Glycine Schiff Base Research Articles

Copper-Catalyzed Direct Asymmetric Aldol Reaction of Glycine Schiff Bases to Access syn-β-Hydroxy-α-amino Esters.

This study reported a copper-catalyzed direct asymmetric aldol reaction between aldehydes and glycine Schiff bases with methyl, allyl, and tert-butyl esters. Additionally, this reaction afforded high yields of syn-β-hydroxy-α-amino esters with excellent enantio- and diastereoselectivities (93-99% ee, up to >99:1 dr). The aldol reaction accepted aromatic, linear aliphatic, and α-substituted aliphatic aldehydes.

Determination of pKa of the methylene moiety of the Ni(II) complexed glycine Schiff base with N-(2-benzoyl-4-chlorophenyl)-2-dibutylamino-acetamide by spectroscopic methods in non-aqueous conditions

The C-H substitution of the methylene moiety of glycine in nickel(II) glycine Schiff bases has proven useful for the preparation of a variety of α-amino acids. Recently, it has been shown that the integration of electron withdrawing groups into the ligand system of these nickel(II) complexes enhances their reactivity. It is hypothesized that this enhanced reactivity is, in part, due to decreased pKa of the α-proton of glycine due to delocalization of the resulting charge. However, there is a lack information or direct evidence of the relationship between the pKa of the α-protons of glycine in these complexes and perturbation of the electronic system of the ligand in the literature. Therefore, to better understand the observed reactivity, a method to determine the pKa of these complexes in non-aqueous solvent conditions is needed. In this work, the method and data analysis to find the pKa of the Ni(II) complex of glycine Schiff base with N-(2-benzyoly-4-chlorophenyl)-2-dibutylamino-acetamide is described.

α‐Alkylation of Mono‐Carbonyl Compounds with N‐Allylamines through Cooperative Actions of Lewis Acids and a Brønsted Base

AbstractWe present a strategy for the union of N‐allylamines and carbonyl compounds by the concerted action of B(C6F5)3 and a N‐based Brønsted base under redox‐neutral conditions. The reaction of in situ generated conjugated iminium ions and enolates affords δ‐aminocarbonyl compounds without waste generation. Furthermore, we describe that the cooperative action of B(C6F5)3, a chiral Zn‐based complex, and an amine facilitates the stereoselective reaction of a glycinate Schiff base ester and an N‐allylamine to afford an α‐substituted α‐amino ester.

Synthesis and Resolution of an Axially Chiral Spirocyclic Quaternary Ammonium Ion‐Based Phase‐Transfer Catalyst

AbstractWe report the synthesis of a novel spirocyclic quaternary ammonium salt that possesses axial chirality. Enantiopure material was obtained by fractional crystallization of the corresponding (R,R)‐tartrate salt. Application of this chiral quaternary ammonium salt in phase‐transfer catalytic asymmetric alkylation of glycinate Schiff base was examined.

Stereoselective synthesis of S-norvaline and related amino acids through a common intermediate.

A divergent, enantioselective synthetic strategy is reported to produce the non-proteinogenic, biologically active natural amino acids norvaline, 5-hydroxy-4-oxo-L-norvaline, and ɣ-oxonorvaline. These were synthesized in good yields (45-75%) from the common starting material (S)-allylglycine obtained by asymmetric transfer allylation of glycine Schiff base using the Corey catalyst derived from cinchonidine in more than 97% enantiomeric excess.

α,β-Dehydroamino Acid Synthesis through Proline-Catalyzed Aldol Condensation with a Glycine Schiff Base.

A general protocol for the synthesis of α,β-dehydroamino acids and their peptides was developed. Proline efficiently catalyzed an aldol condensation reaction of a glycine Schiff base with a variety of aldehydes. The hydroxy group on the benzophenone imine was crucial for high Z/E selectivity and further transimination for protecting group-free α,β-dehydroamino esters. Peptide elongation of both the C- and N-terminals highlighted the usefulness of our present protocol.

Isothiourea-Catalyzed Enantioselective Functionalisation of Glycine Schiff Base Aryl Esters via 1,6- and 1,4-Additions.

