Cleavage of Menger’s aliphatic amide: A model for peptidase enzyme solely explained by proximity orientation in intramolecular proton transfer

Ab initio HF/6-31G and DFT B3LYP/6-31G (d,p) calculations for the cleavage of Menger’s aliphatic amide 3 (a peptidase model) under physiological conditions, indicate that the rate limiting step in the cleavage process is a proton transfer from one of the carboxyl groups onto the amidic carbonyl oxygen. The acceleration in rates is mainly due to proximity orientation, and the effect of pseudoallylic strain relief on the rates is negligible. Moreover, the calculations reveal that the mode and the mechanism of the amide cleavage are largely dependent on the pH of the reaction. These results explain the findings that peptidase enzymes are reactive around neutral pH while their activities vanish under basic medium.     

Catalytic enantioselective 1,3-dipolar cycloadditions of nitrones with propioloylpyrazoles and acryloylpyrazoles induced by chiral π-cation catalysts

A chiral copper(II) complex of 3-(2-naphthyl)-l-alanine amide successfully catalyzes the enantioselective 1,3-dipolar cycloaddition reaction of nitrones with propioloylpyrazole and acryloylpyrazole derivatives. The asymmetric environment created by intramolecular π-cation interaction gives the corresponding adducts in high yields with excellent enantioselectivity. This is the first successful method for the catalytic enantioselective 1,3-dipolar cycloaddition of nitrones with acetylene derivatives. The 1,3-dipolar cycloadducts can be stereoselectively converted to β-lactams via reductive cleavage of the N-O bond using SmI(2).     

Reactions of silamorpholinones and acylsilamorpholines with electrophilic reagents. X-ray structure of products including a pentacoordinated silicon compound

Reactions of 2-sila-5-morpholinones, 4-acyl-2-silamorpholines and 4-acyl-2,6-disilamorpholines with electrophilic reagents generally lead to the opening of the sila- or disilacycle by cleavage of the Si–O bond with subsequent rearrangement to form five-membered chelate derivatives where the amide oxygen atoms coordinate with the silicon to form pentacoordinate silicon species. Multinuclear NMR spectroscopy and X-ray diffraction studies were used for structural investigation of the products. 4-Acyl-2,6-disilamorpholines initially form adducts with strong acids where the amide oxygen is protonated by the acid as demonstrated by X-ray crystallography.     

Short synthesis of skeleton-modified cyclodextrin derivatives with unique inclusion ability

[reaction: see text] Skeleton-modified cyclodextrin (CD) derivatives, in which an alpha-(1,4)-glucosidic bond is converted into a beta-(1,4)-glucosidic bond, were conveniently synthesized by cleavage of a single glucosidic bond in permethylated and 2,6-di-O-methylated alpha- and beta-CDs and subsequent recyclization via the trichloroacetoimidate intermediates. The selective cleavage of an alpha-(1,4)-glucosidic bond of permethylated alpha- and beta-CDs was accomplished by stirring in 30% aq HClO(4) at 25 degrees C to give the corresponding maltohexaose and maltoheptaose derivatives, respectively. The cleavage of a glucosidic bond of hexakis(3-O-benzyl-2,6-di-O-methyl)-alpha-CD was successfully carried out in a mixed 60% aq HClO(4) and 1,4-dioxane solution (1:20). In the case of heptakis(3-O-benzyl-2,6-di-O-methyl)-beta-CD, the solvent-free reaction with p-toluenesulfonic acid was found to be effective for selective cleavage of one glucosidic bond. The permethylated beta-CD derivative with a beta-(1,4)-glucosidic bond (4b) exhibited higher inclusion ability toward sodium m-nitrobenzoate than the parent permethylated beta-CD, while these hosts showed the same inclusion ability toward sodium p-nitrobenzoate. On the other hand, the beta-(1,4)-type permethylated alpha-CD derivative 4a exhibited lower inclusion ability toward sodium p- and m-nitrobenzoates than the parent permethylated alpha-CD. Interestingly, host molecules 4a and 4b showed inclusion selectivity for sodium m-nitrobenzoate as compared with the corresponding para-isomer, in contrast to permethylated CDs which possessed para-isomer selectivity. On the other hand, host molecules 4a and 4b showed para-isomer selectivity toward sodium nitrophenoxide guests, indicating that the inclusion selectivity was remarkably influenced by the guest hydrophilic groups. (1)H NMR studies on complexes of those beta-(1,4)-type CD derivatives with p- and m-nitrobenzoates and p- and m-nitrophenolates were carried out to estimate their structures.     

