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Unnatural α-amino acids form a family of essential molecules used for, among other applications, the synthesis of modified peptides, to improve resistance to proteolytic enzyme degradation, and to modulate physico- and biochemical properties of bioactive peptides as well as chiral inducers in asymmetric synthesis. Among them, silicon-containing unnatural amino acids are becoming an interesting new class of building blocks. The replacement of carbon atoms in bioactive substances with silicon is becoming increasingly popular. Peptides containing silyl amino acids hold great promise for maintaining or reinforcing the biological activity of active compounds, while they simultaneously enhance their resistance to enzyme degradation. In addition, the lipophilicity of the silicon atom facilitates their membrane crossing and their bioavailability. Nowadays, the interest of the pharmaceutical industry in peptide- and protein-based therapies is increasing. In this respect, silicon-containing amino acids and peptides...

Catalytic properties of 15 N-pyrrolidine-based α,β-peptides incorporating a constrained 2-aminobicyclo[2.2.2]octane carboxylic acid (ABOC) are evaluated in the asymmetric aldol reaction from acetone and some p-substituted benzaldehydes.

It is shown that the complete elimination of organic solvents for the synthesis, purification, and isolation of the products resulting from acylation reactions of amines and other nucleophiles is possible.

An efficient and stereoselective method for the preparation of 4-amino(methyl)-1,3-thiazole-5-carboxylic acids starting from N-Fmoc-amino acids is reported.

A new hybrid microwave (MW) and ultrasound (US)-assisted reactor concept was investigated. The 2.45 GHz microwaves were delivered by a semiconductor generator via a coaxial cable to a monomode Transverse Electric (TE) microwave resonant cavity within which the reactor was placed; the US (25 kHz) were delivered at the bottom of the TE cavity via a novel designed sonotrode consisting of a detachable metallic plate-probe (indirect sonication). The semiconductor microwave generator helped to optimize the absorbed energy via its automatic frequency tuning function. The dual MW/US device allowed the use of both technologies separately or in a simultaneous combined manner. The ring-closing metathesis of diethyl diallyl malonate in glycerol micellar conditions was studied as an example using this novel hybrid technology. The results were compared with those obtained when microwaves or ultrasound were applied individually. Various benzylidene-, indenylidene- and Hoveyda–Grubbs-type catalysts were screened. The novel reactor for combined MW/US irradiation showed beneficial effects on the outcome of the reaction.

The amide bond is an essential unit in many drugs and polymers. The catalyzed oxidation of alcohols and amines is an effective method to form amides with limited undesired waste. Herein, we demonstrate the beneficial effect of microwave activation for this reaction. The benzamides were directly formed from alcohols and amine hydrochloride salts in short reaction times with yields up to 84 % and TOFs (turnover frequencies) up to 33.6 h–1. Among the examined transition metals, only nontoxic and inexpensive FeCl2·4H2O together with caffeine as a stabilizing ligand provided a uniquely efficient catalytic system for the transformation. Natural sources of caffeine were also evaluated under the amidation conditions.

The title species (V) and (VIII) are prepared from amines (I) via persilylation used for temporary protection, alkylation with ester (II), N-protection and ester cleavage.

A convenient and user-friendly method to yield benzamides from primary and secondary amines and various benzylic alcohols in the presence of a cheap iron salt (FeCl 2 ·4H 2 O) and tert -butylhydroperoxide (70% in water) as a stoichiometric oxidant is described. Control experiments indicated that this reaction might involve radical species. This method proved to be general, generating a family of 30 benzamides and was applied to the preparative synthesis of anti-anxiety drug moclobemide.

Ester (I), readily available from isoxazole in 3 steps, is transformed to the desired ring system (III) whose reactivity toward amines, thiols, alcohols, and amino acids is investigated.

Mechanochemical derivatizations of either N- or C-unprotected amino acids are performed in a vibrational or planetary ball mill under neat conditions.

Melted poly(ethylene glycols) (PEGs) were used for the first time as solvent for the sonochemically promoted cyanation of aryl halides employing inexpensive and safe K4[Fe(CN)6] and a relatively low amount of Cu-based catalyst. The Mw (weight-average polymer molecular weight) of PEG proved to notably influence the substrate conversion, which is indicative of a strong dependence of the sonication efficacy on solvent properties. Gel permeation chromatography (GPC), X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM) contributed to the characterization of the polymer and the elucidation of the catalytic system.

Bis-Boc-activated 2,5-diketopiperazines on reaction with potassium hydroxide or sodium methoxide in dry tetrahydrofuran led to Boc-protected hydantoins through an unprecedented ring contraction. This rearrangement was applied to several monosubstituted 2,5-diketopiperazines with good yields and regioselectivity.