The enantioselective α-functionalisation of glycine Schiff base aryl esters through isothiourea catalysis is successfully demonstrated for 1,6-additions to para-quinone methides (21 examples, up to 95:5 dr and 96:4 er) and 1,4-additions to methylene substituted dicarbonyl or disulfonyl Michael acceptors (17 examples, up to 98:2 er). This nucleophilic organocatalysis approach gives access to a range of α-functionalised α-amino acid derivatives and further transformations of the activated aryl ester group provide a straightforward entry to advanced amino acid-based esters, amides or thioesters.

Synthesis and Catalytic Activity of Bifunctional Phase-Transfer Organocatalysts Based on Camphor.

Ten novel bifunctional quaternary ammonium salt phase-transfer organocatalysts were synthesized in four steps from (+)-camphor-derived 1,3-diamines. These quaternary ammonium salts contained either (thio)urea or squaramide hydrogen bond donor groups in combination with either trifluoroacetate or iodide as the counteranion. Their organocatalytic activity was evaluated in electrophilic heterofunctionalizations of β-keto esters and in the Michael addition of a glycine Schiff base with methyl acrylate. α-Fluorination and chlorination of β-keto esters proceeded with full conversion and low enantioselectivities (up to 29% ee). Similarly, the Michael addition of a glycine Schiff base with methyl acrylate proceeded with full conversion and up to 11% ee. The new catalysts have been fully characterized; the stereochemistry at the C-2 chiral center was unambiguously determined.

In Situ Generated DBU⋅HF Acts as a Fluorinating Agent in a Hexafluoroisobutylation Tandem Reaction: An Effective Route to 5,5,5,5’,5’,5’‐Hexafluoroleucine

AbstractWe report the direct incorporation of the hexafluoroisobutyl group on a chiral glycine Schiff base complex mediated by 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU). The fluoroalkylation involves 2‐(bromomethyl)‐1,1,1,3,3,3‐hexafluoropropane reagent, which generates in situ hexafluoroisobutylene (HFIB), and reacts then with the enolate through a tandem allylic shift/hydrofluorination process. We showed that the use of neutral organic base DBU generates in situ an original DBU⋅HF salt, which preserves the fluoride nucleophilicity and acts as a fluorinating agent. This fluoride salt promotes the hydrofluorination of the pentafluorinated alkene overcoming the usual fluoride β‐elimination observed with α‐CF3‐vinyl reagents. With alkali metal bases, by contrast, the hydrofluorination is disfavored and the pentafluorinated alkene intermediate is obtained predominantly. This study highlights the critical role of the fluoride counter ion to preserve its nucleophilicity. The protocol is amenable to multidecagram scale synthesis of enantiopure (S)‐ and (R)‐5,5,5,5’,5’,5’‐hexafluoroleucine and their N‐Fmoc or N‐Boc derivatives in good overall yield.

Mechanochemical generation of N,N-diglycated glycine and MS/MS characterization of its isomeric composition

The formation of Schiff bases and Amadori rearrangement products (ARP) during the Maillard reaction in solutions is well documented, but their studies in solid-state are limited. Here we report mass-spectrometric characterization of N,N-diglycated Schiff bases and Amadori products obtained during ball milling of amino acids and glucose. Signal intensities of the diglycated adducts in mass-spectra depended on type of the amino acid and the MS ionization mode. Glycine provided for the highest yields of N,N-diglycation, followed by lysine, when the reaction was analyzed under negative ionization mode. Using diagnostic MS/MS fragmentation, we were able to distinguish between Schiff-Schiff, Schiff-Amadori, or Amadori-Amadori isomers. Milling glucose/glycine model for 30 min at ambient temperature produced diglycated glycine as a mixture of the three possible isomers in approximately equal molar proportions. Milling of synthetic Schiff base or ARP of glycine with [U-13C]-glucose generated the same but partially labelled isomers, with respective predominance of N,N-diglucosyl-glycine or N,N-difructosyl-glycine.

Enantioselective Synthesis and Application of Small and Environmentally Sensitive Fluorescent Amino Acids for Probing Biological Interactions.

