N-protected Amino Research Articles

Nickel-Catalyzed O-Arylation of N-Protected Amino Alcohols with (Hetero)aryl Chlorides.

The aryloxyamine motif is a prominent pharmacophore in drug design and development. While these biologically relevant structures could in principle be sustainably assembled from the base metal-catalyzed O-arylation of inexpensive and abundant amino alcohols with (hetero)aryl chlorides, reports of such challenging C-O bond formations with useful scope are lacking. In response, we report herein the hitherto unknown Ni-catalyzed C-O cross-coupling of N-protected amino alcohols (primary, secondary, and tertiary) with (hetero)aryl chlorides. Also presented are chemoselective sequential/telescoped C-N and C-O cross-couplings of the unprotected amino alcohol prolinol to afford an unsymmetrical diarylated product.

Decarboxylative Cross-Coupling Enabled by Fe and Ni Metallaphotoredox Catalysis.

Decarboxylative cross-coupling of carboxylic acids and aryl halides has become a key transformation in organic synthesis to form C(sp2)-C(sp3) bonds. In this report, a base metal pairing between Fe and Ni has been developed with complementary reactivity to the well-established Ir and Ni metallaphotoredox reactions. Utilizing an inexpensive FeCl3 cocatalyst along with a pyridine carboxamidine Ni catalyst, a range of aryl iodides can be preferentially coupled to carboxylic acids over boronic acid esters, triflates, chlorides, and even bromides in high yields. Additionally, carboxylic acid derivatives containing heterocycles, N-protected amino acids, and protic functionality can be coupled in 23-96% yield with a range of sterically hindered, electron-rich, and electron-deficient aryl iodides. Preliminary catalytic and stoichiometric reactions support a mechanism in which Fe is responsible for the activation of carboxylic acid upon irradiation with light and a NiI alkyl intermediate is responsible for activation of the aryl iodide coupling partner followed by reductive elimination to generate product.

Rapid and practical synthesis of N-protected amino ketones in continuous flow via pre-deprotonation protocol

Rapid and practical synthesis of N-protected amino ketones in continuous flow via pre-deprotonation protocol

Ultrasound-accelerated Synthesis of N-protected Amino Alkyl Iodides from Amino Alcohols Using P2I4 Reagent and its Application in the Synthesis of Amino Alkyl Thiols

Abstract: Synthesis of amino acid-derived alkyl iodides results in versatile intermediates for many peptidomimetics, and hence, the approach for their synthesis under neutral conditions was achieved in the present work. : The N-protected amino acids were reduced to amino alcohols under T3P as an activator and NaBH4 as a reducing partner. Thus, synthesized aminols were sonicated with diphosphorus tetraiodide (P2I4) in CS2 to obtain the N-protected amino alkyliodides. : We established the utilisation of the alkyl iodides by converting them to amino alkyl thiols, which serve as building blocks for many heterocycles and other drug candidates. The ultrasonication medium works effectively for all the intermediates preparation; the conditions are mild, and yields are almost quantitative in all steps. : The synthesized compounds were characterized by 1H NMR, 13C NMR, and HRMS analysis.

TFAA mediated one-pot synthesis of chiral N-protected amino acid-derived 1,2,4-oxadiazoles and their antibacterial studies.

A scalable and environment-friendly one-pot two-component synthesis of chiral N-protected amino acid substituted 1,2,4-oxadiazoles from hydroxyl amidine and (S)-2-(2,2,2-trifluoroacetamido)propanoic 2,2,2-trifluoroacetic anhydride is described. This operationally simple methodology affords an efficient and convenient solution to synthesize chiral N-protected amino acids under catalyst-free conditions. All the synthesized compounds were screened for their in vitro antibacterial activity towards six human pathogenic bacterial species, among which, 4al exhibited a significant efficacy against Escherichia coli with the MIC value of 0.19 μg mL-1.

TiF4-catalyzed direct amidation of carboxylic acids and amino acids with amines.

Unlike other metal fluorides, catalytic titanium tetrafluoride enhances the direct amidation of aromatic and aliphatic carboxylic acids and N-protected amino acids in refluxing toluene. While aromatic acids were converted to amides with 10 mol% of the catalyst within 24 h, aliphatic acids underwent a faster reaction (12 h), with lower catalyst loading (5 mol%). This protocol is equally efficient with alkyl and aryl amines providing a variety of carboxamides and peptides in 60-99% yields.

Cross-linked polysiloxane-coated stable bond O-9-(2,6-diisopropylphenylcarbamoyl)quinine and quinidine chiral stationary phases as well as application in enantioselective cryo-HPLC.