Analysis of amide bond formation with an alpha-hydroxy-beta-amino acid derivative, 3-amino-2-hydroxy-4-phenylbutanoic acid, as an acyl component: byproduction of homobislactone

In the synthesis of peptidomimetics containing alpha-hydroxy-beta-amino acid, the coupling of this N(beta)-protected beta-amino acid with amine components was generally performed without the protection of its alpha-hydroxyl group. However, the formation of dipeptides in low yield was often observed when sterically hindered amine components were used. Boc-Apns-OH [Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid, allophenylnorstatine] (6), which is one of such beta-amino acid derivatives, is intensively employed as a core structure in the development of HIV-1 protease inhibitors. There have been no precise studies, to date, that have examined amide bond formation with alpha-hydroxy-beta-amino acid derivatives as an acyl component. To determine the cause of this low-yield reaction, we studied the amide bond formation focusing on the activation step of N(beta)-protected alpha-hydroxy-beta-amino acid by using a model coupling reaction between 6 and H-Dmt-OR [Dmt: (R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid] (7). A significant amount of homobislactone 9 was formed through the activation of the carboxyl group of 6 to the benzotriazole-type active esters such as OBt and OAt. In addition, this homobislactone formation was markedly increased in the presence of a catalytic amount of a base, which exhibited good correlation with the low yield of the amide bond formation, suggesting that homobislactone formation is one major reason for the low yield of the amide bond formation. Moreover, homobislactones were also formed in other derivatives of the N(beta)-protected alpha-hydroxy-beta-amino acid, suggesting a common feature of this type of amino acids. The use of a strong activation method like EDC--HOAt without base addition enhanced amide bond formation, although a small amount of homobislactone may be formed during the coupling reaction.     

Structure-Acid Lability Relationship of N-alkylated α,α-dialkylglycine Obtained via a Ugi Multicomponent Reaction

Using the classical Ugi four-component reaction to fuse an amine, ketone, carboxylic acid, and isocyanide, here we prepared a short library of N-alkylated α,α-dialkylglycine derivatives. Due to the polyfunctionality of the dipeptidic scaffold, this highly steric hindered system shows an interesting acidolytic cleavage of the C-terminal amide. In this regard, we studied the structure-acid lability relationship of the C-terminal amide bond (cyclohexylamide) of N-alkylated α,α-dialkylglycine amides 1a–n in acidic media and, afterward, it was established that the most important structural features related to its cleavage. Then, it was demonstrated that electron-donating effects in the aromatic amines, flexible acyl chains (Gly) at the N-terminal and the introduction of cyclic compounds into dipeptide scaffolds, increased the rate of acidolysis. All these effects are related to the ease with which the oxazolonium ion intermediate forms and they promote the proximity of the central carbonyl group to the C-terminal amide, resulting in C-terminal amide cleavage. Consequently, these findings could be applied for the design of new protecting groups, handles for solid-phase synthesis, and linkers for conjugation, due to its easily modulable and the fact that it allows to fine tune its acid-lability.     

The Driving Force for the Acylation of β-Lactam Antibiotics by L,D-Transpeptidase 2: Quantum Mechanics/Molecular Mechanics (QM/MM) Study

β-lactam antibiotics, which are used to treat infectious diseases, are currently the most widely used class of antibiotics. This study focused on the chemical reactivity of five- and six-membered ring systems attached to the β-lactam ring. The ring strain energy (RSE), force constant (FC) of amide (C−N), acylation transition states and second-order perturbation stabilization energies of 13 basic structural units of β-lactam derivatives were computed using the M06-2X and G3/B3LYP multistep method. In the ring strain calculations, an isodesmic reaction scheme was used to obtain the total energies. RSE is relatively greater in the five-(1a–2c) compared to the six-membered ring systems except for 4b, which gives a RSE that is comparable to five-membered ring lactams. These variations were also observed in the calculated inter-atomic amide bond distances (C−N), which is why the six-membered ring lactams C−N bond are more rigid than those with five-membered ring lactams. The calculated ΔG^# values from the acylation reaction of the lactams (involving the S−H group of the cysteine active residue from L,D transpeptidase 2) revealed a faster rate of C−N cleavage in the five-membered ring lactams especially in the 1–2 derivatives (17.58 kcal mol⁻¹). This observation is also reflected in the calculated amide bond force constant (1.26 mDyn/A) indicating a weaker bond strength, suggesting that electronic factors (electron delocalization) play more of a role on reactivity of the β-lactam ring, than ring strain.     

