Α-amino Esters Research Articles

Heteroannulation of Arynes with α-Amino Imides: Synthesis of 2,2-Disubstituted Indolin-3-ones and Application to the Enantioselective Total Synthesis of (+)-Hinckdentine A.

A novel heteroannulation reaction between α-amino imides and in situ generated arynes has been developed for the synthesis of 2,2-disubstituted indolin-3-ones. An enantioselective total synthesis of the marine alkaloid (+)-hinckdentine A was subsequently accomplished using this reaction as a key step. A catalytic enantioselective Michael addition of an α-aryl-α-isocyanoacetate to phenyl vinyl selenone was employed for the construction of the enantioenriched α-quaternary α-amino ester.

Comparing the fragmentation reactions of protonated cyclic indolyl α-amino esters in quadrupole/orbitrap and quadrupole time-of-flight mass spectrometers.

The comparative study of higher-energy collisional dissociation (HCD) and collision-induced dissociation (CID) mechanisms for protonated cyclic indolyl α-amino esters in quadrupole/orbitrap (Q/Orbitrap) and quadrupole time-of-flight (QTOF) mass spectrometers, respectively, is helpful to study the structures and properties of biologically active indole derivatives using tandem mass spectrometry (MS/MS) technology. HCD and CID experiments were carried out using electrospray ionization Q/Orbitrap MS and QTOFMS in positive ion mode, respectively. Only the labile hydrogens were exchanged with deuterium in hydrogen/deuterium exchange (HDX) experiments and only the aromatic indole C-H hydrogens were substituted with deuterium in regiospecific hydrogen-deuterium labeling experiments. Theoretical calculations were carried out using the density functional theory (DFT) method at the B3LYP level with the 6-311G(d,p) basis set in the Gaussian 03 package of programs. In Q/Orbitrap MS/MS, when the added proton on the N8 position of protonated cyclic indolyl α-amino esters migrated in a stepwise fashion to the C3 position via two sequential 1,4-H shifts, an ion-neutral complex INC1 of [protonated cyclic N-sulfonyl ketimino esters/indoles] was formed by a charge-directed heterolytic cleavage of the C3 -C10 bond, while an ion-neutral complex INC3 of [cyclic N-sulfonyl ketimino esters/protonated indoles] was formed when another labile hydrogen on the N8 position successively migrated to the C4 position. Direct decomposition of INC1 and INC3 resulted in protonated cyclic N-sulfonyl ketimino esters and protonated indoles, respectively, while proton transfer led to protonated indoles and protonated cyclic N-sulfonyl ketimino esters. The HDX reaction with residual water in the HCD cell was also observed. In QTOF-MS/MS, protonated cyclic N-sulfonyl ketimino esters and protonated indoles resulted from direct decomposition of INC1 and INC3 , respectively, rather than proton transfer. Due to the specific construction of the Q/Orbitrap and QTOF mass spectrometers, different fragmentation mechanisms medicated by ion-neutral complexes of protonated cyclic indolyl α-amino esters were proposed. This study is desirable for qualitative and quantitive investigation of indole derivatives using MS/MS technology.

Memory of Chirality Concept in Asymmetric Intermolecular Michael Addition of α-Amino Ester Enolates to Enones and Nitroalkenes

A highly stereoselective asymmetric intermolecular conjugate addition of α-amino ester derivatives to cyclic enones via the memory of chirality (MOC) concept in high yields with excellent diastereo- and enantioselectivity (dr >99:1, up to 99% ee) is reported. The applicability and the generality of the strategy was demonstrated by its further exploration to acyclic α,β-unsaturated ketone and aromatic nitroalkenes, resulting in the formation of δ-keto-α-amino ester derivative and γ-nitro-α-amino ester derivatives, respectively, with excellent ee and dr.

Phospholyl(borane) Amino Acids and Peptides: Stereoselective Synthesis and Fluorescent Properties with Large Stokes Shift.

The synthesis of phospholyl(borane) amino acids was stereoselectively achieved by reaction of phospholide anion with iodo α-amino ester derived from l-aspartic acid or l-serine, followed by in situ complexation with borane. Phospholyl(borane) amino acids are easy to store and can be subjected to direct transformation into the corresponding free phospholyl, gold complex, oxide or sulfur derivatives as well as phospholinium salts, thus offering a variety of side chains. After selective deprotection of carboxylic function or amine, C- or N- peptide coupling with an alanine moiety proved the possible incorporation into peptides. Such phospholyl amino acid and peptide derivatives exhibit fluorescent properties with a large Stokes shift (160 nm) and fluorescence up to 535 nm, depending on the phosphole aromaticity and the chemical environment. These phospholyl(borane) amino acids constitute a new class of unnatural amino acids useful for structure-activities relationship studies and appear to be promising fluorophores for the development of labeled peptides.