Environmentally sensitive fluorescent amino acids (FlAAs) have been used extensively to probe biological interactions. However, most of these amino acids are large and do not resemble amino acid side chains. Here, we report the enantioselective synthesis of two small and environmentally sensitive fluorescent amino acids bearing 7-dialkylaminocoumarin side chains by alkylation of a Ni(II) glycine Schiff base complex. These amino acids exhibit a large increase in fluorescence as environment polarity decreases. One of these FLAAs was incorporated into a highly active analog of the cyclic lipopeptide antibiotic paenibacterin by Fmoc solid-phase peptide synthesis via a new and very efficient route. This peptide was used to probe the interaction of the antibiotic with model liposomes, lipopolysaccharides, and live bacteria.

Aldol Addition-Cyclization Reaction Cascade on a Platform of Chiral Ni(II) Complex of Glycine Schiff Base

Using platform of a new type of chiral Ni(II) complex of glycine Schiff base we designed addition-cyclization reaction cascade to explore aspects of kinetic/thermodynamic formation of the corresponding (S)(2S,3S)/(S)(2S,3R) diastereomers. It was found that the final lactone products reflect the thermodynamic stereocontrol due to much greater rates of the reversible aldol addition vs. subsequent cyclization step. The observed 4/1 (S)(2S,3S)/(S)(2S,3R) diastereoselectivity in the reactions of new type of (S)-Ni(II) complexes constitute an improvement over the previously reported 1.7/1 ratio.

Asymmetric Synthesis of N‐Fmoc‐(S)‐7‐aza‐tryptophan via Alkylation of Chiral Nucleophilic Glycine Equivalent

AbstractNi(II)‐complexes, derived from glycine Schiff bases with chiral tridentate ligands, have been used as powerful tools for the synthesis of structurally diverse tailor‐made amino acids. In this manuscript, asymmetric alkylation reaction between chiral nucleophilic glycine derived Ni‐complex and 3‐(chloromethyl)‐1H‐pyrrolo[2,3‐b]pyridine has been developed under convenient conditions, which affords the corresponding alkylated Ni‐complex in 74 % yield and excellent diastereoselectivity (only one isomer). This reaction features convenient conditions and completely controlled diastereoselectivity, which provides a highly valuable approach for asymmetric synthesis of 7‐aza‐tryptophan.

Development of C2-Symmetric Chiral Spirocyclic Phase-Transfer Catalysts: Synthesis and Application to Asymmetric Alkylation of Glycinate Schiff Base.

A class of C2-symmetric chiral spirocyclic phase-transfer catalysts based on tetramethyl-1,1'-spirobiindane scaffold was synthesized from commercially available bisphenol A in 12 steps with 22-25% total yields, which features a more rigid and stable backbone and smaller dihedral angles and can be easily modified. These catalysts show high catalytic performance in the asymmetric alkylation of tert-butyl glycinate Schiff base at only 2 mol % catalyst loading, giving the target products with up to 92% yield and 98% ee.

A combined DFT and experimental study into the optoelectronic and charge transport properties of ninhydrin–glycine Schiff base complexes for efficient LED applications

A combined theoretical and experimental study has been performed on four synthesized Schiff base complexes derived from ninhydrin–glycine ligand (NG) with Co(II), Zn(II), Al(III) and Fe(III) metal cations. The FT-IR spectra clearly showed that the complexes behave as tridentate monobasic ONO donor ligand. Furthermore, the energy levels of HOMO, LUMO levels and band gap were determined using the Density Functional Theory (DFT). The experimental and theoretical optical investigation showed that the complexes have good absorption in visible region and blue emission with a maximum emission wavelength located at 436 nm, 471 nm and 478 nm for Co–NG, Zn–NG and Al–NG, respectively. Moreover, based on Marcus theories, we estimated the rate of electron and hole charge transfer. As a result, Al–NG complex has the better electron and hole transport than the other complexes with Ket = 4.10 × 1014 and Kht = 4.86 × 1014, respectively. Finally, to predict the possibility of introducing the studied complexes in light emitting diode (LED) devices, the electron and hole injection barriers were estimated. The found results are interesting which make the studied complexes potential candidates for LED application.