Rhodium(III)‐Catalyzed Redox‐Neutral Coupling of α‐Trifluoromethylacrylic Acid with Benzamides through Directed C−H Bond Cleavage

A rhodium(III)‐catalyzed redox‐neutral coupling of α‐trifluoromethylacrylic acid with bezamides proceeds smoothly accompanied by amide‐directed C?H bond cleavage to produce β‐[2‐(aminocarbonyl)phenyl]‐α‐trifluoromethylpropanoic acid derivatives. One of the products can be transformed to a trifluoromethyl substituted heterocyclic compound. In addition, the redox‐neutral coupling of α‐trifluoromethylacrylic acid with related aromatic substrates possessing a nitrogen‐containing directing group can also be conducted under similar conditions.     

A novel salt bridge mechanism highlights the need for nonmobile proton conditions to promote disulfide bond cleavage in protonated peptides under low-energy collisional activation

The gas-phase fragmentation mechanisms of small models for peptides containing intermolecular disulfide links have been studied using a combination of tandem mass spectrometry experiments, isotopic labeling, structural labeling, accurate mass measurements of product ions, and theoretical calculations (at the MP2/6-311 + G(2d,p)//B3LYP/3-21G(d) level of theory). Cystine and its C-terminal derivatives were observed to fragment via a range of pathways, including loss of neutral molecules, amide bond cleavage, and S-S and C-S bond cleavages. Various mechanisms were considered to rationalize S-S and C-S bond cleavage processes, including charge directed neighboring group processes and nonmobile proton salt bridge mechanism. Three low-energy fragmentation pathways were identified from theoretical calculations on cystine N-methyl amide: (1) S-S bond cleavage dominated by a neighboring group process involving the C-terminal amide N to form either a protonated cysteine derivative or protonated sulfenyl amide product ion (44.3 kcal mol(-1)); (2) C-S bond cleavage via a salt bridge mechanism, involving abstraction of the alpha-hydrogen by the N-terminal amino group to form a protonated thiocysteine derivative (35.0 kcal mol(-1)); and (3) C-S bond cleavage via a Grob-like fragmentation process in which the nucleophilic N-terminal amino group forms a protonated dithiazolidine (57.9 kcal mol(-1)). Interestingly, C-S bond cleavage by neighboring group processes have high activation barriers (63.1 kcal mol(-1)) and are thus not expected to be accessible during low-energy CID experiments. In comparison to the energetics of simple amide bond cleavage, these S-S and C-S bond cleavage reactions are higher in energy, which helps rationalize why bond cleavage processes involving the disulfide bond are rarely observed for low-energy CID of peptides with mobile proton(s) containing intermolecular disulfide bonds. On the other hand, the absence of a mobile proton appears to "switch on" disulfide bond cleavage reactions, which can be rationalized by the salt bridge mechanism. This potentially has important ramifications in explaining the prevalence of disulfide bond cleavage in singly protonated peptides under MALDI conditions.     

Energetics and dynamics of the fragmentation reactions of protonated peptides containing methionine sulfoxide or aspartic acid via energy- and time-resolved surface induced dissociation