An Old Story in the Parallel Synthesis World: An Approach to Hydantoin Libraries.

An approach to the parallel synthesis of hydantoin libraries by reaction of in situ generated 2,2,2-trifluoroethylcarbamates and α-amino esters was developed. To demonstrate utility of the method, a library of 1158 hydantoins designed according to the lead-likeness criteria (MW 200-350, cLogP 1-3) was prepared. The success rate of the method was analyzed as a function of physicochemical parameters of the products, and it was found that the method can be considered as a tool for lead-oriented synthesis. A hydantoin-bearing submicromolar primary hit acting as an Aurora kinase A inhibitor was discovered with a combination of rational design, parallel synthesis using the procedures developed, in silico and in vitro screenings.

Chiral trans-carboxylic trifluoromethyl 2-imidazolines by a Ag2O-catalyzed Mannich-type reaction

Trifluoromethyl aldimines derived from α-amino esters have proven to be very good starting materials to obtain the title compounds. A Ag2O-catalyzed Mannich-type/cyclization cascade reaction starting from suitable α-isocyano acetates leads to enantiopure valuable trans-carboxylic trifluoromethyl substituted 2-imidazolines by a highly stereoselective addition without the need to add organocatalysts.

From Molecules to Silicon-Based Biohybrid Materials by Ball Milling

Hybrid nanoparticles with a large bridging organic group were prepared by mechanochemical-assisted sol–gel reaction. Planetary ball mill (PBM) was used for the first time to access the bis-silylated precursors, containing complex functionalities (such as hydantoins or a symmetrical urea obtained from α-amino esters). The process is based on a sequential reaction pathway involving liquid-assisted grinding (LAG) and 1,1′-carbonyldimidazole (CDI)-mediated one-pot/two-step reactions. Then hydantoins and the symmetric urea were used for the one-pot preparation of the corresponding bis-silylated compounds in a vibrational ball mill (VBM), followed by the mechanochemical sol–gel preparation of biohybrid bridged silsesquioxane nanospheres of uniform size.

Phosphine-Catalyzed Asymmetric Synthesis of α-Quaternary Amine via Umpolung γ-Addition of Ketimines to Allenoates.

A first phosphine-catalyzed enantioselective umpolung γ-addition of ketimines to allenoates has been developed that provides efficient access to optically active γ,δ-unsaturated α-amino esters and δ-amino esters with a chiral tertiary stereocenter under mild conditions. The salient features of this reaction include general substrate scope, mild conditions, good yields, high enantioselectivity, ease of scale-up to gram scale, and further transformations.

A short synthesis of 3-enoyltetramic acids employing a new acyl ylide conjugate of Meldrum’s acid

2,2-Dimethyl-5-(triphenylphosphoranylidene)acetyl-1,3-dioxan-4,6-dione (3) is a new activated β-ketoacyl equivalent, readily prepared in quantitative yield by reaction of Meldrum’s acid with the stable ylide Ph3PCCO. Its reaction with α-amino esters affords the corresponding N-(β-ketoacyl)amino ester ylides which, when treated with aldehydes and KOtBu, undergo a simultaneous Wittig olefination cum Dieckmann cyclisation to yield the respective 3-enoyltetramic acids.

Co-Catalyzed C(sp3)-H Oxidative Coupling of Glycine and Peptide Derivatives.

Cobalt-catalyzed selective α-alkylation and α-heteroarylation processes of α-amino esters and peptide derivatives are described. These cross-dehydrogenative reactions occur under mild conditions and allow for the rapid assembly of structurally diverse α-amino carbonyl compounds. Unlike enolate chemistry, these methods are distinguished by their site-specificity, occur without racemization of the existing chiral centers, and exhibit total selectivity for aryl glycine motifs over other amino acid units, hence providing ample opportunities for peptide modifications.

Designing Pd-N-Heterocyclic Carbene Complexes for High Reactivity and Selectivity for Cross-Coupling Applications.

