Haval-Argade contrathermodynamic rearrangement of alkylidenesuccinimides to alkylmaleimides via the corresponding isoimides: a general approach to alkyl and dialkyl substituted maleimides

A simple and efficient access to alkyl and dialkyl substituted maleimides has been demonstrated via the new contrathermodynamic rearrangement of (E)-alkylidenesuccinimides to alkylmaleimides. The (E)-alkylidenesuccinimides obtained from the Wittig-condensation of N-arylmaleimide with aliphatic aldehydes on regioselective hydrolysis furnished the corresponding (E)-alkylidenesuccinanilic acids in 95-98% yields. The β-alkylidenesuccinanilic acids on treatment with cyanuric chloride in the presence of triethylamine gave the corresponding β-alkylisomaleimides in 78-80% yields via the β-alkylideneisosuccinimides with the exocyclic to endocyclic carbon-carbon double bond migration. The kinetically controlled products alkylisomaleimides in refluxing acetic acid furnished the thermodynamically controlled alkylmaleimides in 98% yield. The Wittig condensation of alkyl substituted isomaleimides/maleimides with aliphatic aldehydes gave the desired dialkyl substituted maleimides in high yields. A conversion of α-methylenesuccinanilic acids to α-methylisomaleimides has also been described, with 90% yield.     

Facile approach to diverse range of 1,3-diaza-heterocycles: angular/linear selectivity paradigm and a remarkable intramolecular methyl migration

Starting from cyclic anhydrides and tert-butyl 2-aminobenzylcarbamate, simple and efficient synthesis of diverse range of kinetically controlled angular and thermodynamically controlled linear tricyclic and tetracyclic 1,3-diaza-heterocycles have been described via the intramolecular cyclizations of the corresponding imides/anilic acid esters. The effect of imide stability on the angular/linear product selectivity has also been described. The kinetically controlled angular products were successfully transformed to the corresponding thermodynamically controlled linear products by refluxing in methanol or methanol and acetic acid mixture. An interesting in situ 1,2-intramolecular methyl group migration has also been described.     

Kinetics of the acid-catalysed formation of aliphatic peracids from hydrogen peroxide and aliphatic acids in dioxan

The acid catalysed formation of peracids from substituted acetic acids and hydrogen peroxide has been studied kinetically in dioxan. The rates of peracid formation together with equilibrium constants increase with increasing concentration of sulphuric acid and are correlated with the acidity of the media. The substituent effect suggests that the reaction is controlled by steric rather than polar effects. A mechanism similar to acid-catalysed esterification is discussed.     

Chemo-Enzymatic Synthesis of Optically Active Amino Acids and Peptides

The industrial alkaline protease, alcalase, is stable and active in a high concentration of organic solvents and useful as a biocatalyst for (i) diastereoselective hydrolysis of peptide esters and preparation of racemization-free peptides; (ii) selective incorporation of esters of D-amino acid into peptides in t-butanol via a selective hydrolysis of esters of D,L-amino acid, followed by using the unhydrolyzed D-esters as a nucleophile in a kinetically controlled peptide bond formation; (iii) resolution of esters of amino acid in 95% t-butanol/5% water, followed by saponification of the unreacted esters to offer both enantiomers with high yield and optical purity; (iv) completely resolve amino-acid esters with high yield and optical purity via in situ racemization of the unreacted antipode catalyzed by pyridoxal 5-phosphate; (v) cryobioorganic synthesis of peptides with increased yields 15%–40% of peptide bond formation by reaction at 5 °C instead of 25–30 °C of a kinetically controlled enzymatic reaction in alcohols.     

Amination of 2,6- and 2,7-Naphthyridine. An NMR study on σ-Adducts of heterocyclic systems with amide ions

A facile synthesis of 2,6-naphthyridine is described. Both 2,6- and 2,7-naphthyridine undergo with potassium amide under kinetically and thermodynamically controlled conditions σ-adduct formation at position 1. Chichibabin amination of 2,6-naphthyridine yields 1-amino-2,6-naphthyridine in 54% yield.     