Lessons in Stereochemistry: Resolution, Synthesis, and Characterization of Chiral Compounds

This modular, open-framework capstone course delves deeply into the synthesis, separation, and characterization of chiral molecules while teaching critical thinking and writing skills in a research-like setting within a fertile area for discovery. This course has evolved over 30 years and has been in its present form for 5 years at the time of this writing. The studies described can be easily integrated into a curriculum with other related disciplines, including medicinal, synthetic, analytical, and physical chemistry. The first procedure introduces Pasteur’s classic resolution of (±)-α-phenylethylamine by cocrystallization with enantio-pure d-tartaric acid. The enantiomerically enriched α-phenylethylamine is then characterized using three different methods: polarimetry to measure [α]D, high-performance liquid chromatography (HPLC) with a chiral column to determine the enantiomeric ratio (e.r.), and by proton nuclear magnetic resonance (1H NMR) using a chiral shift reagent. In the second experiment, students carry out a stereoselective alkylation of a glycine Schiff base using a cinchonine-derived phase-transfer catalyst and methods first developed by O’Donnell and expanded on by many other chemists around the world. The students are encouraged to read the primary literature and design their own experiments with the guidance of the instructors and graduate student teaching assistants (TAs). In our course, the first experiment is described as a communication and the alkylation experiment is reported in the format of a full paper.

Synthesis of trifluoromethyl substituted nucleophilic glycine equivalents and the investigation of their potential for the preparation of α-amino acids

Abstract The synthetic preparation of several Ni(II) complexed Schiff Bases of glycine will be introduced, as well as investigations into their reactivity and utility. Key to these investigations is the incorporation of electron-withdrawing trifluoromethyl groups within the framework of the conjugated system that stabilizes the enolate derived from the glycine component. Reactivity was evaluated for each of the complexes under phase transfer catalyzed alkylations with hydroxide bases, as well as the DBU catalyzed Michael Additions of optically active 3′-substituted-2-oxazoladinone amides of unsaturated carboxylic acids. It was found that the trifluoromethyl containing nucleophilic glycine equivalents were more reactive than their non-trifluoromethyl analogues in both reaction types. Therefore, the application of these modified Ni(II) complexes of glycine Schiff Bases are useful for the preparation of α-amino acids through phase transfer catalyzed alkylation as well as the preparation of optically pure β-substituted pyroglutamic acid precursors.

A Computational and Numerical Studies of OLED Based on Ninhydrin–Glycine Schiff Base Complex

In this work, detailed experimental and theoretical studies are performed on the optoelectronic properties of a Schiff base complex derived from a ninhydrin–glycine (NG) ligand with Al (III) metal. The good functionality and experimental results were confirmed by simulations. The complex shows absorption in the visible range and a blue emission. Furthermore, the charge transport investigation showed that Al–NG has good and balanced hole and electron mobilities equal to 8.44 $\times \,\,10^{-6}$ cm $^{2}\,\,\text{V}^{-1}\,\,\text{s}^{-1}$ and 7.10 $\times \,\,10^{-6}$ cm $^{2}\,\,\text{V}^{-1}\,\,\text{s}^{-1}$ , respectively. The favorable properties make Al–NG complex a promising candidate for the development of organic light-emitting diode (OLED) applications. Using these interesting characteristics, a numerical simulation is performed to have the predictive behavior of indium tin oxide (ITO)/Al–NG/Al OLED device. Finally, we present the effect of thickness and temperature on the OLED electric characteristics.

Synthesis of Ahod Moiety of Ralstonin A Using Amino Acid Schiff Base Ni(II)‐Complex Chemistry

AbstractReported here is the asymmetric synthesis of N‐Boc‐protected (2S,3S)‐3‐amino‐2‐hydroxyoctadecanoic acid, a component of ralstonin A and ralstoamide A. Key synthetic steps include alkylation of chiral Ni(II) complex of glycine Schiff base, conversion of COOH to keto acid (CO−COOH) and reduction of the carbonyl group to generate α‐hydroxy functionality. The structure and absolute configuration of (2S,3S)‐N‐Boc‐3‐amino‐2‐hydroxyoctadecanoic acid was shown to be identical to that of the naturally occurring compound.

Palladium-catalyzed asymmetric allylic C-H alkylation of 1,4-dienes and glycine Schiff bases

A highly regio- and enantioselective allylic C–H alkylation of 1,4-dienes with glycine Schiff bases has been established by chiral palladium-phosphoramidite catalysis. This reaction can proceed under mild conditions and tolerate a wide scope of 1,4-dienes, delivering structurally diverse chiral β-branched α-amino acid surrogates in moderate to high yields and with high levels of regio-, Z / E -, diastereo- and enantioselectivities.