The surface-induced dissociation (SID) of six model peptides containing either methionine sulfoxide or aspartic acid (GAILM(O)GAILR, GAILM(O)GAILK, GAILM(O)GAILA, GAILDGAILR, GAILDGAILK, and GAILDGAILA) have been studied using a specially configured Fourier transform ion-cyclotron resonance mass spectrometer (FT-ICR MS). In particular, we have investigated the energetics and dynamics associated with (i) preferential cleavage of the methionine sulfoxide side chain via the loss of CH3SOH (64 Da), and (ii) preferential cleavage of the amide bond C-terminal to aspartic acid. The role of proton mobility in these selective bond cleavage reactions was examined by changing the C-terminal residue of the peptide from arginine (nonmobile proton conditions) to lysine (partially mobile proton conditions) to alanine (mobile proton conditions). Time- and energy-resolved fragmentation efficiency curves (TFECs) reveal that selective cleavages due to the methionine sulfoxide and aspartic acid residues are characterized by slow fragmentation kinetics. RRKM modeling of the experimental data suggests that the slow kinetics is associated with large negative entropy effects and these may be due to the presence of rearrangements prior to fragmentation. It was found that the Arrhenius pre-exponential factor (A) for peptide fragmentations occurring via selective bond cleavages are 1-2 orders of magnitude lower than nonselective peptide fragmentation reactions, while the dissociation threshold (E0) is relatively invariant. This means that selective bond cleavage is kinetically disfavored compared to nonselective amide bond cleavage. It was also found that the energetics and dynamics for the preferential loss of CH3SOH from peptide ions containing methionine sulfoxide are very similar to selective C-terminal amide bond cleavage at the aspartic acid residue. These results suggest that while preferential cleavage can compete with amide bond cleavage energetically, dynamically, these processes are much slower compared to amide bond cleavage, explaining why these selective bond cleavages are not observed if fragmentation is performed under mobile proton conditions. This study further affirms that fragmentation of peptide ions in the gas phase are predominantly governed by entropic effects.     

Synthesis of new functionalized imidazo[2,1‐b]thiazoles and thiazolo[3,2‐a]pyrimidines

5‐Oxo‐5H‐[1,3]thiazolo[3,2‐a]pyrimidine‐6‐carboxylic acid ( 4 ), and 6‐methylimidazo[2,1‐b]thiazole‐5‐carboxylic acid ( 17 ) were reacted with amines 6a‐i by the reaction with oxalyl chloride and N, N‐di methyl‐formamide as a catalyst into primary and secondary amide derivatives 7‐14 and 19‐22. From compound 24 N,N'‐disubstituted ureas 26, 27 and perhydroimidazo[1,5‐c]thiazole 29 derivatives of imidazo[2,1‐b]thiazole were prepared. By nmr analysis of compound 29 , the existence of two stereoisomers resulting from both optical, due to centre of chirality at C7′a, and conformational isomerism, due to restricted C5? N6′ bond rotation were proved.     

Photochemical 1,3-acyl migration in cyclic dienamides (azepinones)

Irradiation of 1,3-dihydro-2$\text{H}$-azepin-2-ones in aprotic solvents gives azabicycloheptenones by intramolecular cycloaddition, but photochemical isomerization in methanol results in 1,3-acyl migration involving cleavage of the amide bond.     

Functionalization of 6-nitrobenzo[1,3]dioxole with carbonyl compounds via TDAE methodology

We report herein the synthesis of substituted 2-(6-nitrobenzo[1,3]dioxol-5-yl)-1- aryl ethanols and 2-(6-nitrobenzo[1,3]dioxol-5-yl)-propionic acid ethyl esters from the reaction of 5-chloromethyl-6-nitrobenzo[1,3]dioxole with various aromatic carbonyl and alpha- carbonyl ester derivatives using the tetrakis(dimethylamino)ethylene (TDAE) methodology.     

Asymmetric intramolecular [3 + 2] cycloaddition reactions of acylhydrazones/olefins using a chiral zirconium catalyst

Catalytic asymmetric intramolecular [3 + 2] cycloaddition of hydrazone/olefins has been attained. In the presence of a chiral zirconium catalyst prepared from zirconium alkoxide and a BINOL derivative, the desired pyrazolidine derivatives were obtained in high yields with high selectivities. The products were easily converted to 1,3-diamine or beta-aminonitrile derivatives by N-N bond cleavage.     

Enzymatic hydrolysis of alpha- and beta-oligo(L-aspartic acid)s by poly(aspartic acid) hydrolases-1 and 2 from Sphingomonas sp. KT-1

