Synthesis of l-azaisotryptophan and its analogs: a general access to new 2-substituted azaindoles

l-(N-Cbz)-7-azaisotryptophan, l-(N-Cbz)-1a, a new isostere of tryptophan, was synthesized by reacting Li₂-(N-Boc)-2-amino-3-picoline, Li₂-(N-Boc)-2a, with appropriately protected l-aspartic acid followed by simple functional group manipulation. This synthetic success led us to access a set of analogs of azaisotryptophan (4a–c; 6a–c) as well as a new class of chiral amines (7a–c; 8a–c) for future application in asymmetric synthesis and design of homochiral ligands. Further, we have generalized the method substantiating a variety of new azaindol-2-yl derivatives (10aa–10lc) with functionalized substituents. In a preliminary luminescence characterization, l-(N-Cbz)-1a has exhibited about 30 nm bathochromic shifted fluorescence emission compared to tryptophan and (N-Cbz)-tryptophan.     

Synthesis of (S)-2-amino-7-methoxytetralin and isoindolo[1,2-a]isoquinolinone derivatives from l-aspartic acid

This paper describes a new total synthesis for (S)-2-amino-7-methoxytetralin, (S)-7-MeO-AT, from l-aspartic acid in an overall yield of 10% over nine steps. The major loss was ascribed to a key intramolecular Friedel–Crafts cyclization step, which afforded up to 36% yield. Attempts to perform a Friedel–Crafts cyclization of an intermediate phthalimide protected amino alcohol 13 did not give the desired protected (S)-7-MeO-AT. On the other hand, two new isoindolo[1,2-a]isoquinolinone derivatives 14 and 15, were isolated in 21 and 11% yield, respectively. The yield of 15 was improved to 70%.     

Poly l-lactide-layered double hydroxide nanocomposites via in situ polymerization of l-lactide

The use of clay nanofillers offers a potential route to improved barrier properties in polylactide films. Magnesium-aluminium layered double hydroxides (LDHs) are interesting in this respect and we therefore explored synthesis of PLA-LDH nanocomposites by ring-opening polymerization. This method is attractive because it should ensure good dispersion of LDH in the polymer. The effect of adding either LDH carbonate (LDH-CO₃) or laurate-modified LDH (LDH-C₁₂) was investigated. X-ray diffraction, scanning electron microscopy, and transmission electron microscopy revealed that exfoliated nanocomposites were obtained when using LDH-C₁₂ but that LDH-CO₃ gave a partly phase-separated morphology. Thermogravimetric analysis showed that PLA-LDH combinations exhibited higher degradation onset temperatures and differential scanning calorimetry confirmed that LDHs can act as nucleating agents. However, PLA molecular weight was significantly reduced when in-situ polymerization was conducted in the presence of the LDHs and we suggest that chain termination via LDH surface hydroxyl groups and/or metal-catalyzed degradation could be responsible.     

Thermal phase transitions of solid chiral N,N′-carbonyl-bis-(l-amino acids) and their methyl and benzyl esters

Compounds derived from different N,N′-carbonyl-bis-(l-amino acids) and their methyl and benzyl esters were synthesized and characterized by elemental analysis, infrared and nuclear magnetic resonance. The amino acids used were valine, leucine, phenylglycine and phenylalanine. All compounds revealed complex thermal behaviour as proved by differential scanning calorimetry, X-ray powder diffractometry and optical birefringence observation by polarizing microscope. Above isotropization temperature N,N′-carbonyl-bis-(l-amino acids) decomposed. The number and kinds of thermal phase transitions of investigated esters vary from a simple phase transition and melting to a complex polymorphism, and strongly depends on molecular structure. One to four phase transitions have been observed upon heating. Phase transition temperatures showed considerable variation with choice of the supstituent on symmetric carbons and therminal carboxylic groups. The results are discussed in terms of the architecture of investigated molecules that hinder mesomorphism.     

Synthesis of l,l-puromycin

l,l-Puromycin, a diastereomer of the natural peptidyl nucleoside antibiotic puromycin, has been synthesized from l-xylose in 13 steps.     

Rearrangement of N-alkyl 1,2-amino alcohols. Synthesis of (S)-toliprolol and (S)-propanolol

N-alkyl 1,2-amino alcohols were rearranged stereospecifically by using TFAA/Et₃N. This rearrangement has been used to synthesize N-isopropyl-3-(aryloxy)-2-hydroxypropylamines, β-adrenergic blocking agents such as (S)-toliprolol and (S)-propanolol.     

trans-4-Hydroxy-l-proline: a novel starting material for N-alkylpyrroles synthesis

The reaction of aldehydes with trans-4-hydroxy-l-proline was studied for the first time, resulting in the formation of N-alkylpyrroles in good to excellent yields, via decarboxylation followed by redox isomerization under neutral conditions. The neutral conditions allow access to efficient synthesis of N-alkyl pyrroles with high functional group tolerance.     

