid catalysis. Moreover, this catalytic system even tolerated Lewis-basic-protecting groups like mesylates that are not compatible with alternative catalysts. As expected for conversion inside a closed cavity, the product yield and selectivity depended on the size of the substrates.

Directed evolution of formate dehydrogenase and its application in the biosynthesis of L-phenylglycine from phenylglyoxylic acid

Formate dehydrogenase (FDH) is a d-2‑hydroxy acid dehydrogenase, and catalyzes the oxidation of formate to carbon dioxide, coupled with reduction of NAD+ to NADH that plays a key role in the process of NADH regeneration. In order to obtain high activity formate dehydrogenase mutants, the formate dehydrogenase CbFDHC23S was used as the parent to conduct two rounds of directed evolution, and a mutant M2 was obtained which specific activity was about 4 times more than the parent and was more suitable for coenzyme regeneration under physiological conditions. Then, the molecular mechanism of temperature characteristic and catalytic efficiency change was preliminarily elucidated by computer-aided method. Finally, an engineered E. coli strain was established to co-express formate dehydrogenase and l-leucine dehydrogenase and enantioselectively transform phenylglyoxylic acid to give l- phenylglycine (e.e. >99%), the yield and space-time yield of l- phenylglycine can reach 90.46% and 82.07 g·L−1·d−1. This study laid a theoretical foundation for the green biosynthesis of food additives such as chiral alcohols and amino acid derivatives catalyzed by FDH coupling to enhance the regeneration capacity of NADH, reduce the regeneration cost of NADH, and achieve high efficiency and low cost.

A β-cyclodextrin covalent organic framework used as a chiral stationary phase for chiral separation in gas chromatography

Chiral covalent organic frameworks (CCOFs) featuring chirality, stability, and good porosity have attracted a considerable amount of attention due to their important applications, such as asymmetric catalysis, chiral separation, and chiral recognition. In this study, a β-cyclodextrin (β-CD) covalent organic framework (β-CD-COF) diluted with polysiloxane OV-1701 was explored as a novel chiral stationary phase (CSP) for gas chromatography (GC) separation of racemates. The β-CD-COF coated capillary column had excellent selectivity, not only for the separation of linear alkanes, linear alcohols, fatty acid methyl esters mixture, the Grob mixture and positional isomers, but also for the resolution of chiral compounds, including chiral alcohols, aldehydes, ethers, and amino acid derivatives. In addition, the β-CD-COF-coated capillary column presented good repeatability and reproducibility. This work indicated the great potential of the CCOFs coated capillary column for the chromatographic separation of enantiomers.

Symmetry breaking-induced double-strand helices in H-bonded coassembly.

Double-strand helical structures are important in information storage of biomacromolecules, while the artificial synthesis depends on chirality transfer from the molecular to supramolecular scale, and the synthesis through symmetry breaking has yet been accomplished. In this work, we present the multiple-constituent coassembly of a melamine derivative and an N-terminal aromatic amino acid into double helical nanoarchitectures via symmetry breaking. Multiple intramolecular H-bond formation between constituents played key roles in directing the formation of helical structures. Intertwining of single helices with identical helical parameters afforded double helical structures, benefiting from the uniformity and monodispersity of nanoarchitectures. With introduction of coded chiral amino acid derivatives as chiral sources, the handedness could be readily manipulated with exclusive correlation to the absolute chirality of amino acids. Molecular flexibility of the melamine derivative facilitates the propeller-shaped complex formation to afford helical columnar coassemblies and double helical structures. This work presents a rational control over the emergence and properties of double helical structures in multiple-constituent coassemblies through symmetry breaking, which provides an alternative method towards the synthesis of topological chiral composites and chiroptical materials.

Enantioselective Intermolecular Radical C-H Amination.

Radical reactions hold a number of inherent advantages in organic synthesis that may potentially impact the planning and practice for construction of organic molecules. However, the control of enantioselectivity in radical processes remains one of the longstanding challenges. While significant advances have recently been achieved in intramolecular radical reactions, the governing of asymmetric induction in intermolecular radical reactions still poses challenging issues. We herein report a catalytic approach that is highly effective for controlling enantioselectivity as well as reactivity of the intermolecular radical C-H amination of carboxylic acid esters with organic azides via Co(II)-based metalloradical catalysis (MRC). The key to the success lies in the catalyst development to maximize noncovalent attractive interactions through fine-tuning of the remote substituents of the D2-symmetric chiral amidoporphyrin ligand. This noncovalent interaction strategy presents a solution that may be generally applicable in controlling reactivity and enantioselectivity in intermolecular radical reactions. The Co(II)-catalyzed intermolecular C-H amination, which operates under mild conditions with the C-H substrate as the limiting reagent, exhibits a broad substrate scope with high chemoselectivity, providing effective access to valuable chiral amino acid derivatives with high enantioselectivities. Systematic mechanistic studies shed light into the working details of the underlying stepwise radical pathway for the Co(II)-based C-H amination.