Over the past decade, the use of Pd-NHC complexes in cross-coupling applications has blossomed, and reactions that were either not previously possible or possible only under very forcing conditions (e.g., > 100 °C, strong base) are now feasible under mild conditions (e.g., room temperature, weak base). Access to tools such as computational chemistry has facilitated a much greater mechanistic understanding of catalytic cycles, which has enabled the design of new NHC ligands and accelerated advances in cross-coupling. With these elements of rational design, highly reactive Pd-NHC complexes have been invented to catalyze the selective formation of single products in a variety of transformations that have the potential to afford multiple compounds (e.g., isomers). Pd-NHC catalysts may be prepared as stable Pd(II) precatalysts that are readily reduced to the active Pd(0) species in the presence of an organometallic cross-coupling partner or nucleophile possessing β-hydrogens. It has been found from computational and experimental results that Pd-NHC complexes bearing a single bulky NHC ligand are well-suited to tackle challenging cross-coupling reactions. N-Aryl-substituted imidazole-2-ylidenes with branched alkyl chains at the ortho positions of the aryl group are effective for the challenging couplings of hindered biaryls, secondary alkyl organozincs, electron-deficient anilines, α-amino esters, primary alkylamines, and ammonia. The bulk of the NHC has been tuned by increasing the size of the alkyl groups at the ortho positions and substituting the NHC core with chlorine substituents. All of the cross-coupling transformations studied benefit from the increased bulk when the ortho groups are changed from methyl to 2-propyl to 3-pentyl. However, there is a limit to the positive effect of steric bulk, as some reactions do not benefit from the increased size of the 4-heptyl group compared with 3-pentyl. Thus, there is an optimum size for the NHC ligand that depends upon whether reactivity (turnover frequency and turnover number), selectivity, or both are needed to obtain the desired reaction outcome. In the cases that we have studied, reactivity and selectivity increase together (i.e., the fastest catalyst is also the most selective), allowing cross-couplings to be carried out under mild conditions to obtain one product with high selectivity. This Account focuses on seminal literature reports that have disclosed new Pd-NHC complexes that have led to significant breakthroughs in efficacy for challenging couplings while demonstrating high selectivity for the desired target. These catalysts have been used widely in materials science, pharmaceutical, and agrochemical applications.

Synthesis of α-Amino Esters via α-Nitro or α-Oxime Esters: A Review

This review is an in-depth survey of the reported synthetic approaches for the preparation of racemic α-amino esters via the reduction of α-nitro or α-oxime ester intermediates. Accordingly, it describes the many pathways that have been designed to prepare such intermediates­. This includes synthesis starting with α-nitroacetates, dialkyl malonates, acetoacetates, diethyl oxalates as well as [2+3] or [2+4] cycloadditions using, respectively, alkyl carbonocyanidate N-oxides or alkyl 2-nitrosoacrylates. This review also contains the description of a myriad of side reactions which can occur when working with α-nitro esters­.1 Introduction2 α-Amino Esters from α-Nitroacetates via Condensation Reactions3 α-Amino Esters via C-Alkylation or C-Arylation of α-Nitroacetates4 α-Amino Esters from α-Nitroacetates Using Other Reactions5 Synthesis of α-Amino Esters via α-Oxime Esters6 Synthesis of α-Amino Esters via [2+3] Cycloadditions7 Synthesis of α-Amino Esters via [2+4] Cycloadditions8 On the Reduction of α-Oxime Esters9 Conclusion

In Situ-Generated Glycinyl Chloroaminals for a One-Pot Synthesis of Non-proteinogenic α-Amino Esters.

An acetyl chloride-mediated cascade transformation involving a primary carbamate, ethyl glyoxylate, and various types of nucleophiles is reported for the synthesis of orthogonally protected α-amino esters. These reactions proceeded rapidly to afford the pivotal α-chloroglycine intermediate in excellent yields, which can be directly functionalized in situ with various types of nucleophiles. A mild and unique AcOH(cat.)/AcCl system was found to promote an autocatalytic-like condensation and facilitate the multicomponent assembly of non-proteinogenic α-amino esters. To better understand this one-pot transformation and the orchestration of the components' condensations, the investigation of a broader scope of nucleophiles and some kinetic studies are presented. Our findings suggest that the halogenation step toward the formation of α-chloroglycine is the rate-determining step likely proceeding through the formation of N-carbamoyl iminium. Also, the initial kinetic profiling for the nucleophilic substitution supports an SN1-like (SN2C+) mechanism in which nucleophiles add to the iminium-chloride tight ionic pair. These results lead ultimately to the design of a new protocol in which an achiral hydrogen bond donor thiourea catalyst was utilized to enhance the reaction scope and enable silylated nucleophiles to be efficiently exploited to synthesize novel non-proteinogenic α-amino esters.

Unified Synthesis of 1,2-Oxy-aminoarenes via a Bio-inspired Phenol-Amine Coupling

Summary 1,2-Aminophenols and their related nitrogen-containing heterocycles are ubiquitous in medicine, agriculture, and materials science. Here, we describe a bio-inspired and unified approach for their synthesis through a direct, catalytic aerobic coupling of phenols and amines. Key to the formation of the aromatic C–N bond is a facile condensation between the amine and an ortho -quinone, which triggers redox isomerization to an ortho -iminophenol before a series of downstream events. We discuss the factors that govern regioselectivity during aerobic ortho -oxygenation of the phenol and condensation of the amine, and we demonstrate synthetic utility by preparing a structurally diverse family of immunosuppressive heterocycles and the indole alkaloid cephalandole A. Our conditions involve a wide range of simple, un-activated substrates, occur at room temperature with an earth-abundant copper-catalyst and a commercially available diamine ligand, and produce water as the only stoichiometric by-product.