In this work, brush-type chiral stationary phases (CSPs) with O-9-(2,6-diisopropylphenylcarbamoyl)-modified quinidine (DIPPCQD-brush/-SH) and O-9-(2,6-diisopropylphenylcarbamoyl)-modified quinine (DIPPCQN-brush/-SH) were prepared as benchmarks for comparison with new corresponding polymeric CSPs with more stable bonding chemistry. These polymeric CSPs were prepared by coating a thin poly(3-mercaptopropyl)-methylsiloxane film together with the chiral selector onto vinyl-modified silica. In a second step, immobilization of the quinine/quinidine derivatives as well as cross-linking of the polysiloxane film to the vinyl-silica is achieved by a double thiol-ene click reaction. The polymeric CSPs exhibited similar enantioselectivity as the corresponding brush phases, but showed lower chromatographic efficiencies. Chiral acidic substances were separated into enantiomers (e.g., N-protected amino acids, herbicides like dichlorprop) in accordance with an enantioselective anion-exchange process. Oxidation of residual thiol groups of the polymer DIPPCQN-CSP introduced sulfonic acid co-ligands on the silica surface, which resulted in greatly reduced retention times. Acting as immobilized counterions, they allowed to reduce the concentration of counterions in the mobile phase, which is favorable for liquid chromatography (LC)-electrospray ionization-mass spectrometry application. Ibuprofen showed a single peak under ambient column temperature. However, application of cryogenic cooling of the column enabled to achieve baseline separation at -20°C column temperature. It can be explained by an enthalpically dominated separation, which leads to an increase in separation factors when the temperature is reduced. While it is quite uncommon to work at subzero degree column temperature, this work illustrates the potential to exploit such temperature regime for optimization of LC enantiomer separations.

Sulfoximine Assisted C-H Activation and Annulation via Vinylene Transfer: Access to Unsubstituted Benzothiazines.

In this study, we report the synthesis of unsubstituted 1,2-benzothiazines through a redox-neutral Rh(III)-catalyzed C-H activation and [4+2]-annulation of S-aryl sulfoximines with vinylene carbonate. Notably, the introduction of an N-protected amino acid ligand significantly enhances the reaction rate. The key aspect of this redox-neutral process is the utilization of vinylene carbonate as an oxidizing acetylene surrogate and an efficient vinylene transfer agent. This vinylene carbonate enables the cyclization with the sulfoximine motifs, successfully forming a diverse array of 1,2-benzothiazine derivatives in moderate to good yields. Importantly, this study highlights the potential of Rh(III)-catalyzed C-H activation and [4+2]-annulation reactions for the synthesis of optically pure 1,2-benzothiazines with high enantiomeric purity.

Design of Novel Mixed-Mode Columns for Analysis of Amino Acids Derivatized with 4-Fluoro-7-nitro-2,1,3-benzoxadiazole and the Evaluation of Retention Properties

Three-dimensional (3D) HPLC methods are useful tools for the selective analysis of biomolecules in complicated real-world matrices, however, the columns applicable for the second dimension are still limited. In the present study, two types of mixed-mode columns (Singularity MX-102 and 103) were newly designed/developed focusing on the separation of N-protected chiral amino acids. The retention profiles of the two mixed-mode columns were evaluated using 10 proteinogenic amino acids with various chemical properties, namely, alanine, asparagine (Asn), glutamine, glycine, lysine (Lys), phenylalanine, proline, serine (Ser), threonine and valine (Val), and compared to that of a mixed-mode column (Singularity MX-001) previously adopted for the 3D-HPLC analysis of chiral amino acids. The amino acids were derivatized with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) and detected by their fluorescence (ex. 470 nm, em. 530 nm). For the mobile phases, mixed solutions of acetonitrile/methanol containing formic acid were used. As a result, NBD-Val eluted the fastest for all the tested mixed-mode columns. However, the NBD-amino acids most strongly retained on the columns were different (Asn for MX-001, Ser for MX-102 and Lys for MX-103). Also, the elution orders of the 10 NBD-amino acids on the three mixed-mode columns were not the same as that on the reversed-phase C18 column, and characteristic elution orders and retention properties were observed for the individual mixed-mode columns. These results indicated that mixed-mode columns reported in the present study have different retention mechanisms, and the development of highly selective 3D-HPLC systems using these columns is expected.

Understanding the Transition from High-Selective to High-Efficient Chiral Separations by Changing the Organic Modifier with Zwitterionic-Teicoplanin Chiral Stationary Phase.