PEG-based ionic liquids are a new appealing group of solvents making the link between two distinct but very similar fluids: ionic liquids and poly(ethylene glycol)s. They find applications across a range of innumerable disciplines in science, technology, and engineering. In the last years, the possibility to use these as alternative solvents for organic synthesis and catalysis has been increasingly explored. This Review highlights strategies for their synthesis, their physical properties (critical point, glass transition temperature, density, rheological properties), and their application in reactions catalyzed by metals (such as Pd, Cu, W, or Rh) or as organic solvent (for example for multicomponent reactions, organocatalysis, CO2 transformation) with special emphasis on their toxicity, environmental impact, and biodegradability. These aspects, very often neglected, need to be considered in addition to the green criteria usually considered to establish ecofriendly processes.

A stereoselective ring-contraction reaction, the transannular rearrangement of activated lactams (TRAL) is used to access spirocyclic scaffolds.

Novel palladium N-heterocyclic carbene-based complexes with 3,4,5-trimethoxybenzyl, alkyl and sulfonate N-substituents are synthesized and used as pre-catalysts in the title reaction.

The unprecedented eco-friendly Pt-catalyzed 5-endo-dig cycloisomerization of readily available α-amino ynones is reported under microwave irradiation in PEG-3400 as reaction matrix. The corresponding pure pyrrolin-4-ones were obtained in excellent yields (80–98%) directly after a straightforward precipitation–filtration workup, thus avoiding any chromatographic purification. The catalytic system was recycled and the chiral purity of all the products was also investigated.

The synthesis of optically pure heterocyclic scaffolds (V) (12 examples) is achieved through selective C-acylation of the aminoimidazopyridine (I) with various amino acids and subsequent intramolecular carbonylation.

The unprecedented electrophilic iodo-mediated cyclization of α-amino-ynones afforded enantiomerically enriched β-iodopyrrolin-4-ones in excellent yields under mild conditions. The starting substituted α-amino-ynones were obtained from the chiral pool by selective mono-addition of an organolithium to optically pure N-protected carboxyanhydrides of amino acids (UNCAs).

This is a one-pot domino reaction including oxidation and C—N bond formation steps to yield benzamides.

Phosphine-free palladium-catalyzed Mizoroki–Heck reaction was performed using ball-milling in polyethylene glycol under mild conditions. Good to excellent yields of coupling products were obtained. This activation technique also allowed the concomitant formation of round shaped Pd–PEG nanoparticles that were characterized by TEM analysis.

A fast and efficient mechanochemical approach for the synthesis of carboxylic amides in the total absence of any organic solvent is realized and successfully applied to the preparation of the active pharmaceutical ingredient teriflunomide (IX).

Microwave-assisted iodocyclization of diols (I) or amino alcohols (III) is achieved in the presence of NaHCO3.

A protocol for the Lewis acid mediated addition of the new amino acid organozinc compound (VI) to simple aldehydes is developed and successfully applied to the synthesis of novel C-glycosylated amino acids such as (X).

Some new optically pure title compounds such as (VIII) and (XII) are prepared via selective C-3 acylation.

Novel racemic and optically active constrained N-phosphonoalkyl bicyclic β-amino acids have been synthesized via the Kabachnik–Fields reaction of the (RS) or (R)-1-aminobicyclo[2.2.2]octane-2-carboxylic acids with paraformaldehyde and benzaldehyde, and the dimethyl-H-phosphonate. The structure of obtained compounds was characterized by NMR (1H, 13C, and 31P), LC/MS, and X-ray diffraction analyses. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 23:123–130, 2012; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20759

Ball milling of various aldehydes and ketones with hydrazines proceeds without the need for a solvent in one to three hours to give the hydrazones (III) and (VII) in quantitative yields.

The starting materials are readily prepared from the corresponding protected amino acids by amide formation and treatment with Lawesson′s reagent.

A tandem aza-Friedel–Crafts reaction/Hantzsch cyclization is described to access various polysubstituted 2-amino-1,3-thiazoles from electron-rich (hetero)-aromatic rings, aldehydes, thiourea and α-chloroketones.

The synthesis of a new hydrophilic ammonium-based poly(ethylene glycol)-ionic liquid (PEG-IL) is reported; the structure was assigned by NMR (1H, 13C) and MALDI mass spectrometry. The viscosity and thermal stability were also studied, as well as its polarity. Its application as an alternative solvent in the synthesis of dipeptides under microwave irradiation is also described.