Synthesis of 1-deoxy-l-gulonojirimycin and 1-deoxy-l-talonojirimycin

De novo synthesis of noncompetitive glycosidase inhibitors l-gulo-DNJ and l-talo-DNJ has been achieved in 9-10 steps starting from Garner’s aldehyde. Key to the success of this procedure was the construction of the 2,3-unsaturated piperidine 14, which syn dihydroxylation under Kishi’s and Donohoe’s conditions led to the desired iminosugars.     

Concise and divergent approach to 3-O-acyl-l-noviose derivatives and their 3-amino bioisosteres: 3-O-benzoyl-l-noviose and N-benzoyl-3-amino-l-noviose

Generally applicable concise approaches to 3-O-acyl-l-noviose derivatives and their 3-amino bioisosteres, represented by 5 and 6, were described. Chiral aldehyde 7 was thus prepared from dimethyl l-tartrate in five steps, and converted into 5 and 6 by employing substrate induced asymmetric aldehyde or N-sulfinyl aldimine allylation and dihydropyrane epoxidation as key steps, respectively.     

Efficient synthesis of new N-alkyl-d-ribono-1,5-lactams from d-ribono-1,4-lactone

d-Ribono-1,4-lactone was treated with ethylamine in DMF to afford N-ethyl-d-ribonamide 9a in quantitative yield. Bromination of amide 9a by the system SOBr₂ in DMF or PPh₃/CBr₄ in pyridine led, after acetylation, to epoxide 7. However, treatment of amide 9a with acetyl bromide in dioxane followed by acetylation gave 2,3,4-tri-O-acetyl-5-bromo-5-deoxyl-N-ethyl-d-ribonamide 10a. Methanolysis of 10a, with sodium methoxide, afforded the N-ethyl-d-ribonolactam 11a in 51% overall yields. Using this method, N-butyl, N-hexyl, N-dodecyl, and N-benzyl-d-ribonolactams 11b-e were obtained in good yields (48-53%).     

Intermolecular/interionic interactions in l-isoleucine-, l-proline-, and l-glutamine-aqueous electrolyte systems

Speed of sound and density values for ternary systems (amino acid + salt + water): l-isoleucine/l-proline/l-glutamine in aqueous solutions of 1.5 M KCl, 1 M KNO₃, and 0.5 M K₂SO₄ have been measured for several concentrations of amino acids at different temperatures (303.15, 308.15, 313.15, 318.15, and 323.15 K). Using speed of sound and density data, the thermodynamic parameters such as isentropic compressibility (κ_s), change in isentropic compressibility (Δκ_s) and relative change (Δκ_s/κ₀) in isentropic compressibility have been computed. The isentropic compressibility values decrease with increase in the amino acid concentration as well as with temperature. The decrease in κ_s values with increase in concentration of l-isoleucine/l-proline/l-glutamine in 1.5 M KCl, 1 M KNO₃, and 0.5 M K₂SO₄ has been ascribed to an increase in the number of incompressible zwitterions in solutions, and the formation of ‘zwitterions-ions’ and ‘zwitterions-water dipole’ entities in solutions. The decrease in κ_s values with increase in temperature has been attributed to the corresponding decrease of κ_relax (a relaxational part of compressibility), which is dominant over the corresponding increase of κ_∞ (an instantaneous part of compressibility). The trends of variation of Δκ_s and Δκ_s/κ₀ with variations in solute concentration and temperature have also been discussed in terms of solute-solute and solute-solvent intermolecular/interionic interactions operative in the systems.     

Synthesis of a fluoroalkene peptidomimetic precursor of N-acetyl-l-glutamyl-l-alanine

Fluoroolefin peptidomimetics of the dipeptide N-acetyl-Glu-Ala were synthesized via an Evans asymmetric aldol reaction and an Overman rearrangement. This dipeptide is the N-terminal of an octapeptide implicated in the signal transduction via PKCε.     