The retention behavior of small molecules and N-protected amino acids on a zwitterionic teicoplanin chiral stationary phase (CSP), prepared on superficially porous particles (SPPs) of 2.0 μm particle diameter, has shown that efficiency and enantioselectivity, and so enantioresolution, dramatically change depending on the employed organic modifier. In particular, it was found that while methanol permits the boost of enantioselectivity and resolution of the amino acids, at the cost of efficiency, acetonitrile allows for the ability to reach extraordinary efficiency even at high flow rates (with reduced plate height <2 and up to 300,000 plates/m at the optimum flow rate). To understand these features, an approach based on the investigation of mass transfer through the CSP, the estimation of the binding constants of amino acids on the CSP, and the assessment of compositional properties of the interfacial region between bulk mobile phase and solid surface has been adopted.

Regioselective Cyclic Iminium Formation of Ugi Advanced Intermediates: Rapid Access to 3,4-Dihydropyrazin-2(1H)-ones and Other Diverse Nitrogen-Containing Heterocycles

Herein, advanced intermediates were synthesized through Ugi four-component reactions of isocyanides, aldehydes, masked amino aldehyde, and carboxylic acids, including N-protected amino acids. The presence of a masked aldehyde enabled acid-mediated deprotection and subsequent cyclization via the carbonyl carbon and the amide nitrogen. Utilizing N-protected amino acid as a carboxylic acid component, Ugi intermediates could be cyclized from two possible directions to target 3,4-dihydropyrazin-2(1H)-ones. Cyclization to the amino terminus (westbound) and to the carboxyl terminus (eastbound) was demonstrated. Deliberate selection of building blocks drove the reaction regioselectively and yielded diverse heterocycles containing a 3,4-dihydropyrazin-2(1H)-one core, pyrazin-2(1H)-one, and piperazin-2-one, as well as a tricyclic framework with a 3D architecture, 2,3-dihydro-2,6-methanobenzo[h][1,3,6]triazonine-4,7(1H,5H)-dione, from Ugi adducts under mild reaction conditions. The latter bridged heterocycle was achieved diastereoselectively. The reported chemistry represents diversity-oriented synthesis. One common Ugi advanced intermediate was, without isolation, rapidly transformed into various nitrogen-containing heterocycles.

Theoretical Mechanistic Investigation of the Dynamic Kinetic Resolution of N-Protected Amino Acid Esters using Phase-Transfer Catalysts.

A detailed theoretical mechanistic investigation on the dynamic kinetic resolution of N-protected amino acid esters using phase-transfer catalysts is described. Semiautomatic exhaustive conformation search of transition state (TS)-like structures were carried out using the ConFinder program and the pseudo-TS conformational search (PTSCS) method. This conformational search method successfully provided reasonable TS structures for determining the stereoselectivity in the asymmetric base hydrolysis of hexafluoroisopropyl (HFIP) esters as well as the racemization mechanism. Furthermore, the independent gradient model (IGM) analysis of the TS structures suggested that the H-bonding interactions with the oxyanion hole and π-stacking interactions are the common important features of the proposed TS structures that determine the stereoselectivity.

Stereoselective synthesis of backbone extended π-conjugated amino esters.

Utilization of the Wittig reaction to synthesize conjugative multiple double bonds is rare. We examined the utility of the Wittig reaction to construct conjugative two and three carbon-carbon double bonds on the N-protected amino acid backbone. The ethyl esters of N-Boc amino acids with multiple carbon-carbon double bonds in the backbone were isolated in excellent yields with exceptional E-selectivity of the double bonds. The allylic alcohols of α,β-unsaturated γ-amino esters were selectively synthesized from the DIBAL-H and BF3·OEt2. The allylic alcohols were transformed into aldehydes using IBX oxidation. Using this protocol, we synthesized ethyl esters of N-Boc-(E,E)-α,β,γ,δ-unsaturated ε-amino acids with various side-chain functionalities and ethyl esters of N-Boc-(E,E,E)-α,β,γ,δ,ε,ζ-unsaturated η-amino acids with excellent yields. We speculated the exceptional E-selectivity is probably due to the stabilization of the planar transition state of the Wittig reaction with the double bond p-orbitals. No racemization was observed in the synthesis of amino acids. The reported process may serve as an excellent route to synthesize multiple conjugative carbon-carbon double bonds.

Deciphering mechanistic implications of antimicrobial and antioxidant potentials of certain new dibutyltin(IV) formulations as possible therapeutic options based on DFT and hybrid materials paradigm.