Horner—Wadsworth—Emmons reaction of phosphonate (I) with aldehydes is successfully achieved in the presence of a mild carbonate base to give the (Z)-isomers as sole or main products.

The three-component reaction under solvent-less conditions affords the products generally in excellent yields and avoids purification by column chromatography.

Chiral N-protected β-amino alcohols are easily obtained by NaBH 4 reduction of mixed anhydrides of N-protected α-amino acids in an organic/aqueous medium. The alcohols obtained from side chain or main chain reduction of N-protected aspartic acid are converted in good yields into lactones.

A facile synthesis of a wide variety of N-benzyloxycarbonyl-amino acid-tert-butyl ester derivatives under mild conditions is described. N-protected amino acids were esterified with tert-butyl bromide in dimethylacetamide as solvent, in the presence of benzyltriethylammonium chloride (BTEAC)and a large excess of potassium carbonate. Many amino Z-acid-Tert-butyl esters that might be difficult to prepare by other methods have been synthesized in high yields by this procedure. The reaction is simple, unexpansive, easily scaled up, and proceeds without observable racemization.

The synthesis of chiral N-protected tetramic acid derivatives which are important precursors of β-hydroxy γ-amino acid under mild conditions is described. Reaction of urethane-N-carboxyanhydrides (UNCAs) with Meldrum's acid in the presence of a tertiary amine, followed by subsequent cyclisation produced tetramic acid derivatives. This procedure is applicable to Boc-, Fmoc- and Z- N-carboxyanhydrides.

A facile synthesis of a wide variety of N-protected β-amino alcohol derivatives under mild conditions is described. N-urethane protected amino acid N-carboxyanhydrides (UNCAs) were used as starting material and reduced into the corresponding alcohols with the appropriate hydride, sodium borohydride. The reaction is simple, unexpensive, easily scaled up, and proceeds without observable racemization.

A facile one step synthesis of a wide variety of N-protected (Boc, Z, Fmoc) α-amino aldehydes under mild conditions is described. Pure N-protected (Boc, Z, Fmoc) α-amino aldehydes were obtained in high yields by reduction of N-protected (Z, Boc, Fmoc)-N-carboxyanhydrides (UNCAs) with equivalent amounts of lithium tris(tertbutoxy)aluminium hydride [LiAlH(O-t-Bu)3] or lithium tris[(3-ethyl-3-pentyl)oxy]aluminium hydride (LTEPA) in THF as solvent. The reaction is simple, rapid and proceeds without detectable racemization.

The asymmetric synthesis, CCK receptor binding affinities and CCK-A agonist properties of a novel series of non-peptide CCK-A receptor selective ligands is reported.

A mild, simple and efficient microwave-enhanced copper-catalyzed protocol for N-arylation using high molecular weight poly(ethylene glycol) (PEG3400) as a solvent is reported. Indole and benzimidazole have been N-arylated in the presence of cuprous oxide, cesium carbonate, and PEG3400, under microwave activation, with no supplementary ligands. Simple treatment by precipitation in Et2O and filtration provided the expected product after evaporation and recovery of the catalytic system as a precipitate. The recovery and one successful re-use of the catalytic system is also described. The formation of copper-based nanoparticles was demonstrated by TEM analysis.

We report a new method using silver benzoate instead of mercury salts as a key reagent for the synthesis of 3,4,5-trisubstituted 1,2,4-triazoles. This method allows the introduction of a large variety of substituents in the three positions. We demonstrated that we could introduce one chiral center without any loss of the optical purity. This method is compatible with at least multi-gram scale-up.

In the presence of a base in aprotic medium, UNCAs lead to N-urethane protected-3,5-dialkyl-3-amino pyrrolidine-2,4-diones as racemic cis/trans mixtures. Consequently the choice of the base should be carefully considered to optimize yields and avoid side products when UNCAs are used in peptide synthesis.

The synthesis of chiral 3-substituted quinazoline-2,4-diones was performed starting from N-urethane anthranilamides. This synthetic pathway was applied in solid phase, from commercially available anthranilic acid that was bound to hydroxymethyl polystyrene resin via a carbamate linker. In both cases, cyclisation occurred under basic conditions to afford non-racemized quinazolinediones in high purity.

N-protected γ-amino-β-keto-esters were synthesized from the corresponding N-protected N-carboxyanhydride (UNCAs) by reaction with the lithium enolate of ethyl acetate in good yields. These compounds are precursors of statine derivatives.

Functionalized diarylzinc reagents, easily available from the corresponding aryl halides by a halogen-lithium exchange followed by transmetalation with ZnCl2 react with a glycine cation equivalent to afford substituted α-aryl α-amino esters in good yields.