Preparation of α-Bromo- and α-Chlorocarboxylic Acids from α-Amino Acids

Diazotization of α-amino acids in 48:52 (w/w) hydrogen fluoride/pyridine along with excess of potassium halide results in the corresponding α-halocarboxylic acids in good to excellent yields (Table 1 and 2).     

Dielectric Relaxation Studies of Binary Mixture of α‐Picoline and Methanol Using Time Domain Reflectometry at Different Temperatures

Complex permittivity spectra of binary mixtures of varying concentrations of α‐picoline and methanol (MeOH) were obtained using time domain reflectometry (TDR) technique over frequency range 10 MHz to 25 GHz at 283.15 K, 288.15 K, 293.15 K and 298.15 K temperatures. The dielectric relaxation parame‐ ters namely static permittivity (σ₀), high frequency limit permittivity (σ_oo1) and the relaxation time (ρ) were determined by fitting complex permittivity data to the single Debye/Cole‐Davidson model. Complex non linear least square (CNLS) fitting procedure was carried out using LEVMW software. The excess static permittivity (σ₀^E) and the excess inverse relaxation time (1/ρ)^E which contains information regarding mo‐ lecular structure and interaction between polar — polar liquids, were also determined. From the experimental data, effective Kirkwood correlation factor (g^eff) and Bruggeman factor (f_B) were calculated. Excess parameters were fitted to the Redlich‐Kister polynomial equation. The values of static permittivity and relaxation time increase non‐linearly with increase in the mol fraction of MeOH at all temperatures. The values of excess static permittivity (σ₀^E) and the excess inverse relaxation time (1/ρ)^E are negative for the studied α‐picoline — MeOH system at all temperatures.     

Brominations of Cyclic Acetals from α-Amino Acids and α- or β-Hydroxy Acids with N-Bromosucinimide

The preparation of novel electrophilic building blocks for the synthesis of enantiomerically pure compounds (EPC) is described. Thus, the 2-(tert-butyl)dioxolanones, -oxazolidinones, -imidazolidinones, and -dioxanones obtained by acetalization of pivalaldehyde with 2-hydroxy-, 3-hydroxy-, or 2-amino-carboxylic acids are treated with N-bromosuccinimide under typical radical-chain reaction conditions (azoisobuytyronitril/CCl₄/reflux). Products of bromination in the α-position of the carbonyl group of the five-membered-ring acetals are isolated or identified ( 2, 5 , and 8 ; Scheme 1). The dioxanones are converted to 2H, 4H-dioxinones under these conditions ( 12 , 14 , 15 , 21 , and 22 ; Schemes 2 and 3). The products can be converted to chiral derivatives of pyruvic acid (methylidene derivatives 3 and 6 ) or of 3-oxo-butanoic and -pentanoic acid ( 16 and 23 ). The mechanism of the brominations is interpreted. The conversion of serine to enactiomcrically pure dioxanones 26–28 (Scheme 4) is also discussed.     

α-Methylidene- and α-Alkylidene-β-lactams from Nonproteinogenic Amino Acids

Treatment of methyl 2-(1-hydroxyalkyl)prop-2-enoates 1 with conc. HBr solution afforded methyl (Z)-2-(bromomethyl)alk-2-enoates 2 , which were transformed regioselectively into N-substituted methyl (E)-2- (aminomethyl)alk-2-enoates 3 (S_N2 reaction) and into N-substituted methyl 2-(1-aminoalkyl)prop-2-enoates 4 (S_N2′ reaction). Regiocontrol of nucleophilic attack by amine was accomplished simply by choice of solvent, the S_N2 reaction occurring in MeCN and the S_N2′ reaction in petroleum ether. Hydrolysis and lactamization afforded β-lactams 7 and 8 , containing an exocyciic alkylidene and methylidene group at C(3), respectively.     

Lantibiotics—Ribosomally Synthesized Biologically Active Polypeptides containing Sulfide Bridges and α,β-Didehydroamino Acids

Lantibiotics are polycyclic peptide antibiotics containing intrachain sulfide bridges, formed from the thioether groups of the amino acids lanthionine and β-methyllanthionine. They also contain α,β-unsaturated amino acids such as didehydroalanine and didehydroaminobutyric acid. A knowledge of the lantibiotic biosynthetic steps and the enzymes involved makes possible a gene technological construction of analogous highly modified polypeptides. To the family of lantibiotics belong nisin, an important food preservative, epidermin, a highly specific therapeutic agent against acne, a series of enzyme inhibitors, as well as immunologically interesting active peptides. Lantibiotics are produced by ribosomal synthesis, starting from inactive precursor proteins (prelantibiotics). The latter are post-translationally converted into the active peptide antibiotics through enzymic modifications. The modifying enzymes effect dehydrations at the serine and threonine residues and stereospecific additions of the cysteine thiol groups to the resulting α,β-unsaturated double bonds, which lead to the formation of several sulfide bridges. Upon subsequent proteolytic cleavage of the leader peptide, the biologically active lantibiotic is formed. Conformational analyses of the lantibiotics, as well as of their prepeptides, enables one to obtain information about the mechanism and steps of the biosynthesis. Antibodies against synthetic prepeptide sequences, and modern instrumental methods for the analysis of peptides, allow structural elucidation of the biosynthetic intermediates.     

