Carbamate Protection Research Articles

Convenient synthesis of 2-(4-amino-1H-1,2,3-triazol-1-yl) acetic acid

A convenient approach to the synthesis of 2-(4-amino-1 H -1,2,3-triazol-1-yl) acetic acid is shown, that may be general for the synthesis of 4-amino-1 H -1,2,3-triazole carboxylic acid analogues and peptide compounds based on them. As a convenient starting agent, we selected 2-azido-N,N-diethylacetamide, which is readily obtained from the corresponding chloroacetamide and is a stable solid substance. Azide reacts with a methyl propiolate in the presence of a catalytic amount of CuI and triethylamine as a co-catalyst, occurs in high yields and leads to the formation of triazole. The presence of an amide and ester group in the molecule opens the possibility of their selective modification. In addition, it should be noted that the electronegative triazole ring promotes the hydrolysis of the ester group at position 4 intriazole. Thus, by performing the hydrolysis of the ester under mild conditions at room temperature, acid was obtained selectively with a yield close to the quantitative one. Nevertheless, acetamide fragment was not hydrolyzed. The action on acid with oxalyl chloride is quantitatively converted to acyl chloride. The last one easily undergoes aminolysis to form amide and also interacts with sodium azide to form azide. Amide is promising for further studies, in particular as a precursor of the nitrile group. Azide was found to be a stable crystalline at room temperature, was isolated and characterized by 1 H NMR spectroscopy. In the conditions of the Curtius rearrangement, azide was converted to the corresponding tert-butyl carbamate, which is a convenient precursor of the amino acid. The target amino acid was obtained with a good yield after removal of tert-butyl carbamate protection group with trifluoroacetic acid followed by hydrolysis of amide when heated in 10 % NaOH. An example of the synthesis of 2-(4-amino-1 H -1,2,3-triazol-1-yl)acetic acid demonstrates a convenient way of selective modification of the substituents in the triazole, which open prospects for the preparation of isostructural derivatives and the construction of combinatorial libraries of peptidomimetics to find biologically active compounds. Keywords : azides, 1,3-dipolar cycloaddition, 1,2,3-triazoles, amino acids, peptidomimetics.

A New Energetic Binder: Glycidyl Nitramine Polymer

A new energetic glycidyl-based polymer containing nitramine groups (glycidyl nitramine polymer, GNAP) was synthesized using glycidyl azide polymer (GAP) as the starting material. The synthesis involved STAUDINGER azide-amine conversion, followed by carbamate protection of the amino group, nitration with nitric acid (100%) and trifluoroacetic anhydride and was concluded by deprotection with aqueous ammonia. The products obtained were characterized by elemental analysis and vibrational spectroscopy (IR). The energetic properties of GNAP were determined using bomb calorimetric measurements and calculated with the EXPLO5 V6.02 computer code, showing better values regarding the energy of explosion (Delta U-E = -4813 kJ kg(-1)), the detonation velocity (V-Det = 7165 m.s(-1)), as well as the detonation pressure (p(CJ) = 176 kbar), than the comparable polymers GAP and polyGLYN. The explosion properties were tested by impact sensitivity (IS), friction sensitivity (FS), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and electrostatic discharge (ESD) equipment. The results revealed GNAP to be insensitive towards friction and electrostatic discharge, less sensitive towards impact (40 J) and a decomposition temperature (170 degrees C) in the range of polyGLYN.

Carbamate Protection of AChE Against Inhibition by Agricultural Chemicals

The carbamate pyridostigmine bromide has been used as a pretreatment to protect individuals from the nerve agent soman. Previous research showed that pyridostigmine significantly protected human muscle acetylcholinesterase in vitro from soman and bovine red blood cell acetylcholinesterase from some organophosphorous pesticides. Research presented here demonstrates that pretreatment with other carbamates also protects acetylcholinesterase from inhibition by the pesticides chlorpyrifos-oxon and diazinon-oxon, but not from malaoxon.

Dynamic combinatorial libraries of macrocycles derived from phthalic aldehydes and α,ω-diamines

Dynamic combinatorial chemistry methodology was used to obtain eleven new polyazamacrocycles derived from isophthalic and terephthalic aldehyde and α,ω-diamines. Simple templates, such as alkali metal salts, were found to amplify large macrocycles: 45-membered [3+3]hexaazacrown and 60-membered [4+4]octaazacrown. Parent imine libraries were converted into corresponding secondary libraries of amines using a fast reduction protocol. Methyl carbamate protection of amine group allowed convenient isolation of polyazamacrocycles in very good yields.

2-Phenyl-tetrahydropyrimidine-4(1H)-ones--cyclic benzaldehyde aminals as precursors for functionalised beta-amino acids.

Novel procedures have been developed to condense benzaldehyde effectively with β-amino acid amides to cyclic benzyl aminals. Double carbamate protection of the heterocycle resulted in fully protected chiral β-alanine derivatives. These serve as universal precursors for the asymmetric synthesis of functionalised β2-amino acids containing acid-labile protected side chains. Diastereoselective alkylation of the tetrahydropyrimidinone is followed by a chemoselective two step degradation of the heterocycle to release the free β2-amino acid. In the course of this study, an L-asparagine derivative was condensed with benzaldehyde and subsequently converted to orthogonally protected (R)-β2-homoaspartate.