Diastereoselective synthesis of 10b-substituted hexahydropyrroloisoquinolines from l-tartaric acid. Creation of a quaternary carbon stereocentre via N-acyliminium ion cyclization

A simple, three-step synthesis of 10b-substituted-hexahydropyrroloisoquinolines 12-17 starting from an L-tartaric acid derived imide is described. The methodology presented employs the addition of a Grignard reagent to the imide carbonyl group, followed by a one-pot acetylation-cyclization sequence. The crucial step, an acid-catalyzed carbon-carbon bond forming reaction via an N-acyliminium ion offers moderate to high stereoselectivity, which has been shown to be strongly dependent on the size of the R-substituent. The mixtures of pyrroloisoquinolines obtained can be separated as enantiomerically pure 2-silyloxy-derivatives.     

Vinylogous N,N-dimethylaminomethylenation of 3-[(1-substituted)ethylidene]-oxindoles with N,N-dimethylformamide dimethylacetal

An efficient stereoselective synthesis of various 3-(3-dimethylaminoprop-2-enylidene)oxindoles has been disclosed. The compounds were synthesized via a vinylogous N,N-dimethylaminomethylenation at the γ-position of 3-[(1-substituted)ethylidene]oxindoles with DMF-DMA.     

Formation and structures of Pd(II) N,S-heterocyclic carbene-pyridyl mixed-ligand complexes

Mononuclear mixed-ligand complexes of Pd(II) containing a N,S-heterocyclic carbene (NSHC) with a secondary alkyl N-substituent and pyridyl ligand, with the general formula [PdI₂(C₁₀H₁₁NS)L] (C₁₀H₁₁NS = 3-isopropylbenzothiazolin-2-ylidene; L = pyridine, 2-aminopyridine, 3-iodopyridine and 4-tert-butyl-pyridine) have been synthesized and characterized by X-ray single-crystal crystallography. Both solution and solid-state structures, as evident from their ¹H NMR spectra and X-ray structures, show anagostic γ-hydrogen interactions of metal with methine of the substituent on the carbene or pyridyl ligand giving 5-membered-chelate-like structures.     

One-pot synthesis of N-Cbz-l-BMAA and derivatives from N-Cbz-l-serine

We report herein an asymmetric synthesis of the modified amino acid N-Cbz-l-BMAA and seven of its alkyl derivatives (2a-h) from N-Cbz-l-serine via ring-opening of the β-lactone (formed under modified Mitsunobu conditions) by different amines. This procedure is simple, one-pot and can generate various derivatives that can be investigated for their toxicological effects. In addition, it can be employed to produce analytical standards for water monitoring as well as labeled compounds for biotransformation studies. This toxin has been the focus of serious ecological and public concern since its implication in degenerative disease such as Alzheimer and Parkinsonism dementia.     

A concise enantioselective synthesis of l-(−)-733,061 and (2S,3S)-methyl 3-aminopiperidine-2-carboxylate using catalytic enantioselective aza-Henry reaction as key step

An efficient enantioselective synthesis of l-(−)-733,061 and (2S,3S)-methyl 3-aminopiperidine-2-carboxylate is accomplished by means of catalytic enantioselective aza-Henry reaction. A key feature of this protocol is organocatalysis as genesis of chirality to ensure high degree of distereo- and enantiocontrol.     

Synthesis of N,N-dialkylaminobenzonitriles and halo-(N,N-dialkyl)benzamidines by reaction of halobenzonitriles with lithium amides

3- and 4-N,N-Dialkylaminobenzonitriles and 4-chloro-(N,N-dialkyl)benzamidines were isolated by reacting 4-chlorobenzonitrile with hindered lithium amides under thermodynamic (0 °C) and kinetic control conditions (−78 °C), respectively. As previously reported, a benzyne mechanism seems to be confirmed since N,N-dialkylaminobenzonitriles are formed. Only benzamidines were isolated in fair to high yields at both 0 °C and −78 °C with non-hindered lithium amides. Exploitation and mechanistic rationale of the reaction of different halobenzonitriles are also reported.     

A highly efficient synthesis of unnatural l-sugars from d-ribose

A preparative and short synthesis of l-ribose and l-apiose was accomplished starting from d-ribose via stereoselective cis-dihydroxylation and C2-hydroxymethylation, respectively. These l-sugars can serve as versatile intermediates for the synthesis of l-nucleosides.     

Henry condensations with 4,6-O-benzylidenylated and non-protected d-glucose and l-fucose via DBU-catalysis

Mechanistic intermediates, and thermodynamically favored side products, in the Henry condensations of partially protected and non-protected pyranoses with a free anomeric hemiacetal function with nitromethane in various solvents for the kinetically controlled syntheses of C-glycopyranosides in the presence of DBU/molecular sieve catalyst system were identified.