The enzymatic hydrolysis of alpha- and beta-oligo(L-aspartic acid)s by PAA hydrolase-1 and PAA hydrolase-2 (purified from Sphingomonas sp. KT-1) was performed to elucidate the mechanism of the microbial degradation by Sphingomonas sp. KT-1 of the thermally synthesized alpha,beta-poly(D,L-aspartic acid) (tPAA). GPC analysis of the hydrolyzed products of alpha- and beta-tetra(L-aspartic acid)s by PAA hydrolase-1 has showed that PAA hydrolase-1 is capable of hydrolyzing only the specific amide bonds between beta-aspartic acid units. The RP-HPLC analysis of the enzymatic hydrolysis of beta-oligo(L-aspartic acid)s (4 and 5 mers) by PAA hydrolase-1 has suggested that the enzymatic hydrolysis of beta-oligo(L-aspartic acid)s occurs via an endo-mode cleavage. In contrast, PAA hydrolase-2 hydrolyzed both alpha- and beta-oligo(L-aspartic acid)s via an exo-mode cleavage to yield L-aspartic acid as a final product. A kinetic study on the enzymatic hydrolysis of alpha-oligo(L-aspartic acid)s (3 to 7 mers) by PAA hydrolase-2 has indicated that Km values are almost independent of the number of monomer units in oligomers of 4 to 7 mers, while that Vmax values are markedly dependent on the chain length and show a maximum value at 5 mer.     

Synthesis of 2-(N-Acetylamino)-2-deoxy-C-glucopyranosyl nucleosides as potential inhibitors of chitin synthases

The C-glucopyranosyl nucleosides (1-4) containing the N-acetyl glucosaminyl and uridine units have been synthesized as nonhydrolyzable substrate analogues of UDP-GlcNAc aimed to inhibit the chitin synthases. The key intermediate, 4-(2'-(N-acetylamino)-3', 4',6'-tri-O-benzyl-2'-deoxy-alpha-D-glucopyranosyl)but-2-enoic acid (5), was prepared from the perbenzylated (N-acetylamino)-alpha-C-allylglucoside (7), by successive oxidative cleavage, Wittig olefination, and ester deprotection. The coupling of the acid 5 with the hydroxyl or amine function of the uridine derivatives (6a or 6b) afforded, respectively, the ester 12 and amide 14. The dihydroxylation of the conjugated double bond in ester 12 or amide 14 was better achieved with osmium tetraoxide/barium chlorate, leading to the expected diols 13 and 15 as a mixture of two diastereoisomers. The desired compounds 1-4 were obtained after catalytic hydrogenation of compounds 12-15.     

Obtention de dérivés alléniques α-siliciés par monodésilylation du bis(triméthylsilyl)-1,3 propyne

In the presence of electrophilic reagents cleavage occurs at the silicon-propargylic carbon bond of 1,3-bis(trimethylsilyl)propyne with rearrangement to an allene. This reaction is a method of synthesis for α-silylated allenic derivatives.     

一种切断酰胺C—N键的简便方法

研究了一种质子酸和Lewis酸共同催化酰胺C—N键断键的新方法,讨论了温度,CuCl2量以及Lewis酸种类对C—N键断键率的影响,并提出了在此条件下酰胺C—N键断裂的可能机理.新方法反应温度低、耗酸量小、条件温和.     

Stereoselective synthesis of cis- or trans-3,5-disubstituted pyrazolidines via Pd-catalyzed carboamination reactions: use of allylic strain to control product stereochemistry through N-substituent manipulation

The stereoselective synthesis of either trans- or cis-3,5-disubstituted pyrazolidines is accomplished via Pd-catalyzed carboamination reactions of unsaturated hydrazine derivatives. The products are obtained in good yield with up to >20:1 diastereoselectivity. Stereocontrol is achieved by modulating the degree of allylic strain in the transition state for syn-aminopalladation through a simple modification of the substrate N(2)-substituent. The pyrazolidine products can be further transformed to 3,5-disubstituted pyrazolines via deprotection/oxidation, or to substituted 1,3-diamines via N-N bond cleavage.     

Participation d'un groupe amide a la formation de sels de dioxolanne-1,3 ylium-2; Modele biomimetique de reaction de peptidation

An amide group is shown to be capable of intramolecular participation in the formation of an 1,3-dioxolan 2-ylium cation giving a tricyclic organic cation of a new type $\text{5a}$,$\text{b}$. This cation may be considered as a model of an electrophilic intermediate which might be formed from a peptidyl t-RNA during protein biosynthesis.The tricyclic salt $\text{5a}$,$\text{b}$ reacts with water and methanol like a classical dioxolenium salt. An amide acetal $\text{18}$ can be obtained from dimethylamine and 5a; hydrolysis of $\text{18}$ does not lead to the corresponding amide $\text{20}$ but to the cleavage of the CN. bond.