Nature Inspires an Aerobic Coupling of Phenol and Amine

In this issue of Chem , Lumb and colleagues report on an effective and simple catalytic system of copper and diamine ligands for the bio-inspired and unified synthesis of 1,2-aminophenols through direct aerobic phenol-amine coupling. Using this method, they prepared a structurally diverse family of 1,2-aminophenols and their derived heterocycles, including immunosuppressive benzoxazoles and the indole alkaloid cephalandole A.

Isothiourea-catalysed chemo- and enantioselective [2,3]-sigmatropic rearrangements of N,N-diallyl allylic ammonium ylides

The isothiourea-catalysed chemo- and enantioselective [2,3]-sigmatropic rearrangement of N,N-diallyl allylic ammonium ylides is explored as a key part of a route to free functionalised α-amino esters and piperidines. The [2,3]-sigmatropic rearrangement proceeds with excellent diastereo- and enantiocontrol (>95:5 dr, up to 97% ee), with the resultant N,N-diallyl α-amino esters undergoing either mono- or bis-N-allyl deprotection. Bis-N-allyl deprotection leads to free α-amino esters, while the mono-deprotection strategy has been utilized in the synthesis of a target functionalised piperidine.

Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals

Functional delivery of mRNA to tissues in the body is key to implementing fundamentally new and potentially transformative strategies for vaccination, protein replacement therapy, and genome editing, collectively affecting approaches for the prevention, detection, and treatment of disease. Broadly applicable tools for the efficient delivery of mRNA into cultured cells would advance many areas of research, and effective and safe in vivo mRNA delivery could fundamentally transform clinical practice. Here we report the step-economical synthesis and evaluation of a tunable and effective class of synthetic biodegradable materials: charge-altering releasable transporters (CARTs) for mRNA delivery into cells. CARTs are structurally unique and operate through an unprecedented mechanism, serving initially as oligo(α-amino ester) cations that complex, protect, and deliver mRNA and then change physical properties through a degradative, charge-neutralizing intramolecular rearrangement, leading to intracellular release of functional mRNA and highly efficient protein translation. With demonstrated utility in both cultured cells and animals, this mRNA delivery technology should be broadly applicable to numerous research and therapeutic applications.

Ni(ii)-Catalyzed enantioselective Mukaiyama–Mannich reaction between silyl enol ethers and cyclic N-sulfonyl α-ketiminoesters

The first Ni(ii)-catalyzed Mukaiyama–Mannich reaction of cyclic N-sulfonyl α-ketiminoesters with silyl enol ethers was realized and provided enantioenriched benzofused sultams containing a quaternary α-amino ester.

Chiral phosphoric acid catalyzed aza-Friedel-Crafts alkylation of indoles with cyclic aryl α-ketimino esters

A highly enantioselective aza-Friedel-Crafts alkylation of indoles with cyclic aryl α-ketimino esters catalyzed by a chiral phosphoric acid has been developed, the corresponding α,α-disubstituted unnatural α-amino ester derivatives were obtained in moderate to high yields (67–85%) with high enantioselectivities (up to 93% ee) under mild reaction conditions.

α-Azido Esters in Depsipeptide Synthesis: C–O Bond Cleavage during Azido Group Reduction

α-Azido esters, when treated with dithiothreitol (DTT)/diisopropylethylamine (DIPEA), undergo both azido group reduction to give α-amino esters and C-O bond cleavage to give triazoles. The extent of triazole formation depends upon leaving group ability. Some C-O bond cleavage via triazole formation was also found to occur when a resin-bound peptide, which contained a terminal α-azido ester group, was treated with DTT/DIPEA. C-O bond cleavage also took place when this peptide was treated with PPh3, PBu3, or PMe3; however, in these cases, C-O bond cleavage occurred via either triazole formation and/or hydrolysis of the ester bond in the iminophosphorane intermediate to give betaines. The mechanism that dominated for C-O bond cleavage depended upon the phosphine that was used for azido group reduction. C-O bond cleavage during reduction of the azido group in the peptide was minimized by performing the reduction with PBu3 in the presence of a symmetric anhydride derived from an amino acid in dry THF followed by the addition of water. Surprisingly, these conditions provided the amine as the major product, while the expected amide was formed as a minor product. These conditions were employed in an improved synthesis of an analogue of the cyclic lipodepsipeptide antibiotic daptomycin.