Amidation through carbamates

N-Alkyl carbamates of primary amines are easily converted into amides under treatment with Grignard reagents. Consequently, primary amines can be converted into amides in a one-pot reaction through carbamate protection and Grignard addition.

A Protection Strategy Substantially Enhances Rate and Enantioselectivity in ω‐Transaminase‐Catalyzed Kinetic Resolutions

AbstractThe kinetic resolution of 3‐aminopyrrolidine (3AP) and 3‐aminopiperidine (3APi) with ω‐transaminases was facilitated by the application of a protecting group concept. 1‐N‐Cbz‐protected 3‐aminopyrrolidine could be resolved with >99% ee at 50% conversion, the resolution of 1‐N‐Boc‐3‐aminopiperidine yielded 96% ee at 55% conversion. The reaction rate was up to 50‐fold higher by using protected substrates. Most importantly, enantioselectivity increased remarkably after carbamate protection compared to the unprotected substrates (86 vs. 99% ee). Surprisingly, benzyl protection of 3AP had no influence on enantioselectivity. A possible explanation for this observation could be the different flexibility of the benzyl‐ or carbamate‐protected 3AP as confirmed by NMR spectroscopy.

Benzophenone semicarbazone protection strategy for synthesis of aza‐glycine containing aza‐peptides

Aza-glycine has been incorporated into peptide mimics as a tool for studying the active conformation and characterizing structure-function relationships for activity. Side reactions, such as intramolecular cyclizations to form hydantoins and oxadiazalones, have, however, inhibited efforts to make activated aza-Gly residues in solution using carbamate protection. Herein, we describe efficient incorporation of aza-glycine into aza-peptides using diphenyl hydrazone protection. Hydrazone acylation with p-nitrobenzyl chloroformate provided the protected aza-Gly activated ester, which was used to acylate a set of amino ester and amino acids to provide aza-Gly-Xaa aza-dipeptide fragments for peptide synthesis. Removal of the hydrazone protection was performed under acidic conditions to provide the hydrochloride salt of the aza-Gly residue for subsequent elongation of the aza-peptide chain using standard coupling conditions. A proof of concept for the use of benzophenone protection has been established by the synthesis of an aza-peptide analog of a potent activator of caspase 9 in cancer cells.

Selective Synthesis of Carbamate‐Protected Polyamines Using Alkyl Phenyl Carbonates.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Selective Synthesis of Carbamate Protected Polyamines Using Alkyl Phenyl Carbonates

Utilising alkyl phenyl carbonates, an economical, practical and versatile method for selective Boc, Cbz and Alloc protection of polyamines has been developed. This method allows Boc, Cbz and Alloc protection of primary amines in the presence of secondary amines by reaction of the polyamines with the alkyl phenyl carbonates. Also, this method allows mono carbamate protection of simple symmetrical aliphatic α,ω-alkanediamines in high yields with respect to the diamine. Finally, the method allows selective carbamate protection of a primary amine located on a primary carbon in the presence of a primary amine located on a secondary or a tertiary carbon in excellent yields.

A Short Diastereo- and Enantioselective Synthesis of cis-4,5-Disubstituted Oxazolidin-2-ones

The asymmetric synthesis of cis-4,5-disubstituted oxazolidin-2-ones is described. Following a four step reaction sequence of α-alkylation, 1,2-addition with subsequent carbamate protection, cyclization and concluding withcleavage of the auxiliary the title compounds are obtained in moderate yields and in excellent diastereo- and enantiomeric excesses (de = 88 - > 96%, ee > 96%).

In vivo protection against soman toxicity by known inhibitors of acetylcholine synthesis in vitro

Soman inhibits the enzyme acetylcholinesterase, essentially irreversibly, producing an accumulation of acetylcholine (ACh) which is responsible for many of its toxic effects. Current approaches to treatment include: (1) atropine, a muscarinic receptor blocker; (2) pyridine-2-aldoxime methylchloride (2-PAM), an enzyme reactivator; and (3) carbamate protection of the enzyme. However, no fully satisfactory regimen has been found, primarily because of the rapid aging process. In this study, compounds known to inhibit ACh synthesis in vitro were evaluated in combination with atropine and 2-PAM so as to assess their potential utility in protection against soman toxicity in rats. Acetylsecohemicholinium (100 μg/kg, i.c.v.t., 30 min prior to soman), an inhibitor of high affinity choline uptake (HAChU) and cholineacetyltransferase (ChAT) activity in vitro, enhanced the protective effects of atropine and 2-PAM, reducing the mortality within the first 2 hr following soman. N-Hydroxyethylnaphthylvinylpyridine (NHENVP), a quaternary ChAT inhibitor (1.7 μmol/kg, i.m.), significantly reduced the overall percent mortality due to soman from 80% to 20%. The compound was most effective when administered 2–3 min prior to soman and was effective only by the intramuscular route. N-Allyl-3-quinucIidinol, a potent HAChU inhibitor (1 μmol/kg, i.m.) was the most effective quinuclidine analog evaluated, also reducing the percent mortality for a 24-hr period. Unlike NHENVP, it was most effective when given 30–60 min prior to soman. It is suggested from the data that compounds that disrupt presynaptic ACh synthesis in vitro may prove effective in treating organophosphate poisoning. The results demonstrate interesting differences among the compounds studied and provide insight for the design of protectants against soman toxicity. These findings further underscore the need to examine the structure activity and pharmacokinetic properties of these compounds, i.e. comparison of routes of administration, dose-response relationships, and time to effect.