Total syntheses of (+/-)-anchinopeptolide D and (+/-)-cycloanchinopeptolide D

The first synthesis of (+/-)-anchinopeptolide D (4) has been accomplished in seven steps in 10% overall yield from octopamine hydrochloride (17), N-(Boc)glycine (16), and 5-amino-2-hydroxypentanoic acid (22). The key step is the aldol dimerization and hemiaminal formation of alpha-keto amide 26, which gives primarily protected anchinopeptolide D 27 under kinetically controlled conditions. Cycloanchinopeptolide D (31) has been prepared by the unprecedented head-to-head photodimerization of the two hydroxystyrylamides of 4 using the hydrophobic effect in water to force the two side chains into close proximity so that [2 + 2] cycloaddition is faster than trans to cis double bond isomerization. Coupling of amine 21 with pyroglutamic acid affords the naturally occurring tripeptide 35, which had been assigned glutamic acid structure 34.     

Enzyme-catalyzed peptide synthesis in ice

A new method for increasing product yield in kinetically controlled enzymatic peptide synthesis catalyzed by serine and cysteine proteases is proposed - freezing the reaction mixture. The use of the method in preparative synthesis has been demonstrated.     

Stereoselective synthesis of the C1-C13 fragment of bistramide A

The C1-C13 fragment of bistramide A was prepared from 5-hexenoic acid in 15 linear steps and in 16% overall yield. The core 2,6-trans-tetrahydropyran ring was obtained via a kinetically controlled oxa-Michael cyclization from the corresponding chiral α,β-unsaturated hydroxyester. This precursor was prepared by using a diastereoselective alkylation reaction using Davies Superquat auxiliary and a diastereoselective Roush’s allylboration as key steps.     

Enantioselective nitrile anion cyclization to substituted pyrrolidines. A highly efficient synthesis of (3S,4R)-N-tert-butyl-4-arylpyrrolidine-3-carboxylic acid

[reaction: see text] A practical asymmetric synthesis of N-tert-butyl disubstituted pyrrolidines via a nitrile anion cyclization strategy is described. The five-step chromatography-free synthesis of (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid (2) from 2-chloro-1-(2,4-difluorophenyl)-ethanone achieved a 71% overall yield. The cyclization substrate was prepared via a catalytic CBS asymmetric reduction, t-butylamine displacement of the chlorohydrin, and a conjugate addition of the hindered secondary amine to acrylonitrile. The key nitrile anion 5-exo-tet cyclization concomitantly formed the pyrrolidine ring with clean inversion of the C-4 center to afford 1,3,4-trisubstituted chiral pyrrolidine in >95% yield and 94-99% ee. Diethyl chlorophosphate and lithium hexamethyldisilazide were shown to be the respective optimum activating group and base in this cyclization. The trans-cis mixture of the pyrrolidine nitrile undergoes a kinetically controlled epimerization/ saponification to afford the pure trans-pyrrolidine carboxylic acid target compound in >99.9% chemical and optical purity. This chemistry was also shown to be applicable to both electronically neutral and rich substituted phenyl substrates.     

Total synthesis of zaragozic acid C by an aldol-based strategy

A total synthesis of zaragozic acid C by a convergent strategy is described in which the key features include (1) the simultaneous creation of the C4 and C5 quaternary stereogenic centers by a Sn(OTf)₂-promoted aldol coupling reaction between an α-keto ester and a silyl ketene thioacetal derived from l- and d-tartaric acids, respectively, (2) the direct introduction of lithium acetylide as the C1 side chain equivalent onto the fully functionalized aldehyde, and (3) construction of the bicyclic core structure by acid-catalyzed internal ketalization under kinetically controlled conditions.     