Mechanistic implications of antimicrobial and in vitro antioxidant potentials of a set of newly generated nonbridged mononuclear N,O-orthometallated and carboxylate bridged binuclear nonorthometallated dibutyltin(IV) formulations have been investigated. Some of these formulations were screened for their antibacterial and antifungal activities against Escherichia coli and Candida albicans, respectively whereas in vitro antioxidant potential was examined by Ferric reducing antioxidant power (FRAP) assay. Nonbridged mononuclear N,O-orthometallated dibutyltin(IV) formulations were generated by the reactions of Bu2 SnCl2 with sodium salts of 2-aminophenol/substituted 2-aminophenol and flexible N-protected amino acids in 1:1:1 molar ratio in refluxing dry THF. Plausible structures of these nonbridged mononuclear N,O-orthometallated dibutyltin(IV) formulations containing flexible N-protected amino acids have been suggested on the basis of spectroscopic and mass studies of some representative formulations. Plausible structures suggested on the basis of spectroscopic studies are corroborated by density functional theory (DFT/B3LYP method) (SPARTAN-20) investigation of a representative dibutyltin(IV) complex and the ligands involved in it. The presence of two different classes of organic ligands in this complex provides an opportunity to study optimized topologies, bonding, distortions, optimized energy, and stability of the complex.

Cu-Catalyzed N–H Insertion of α-Alkyl-α-Diazo-acetates to Form N-Protected α-Alkyl Amino Esters

Cu-Catalyzed N–H Insertion of α-Alkyl-α-Diazo-acetates to Form N-Protected α-Alkyl Amino Esters

Synthesis of β-Deuterated Amino Acids via Palladium-Catalyzed H/D Exchange.

Despite several synthetic approaches that have been developed for α-deuterated amino acids, the synthesis of β-deuterated amino acids has remained a challenge. Herein, we disclose a palladium catalyzed H/D exchange protocol for a β-deuterated N-protected amino amide, which can be converted to a β-deuterated amino acid simply by removal of protecting groups. This protocol is highly efficient, simply manipulated, and appliable for deuterium-labeling of many amino amides. In addition, deuterium labeling of phenylalanine derivatives was also successful when pivalic acid served as an additive to promote the H/D exchange process.

A Safer Reduction of Carboxylic Acids with Titanium Catalysis.

Ammonia-borane, shown previously to react with carboxylic acids under reflux to form primary amides, reduces acids to alcohols at room temperature in the presence of catalytic TiCl4. The process, which is tolerant of a variety of potentially reactive functional groups, including N-protected amino acids, can be employed for the selective reduction of acids in the presence of amides, nitriles and, to some extent, esters. Aliphatic acids can be selectively reduced in the presence of aromatic acids.

Cobalt-catalyzed O-arylation of N-protected amino alcohols with arenes via cross-dehydrogenative C-O coupling strategy: Direct access to aryloxyamines

An efficient Co(II)-catalyzed cross-dehydrogenative C-O coupling strategy for the arylation of N-protected amino alcohols, including 1,2-, 1,3- and 1,4-amino alcohols, branched amino alcohols and cyclic amino alcohols with different amides derivatives has been developed, affording a wide range of corresponding aryloxyamines compounds with excellent convertibility in moderate to good yields, which are of great interest in medicinal and pharmaceutical chemistry. Furthermore, this reaction system could be further applied to the preparation of potential bioactive molecules.

Application of 2D EXSY and qNMR Spectroscopy for Diastereomeric Excess Determination Following Chiral Resolution of β-Lactams.

Trans-β-lactam isomers have garnered much attention as anti-cancer microtubule targeting agents. Currently available synthetic methods are available for the preparation of enantiopure β-lactams and favour isomeric cis/trans β-lactam mixtures. Indirect chiral resolution offers the opportunity for isolation of exclusively enantiopure trans-β-lactams. In this study, liquid chromatography chiral resolution of β-lactams derivatized as diastereomer mixtures with a panel of N-protected amino acids is explored, where N-(Boc)-L-proline served as the optimal chiral derivatising reagent. High-performance liquid chromatography failed to adequately determine diastereomeric excess (de) of resolved diastereomers. Variable temperature, 1 H NMR and 2D EXSY spectroscopic analyses of proline-derivatised diastereomers were successfully employed to characterise equilibrating rotamers of resolved diastereomers and determine their de. Integration of resolved resonances corresponding to H3 and H4 of the β-lactam ring served as a quantitative qNMR tool for the calculation of de following resolution.

Synthesis of Amino-Acid-Based Nitroalkenes

Fatty-acid-based nitroalkenes have recently received great attention because of their bioactivities. On the contrary, peptide- or amino-acid-based nitroalkenes have been scarcely explored so far, although they may exhibit interesting biological properties, for example, as enzyme inhibitors. In this work, we study protocols for the efficient synthesis of nitroalkenes based on natural amino acids. A variety of N-protected amino alcohols and Weinreb amides, derived from α-amino acids, were converted to the corresponding N-protected amino aldehydes, and, through a Henry reaction with nitroalkanes, produced the corresponding nitro alcohols. The subsequent elimination reaction led to the (E)-isomer of amino-acid-based nitroalkenes in moderate to high yields.