Studies of the γ ← α transition in syndiotactic polystyrene

In this work we compare calorimetric and X-ray diffraction experiments realized on annealed sPS in helical γ forms resulting by different treatements: From clathrate δ form and from interaction of amorphous sample with acetone. The experimental results show that the γ form obtained by acetone converts into the more ordered final α” form modification; while the γ form, obtained by thermal treatments of δ form, transforms into the poorly ordered final α' form.     

A New General Approach to Enantiomerically Pure Cyclic and Open-Chain (R)- and (S)-α,α-Disubstituted α-Amino Acids

A wide range of cyclic and open-chain α,α-disubstituted α-amino acids 1a-p were prepared. The racemic N-acylated α,α-disubstituted amino acids were resolved by coupling to chiral amines 15-18 derived from (S)-phenylalanine to form diastereoisomers 19/20 or 21/22 that could be separated by crystallization and/or flash chromatography on silica gel (Scheme 3). Selective cleavage via the 1,3-oxazol-5(4H)-ones 10a-p gave the corresponding optically pure α,α-disubstituted amino-acid derivatives 11 or 12 in high yield (Scheme 3). The absolute configurations of the α,α-disubstituted amino acids were determined from X-ray structures of the diastereoisomers 20, 21g′, 22d .     

The ‘Azirine/Oxazolone Method’ on Solid Phase: Introduction of Various α,α‐Disubstituted α‐Amino Acids

Peptides containing various α,α‐disubstituted α‐amino acids, such as α‐aminoisobutyric acid (Aib), 1‐aminocyclopentane‐1‐carboxylic acid, α‐methylphenylalanine, and 3‐amino‐3,4,5,6‐tetrahydro‐2H‐pyran‐3‐carboxylic acid have been synthesized from the N‐ to the C‐terminus by the ‘azirine/oxazolone method’ under solid‐phase conditions. In this convenient method for the synthesis of sterically demanding peptides on solid‐phase, 2H‐azirin‐3‐amines are used to introduce the α,α‐disubstituted α‐amino acids without the need for additional reagents. Furthermore, the synthesis of poly(Aib) sequences has been explored.     

Deracemizing α‐Branched Carboxylic Acids by Catalytic Asymmetric Protonation of Bis‐Silyl Ketene Acetals with Water or Methanol

We report a highly enantioselective catalytic protonation of bis‐silyl ketene acetals. Our method delivers α‐branched carboxylic acids, including nonsteroidal anti‐inflammatory arylpropionic acids such as Ibuprofen, in high enantiomeric purity and high yields. The process can be incorporated in an overall deracemization of α‐branched carboxylic acids, involving a double deprotonation and silylation followed by the catalytic asymmetric protonation.     

Experimental and Theoretical Studies on the Rearrangement of 2‐Oxoazepane α,α‐Amino Acids into 2′‐Oxopiperidine β2,3,3‐Amino Acids: An Example of Intramolecular Catalysis

Enantiopure β‐amino acids represent interesting scaffolds for peptidomimetics, foldamers and bioactive compounds. However, the synthesis of highly substituted analogues is still a major challenge. Herein, we describe the spontaneous rearrangement of 4‐carboxy‐2‐oxoazepane α,α‐amino acids to lead to 2′‐oxopiperidine‐containing β^2,3,3‐amino acids, upon basic or acid hydrolysis of the 2‐oxoazepane α,α‐amino acid ester. Under acidic conditions, a totally stereoselective synthetic route has been developed. The reordering process involved the spontaneous breakdown of an amide bond, which typically requires strong conditions, and the formation of a new bond leading to the six‐membered heterocycle. A quantum mechanical study was carried out to obtain insight into the remarkable ease of this rearrangement, which occurs at room temperature, either in solution or upon storage of the 4‐carboxylic acid substituted 2‐oxoazepane derivatives. This theoretical study suggests that the rearrangement process occurs through a concerted mechanism, in which the energy of the transition states can be lowered by the participation of a catalytic water molecule. Interestingly, it also suggested a role for the carboxylic acid at position 4 of the 2‐oxoazepane ring, which facilitates this rearrangement, participating directly in the intramolecular catalysis.     

α-Halogenoketones—XIV: Studies in the chemistry of 2''-hydroxyacrylophenones

The chromone epoxide ring system has been synthesised. Base-catalysed cyclization and dehydrobromination of α-bromo-o-acyl (aroyl) oxyacetopheones or 2-bromo-1, 3-diones yielded 3-substituted chromone epoxides. Acid-catalysed rearrangement of a 2-methylchromone epoxide in an aprotic solvent gave a 2-methylenech-romanonol, while a 3-methoxymethylchromone epoxide fragmented to chromonol under these conditions; in alchols, chromone epoxides gave 2-alkoxychromanonols.