Production of Polymers from the Seed Oil Of Crambe Abyssinica. I. Isolation of Tridecanedioic (Brassylic) Acid

Methyl erucate has been separated from the mixed esters of the fatty acids obtained from the seed oil of Crambe abyssinica. Oxidative cleavage of erucic acid to give brassylic and pelar-gonic acids has been examined. The brassylic acid yield by nitric acid oxidation is less than that from reaction with potassium permanganate which in turn is less productive than ozonolysis. The overall yield of high-purity brassylic acid is 62.4% based on the methyl erucate fraction or 36.4% referred to the seed oil.     

Cyclic tautomers of tryptophans and tryptamines—4: Synthesis of cyclic tautomers of tryptophans and tryptamines

N_b-Methoxycarbonyltryptophan methyl ester (dl- and l-13) was cyclized to the corresponding rans cyclic tautomer (14) in excellent yield in various acids such as 85% phosphoric acid or trifluoroacetic acid. The cis cyclic tautomer (15) was formed as the less stable and kinetically controlled product and converted to the more stable trans isomer (14) under the reaction condition. The trans isomer (14) was reverted to 13 on treatment with 10% sulfuric acid in methanol. Other tryptophan and tryptamine derivatives (6 and 19a) also cyclized to the corresponding cyclic tautomers in similar acidic media.     

α-Chymotrypsin-catalyzed peptide synthesis in frozen aqueous solution using N-protected amino acid carbamoylmethyl esters as acyl donors

A kinetically controlled peptide synthesis catalyzed by α-chymotrypsin was performed in frozen aqueous solution (ice, −24 °C). The yield of the peptide was significantly improved by the use of the carbamoylmethyl (Cam) ester as the acyl donor instead of the conventional ethyl ester. The peptide yield increased up to ca. 90% when N-benzyloxycarbonyl (CBZ)-Phe-OCam and H-Phe-NH₂ were used as the acyl donor and nucleophile, respectively. Such an improvement of the peptide yield in ice was also observed in the coupling of other CBZ-amino acid Cam esters as acyl donors. Furthermore, this approach was applied to the synthesis of peptides containing d-amino acids. The peptides such as CBZ-d-Phe-Phe-NH₂, CBZ-Phe-d-Phe-NH₂ and CBZ-d-Phe-d-Phe-NH₂ were also obtained in excellent to moderate yields in ice. A high diastereoselectivity towards the l–l peptide was observed when the racemic amino acid Cam ester was used as the acyl donor in ice.     

A kinetic and mechanistic study of the amino acid catalyzed aldol condensation of acetaldehyde in aqueous and salt solutions

The amino acid catalyzed aldol condensation is of great interest in organic synthesis and natural environments such as atmospheric particles. However, kinetic and mechanistic information on these reactions is limited. In this work the kinetics of the aldol condensation of acetaldehyde in water and aqueous salt solutions (NaCl, CaCl2, Na2SO4, MgSO4) catalyzed by five amino acids (glycine, alanine, serine, arginine, and proline) at room temperature (295 +/- 2 K) has been studied. Monitoring the formation of three products, crotonaldehyde, 2,4-hexadienal, and 2,4,6-octatrienal, by UV-vis absorption over 200-1100 nm revealed two distinct kinetic regimes: at low amino acid concentrations (in all cases, below 0.1 M), the overall reaction was first-order with respect to acetaldehyde and kinetically limited by the formation of the enamine intermediate. At larger amino acid concentrations (at least 0.3 M), the kinetics was second order and controlled by the C-C bond-forming step. The first-order rate constants increased linearly with amino acid concentration consistent with the enamine formation. Inorganic salts further accelerated the enamine formation according to their pKb plausibly by facilitating the iminium or enamine formation. The rate constant of the C-C bond-forming step varied with the square of amino acid concentration suggesting the involvement of two amino acid molecules. Thus, the reaction proceeded via a Mannich pathway. However, the contribution of an aldol pathway, first-order in amino acid, could not be excluded. Our results show that the rate constant for the self-condensation of acetaldehyde in aqueous atmospheric aerosols (up to 10 mM of amino acids) is identical to that in sulfuric acid 10-15 M (kI approximately 10-7-10-6 s-1) clearly illustrating the potential importance of amino acid catalysis in natural environments. This work also demonstrates that under usual laboratory conditions and in natural environments aldol condensation is likely to be kinetically controlled by the enamine formation. Notably, kinetic investigations of the C-C bond-forming addition step would only be possible with high concentrations of amino acids.     

On the reactions of ortho-positronium with methylmaleic and methylfumaric acids

The o-Ps quenching reactions promoted by methylmaleic (citraconic) and methylfumaric (mesaconic) acids were investigated in aqueous solutions in order to compare their rate constants with those of maleic and fumaric acids. As expected, it was found that the rate constants of citraconic and mesaconic acids are almost equal and are much less than that of maleic acid, which in turn is less than that of fumaric acid. Moreover, it was ascertained that while the o-Ps quenching reactions promoted by maleic and fumaric acids seem to be diffusion controlled, the quenching reactions promoted by citraconic acid are kinetically controlled, its activation energy being 0.45±0.03 eV, which is significantly greater than the activation energy of diffusion-controlled reactions occurring in water, 0.18±0.01 eV.     

Design and concise synthesis of fully protected analogues of l-gamma-carboxyglutamic acid

The design and synthesis of four nonnaturally occurring amino acid analogues of l-gamma-carboxyglutamic acid (Gla), appropriately protected for Fmoc-based solid-phase peptide synthesis (SPPS), is described. These amino acids are Bu-Mal 2, BCAH 3, Pen-Mal 4, and Cm-Gla 5. These Gla analogues have been designed to replace the glutamic acid of position 1 in the cyclic decapeptide G1TE, which is a potent inhibitor of tyrosine kinase, to further enhance binding to the Grb2-SH2 domain of signal transduction receptors. In the new amino acids, the propionic acid side chain of Glu has been replaced by a malonyl or a carboxymethylmalonyl moiety located at different distances from the alpha-carbon to optimize interactions in the phosphotyrosine-binding cavity of the Grb2-SH2 domain. Additionally, a direct and efficient synthetic route for the preparation of Fmoc-protected l-gamma-carboxyglutamic acid, which is amenable to large-scale production, has been developed to provide this important and unique amino acid(1) in 55% overall yield.     

Identification of supramolecular templates: design of solid-state photoreactivity using structural similarity

Structural similarity has been used to identify multifunctional templates for topochemically controlled solid-state photodimerisation. By examination of co-crystal structures of 4,4′-bipyridine with various acids, tricarballylic acid and 1,2,4,5-benzenetetracarboxylic acid have been identified as supramolecular templates for the alignment in the solid-state of 1,2-bis(4-pyridyl)ethylene. As a result, photodimerisation in the solid-state proceeds smoothly and with high yield.     

Insight into acid-mediated asymmetric spirocyclization in the presence of a chiral diol

Asymmetric spirocyclization based on intramolecular conjugate addition using a combination of a Lewis acid and an optically active cyclohexane-1,2-diol has been studied in connection with 1) the effect of substituents on the cyclohexane-1,2-diol and 2) the effect of substituents on the substrate. This reaction was found to be both thermodynamically and kinetically controlled under restricted conditions.     

Regioselective copper-catalyzed amination of bromobenzoic acids using aliphatic and aromatic amines

A chemo- and regioselective copper-catalyzed cross-coupling procedure for amination of 2-bromobenzoic acids is described. The method eliminates the need for acid protection and produces N-aryl and N-alkyl anthranilic acid derivatives in up to 99% yield. N-(1-Pyrene)anthranilic acid has been employed in metal ion-selective fluorosensing. Titration experiments showed that this pyrene-derived amino acid forms an equimolar complex with Hg(II) in water resulting in selective fluorescence quenching even in the presence of other metal ions such as Zn(II) and Cd(II).