磷酰化氨基酸反应性质的理论研究

采用量子化学计算研究了磷酰化氨基酸的反应性质,包括N-磷酰氨基酸成肽反应、成酯反应、磷上酯交换反应和磷上的N→O迁移反应的机理以及计算模型和计算方法的选择,并从理论上解释了自然界选择α-氨基酸而不是β,γ-氨基酸的实验事实.     

N-磷酰化氨基酸生成五配位磷中间体过程中氨基酸侧链立体化学效应的理论研究

用密度泛函(DFT)方法在B3LYP/6-311G(d,p)水平上对N-磷酰化氨基酸生成五配位磷酸羧酸混酐(IMCPA)反应中手性氨基酸残基侧链的立体化学效应进行了研究. 模拟了氨基酸残基上羧基氧原子从磷酰基的不同侧面进攻磷原子从而形成不同构型五配位磷中间体的反应途径, 探讨了IMCPA生成过程中的立体选择性.     

Ab Initio and MNDO Calculation of the Intermediates of N-Diisopropylphosphoryl L-lspartic Acid

Many biological processes are regulated by the phosphorylation and dephosphorylation of amino acid residues in the proteins^[1]. High-coordinate phosphorus intermediates forming from amino acid residues in protein are of great importance in the process of phosphorylation and dephosphorylation of protein. It has been proposed that the mechanisms of phosphorylation through penta-coordinate intramolecular mixed carboxylic-phosphoric anhydride intermediates^[2]. It was found that α-COOH group^[3] and β-COOH group^[4] in aspartic acid had different activities in the ester exchange on phosphorus. So it is important to discuss which carboxylic acids is involved in the penta-coordinate phosphorus intermediate of aspartic acid.     

磷酰化组氨酸形成六配位磷中间体的理论研究

用MNDO方法对磷酰化组氨酸磷上酯交换反应侧链咪唑基所参与的六配位磷机理进行了研究。六配位磷中间体形成后,使咪唑基对面的异丙氧基反应活性提高。当磷上酯交换反应发生时,异丙氧基离去和另一分子醇进攻磷,从咪唑基的对面发生,在能量上和空间上都是有利的。六配位磷机理比较好地解释了咪唑的催化作用。     

丝组二肽对DNA切割作用的QM-MM研究

运用QM-MM方法对丝组二肽切割DNA作用的机理进行了研究．通过计算得到了丝组二肽与DNA形成多氢键作用的有效分子识别模型及相关分子结构参数,从理论上解释了丝组二肽与DNA通过形成五配位磷中间体而使磷酸二酯键发生水解,从而使得DNA被切断的作用机理。     

Amino acids and peptides—V: Novel peptide bond formation catalyzed by metal ions—III Elucidation of the formation mechanism

Elucidation of the mechanism for peptide bond formation observed when an amino acid ester is treated with anhyd CuCl₂ in an anhyd alcoholic solvent, was attempted using results of IR and visible spectra measurements of the amino acid ester-CuCl₂ complex and accumulated experimental data.This novel reaction proceeds through a mechanism in which the amino anion produced by elimination of the proton from the Cu(II)-coordinating amino group, attacks the non-activated ester CO group of the amino acid ester which shares a common Cu(II) ion. It differs completely from the peptide formation reaction featuring a Co(III)-amino acid ester complex.     

Theoretical Prediction of 31P NMR Chemical Shifts of Intermediates in Phosphoryl Ester Exchange and N → O Migration Reactions of Dialkyloxyphosphoryl Amino Acid

Based on a detailed ab initio study on the reaction mechanism of phosphoryl ester exchange and N → O migration reactions of dimethyloxyphosphoryl-threonine, ab initio GIAO magnetic shielding calculations have been carried out on the predicted stable intermediate and the corresponding reactant and product. The ³¹P NMR chemical shift of the most stable penta-coordinate phosphorus intermediate has been predicted as about –71 ppm. The theoretical results may lead to a possible way to experimentally examine our predictions and to monitor the most stable intermediate during the reaction process.     

Synthesis and Theoretical Studies of Phosphoryl Amino Acid Analogue

Phosphoryl amino acids and their analogues are continuing to be increasingly important as potential enzyme inhibitors, mechanistic probes for proteases^[1,2]. Previously, a series of investigations on the structure-reactivity relationship about phosphoryl amino acids 1 had been carried out, the results showed that the co-participation of phosphoryl group, carboxyl group and residues of amino acids were essential and their biomimic reaction mechanisms were commonly through a penta-coordinate intramolecular mixed carboxylic-phosphoric anhydride intermediates^[3].     

Comparison of the isomeric α-amino acyl adenylates and amino acid phosphoramidates of adenosine by electrospray ionization tandem mass spectrometry

The isomeric α-amino acyl adenylates and amino acid phosphoramidates of adenosine were synthesized and analyzed in detail by electrospray ionization tandem mass spectrometry (ESI-MS(n)). In ESI-MS/MS of α-amino acyl adenylates, the novel rearrangement ion [cAMP-H](-) observed as the most intense signal was formed through the pentacoordinate phosphorus intermediate with a six-membered ring by nucleophilic attack of the 3'-hydroxyl group on the phosphorus atom. In contrast, for the amino acid phosphoramidate of adenosine, the phosphorus atom could be attacked not only by the carboxylic group to form the cyclic aminoacyl phosphoramidates (CAPAs), but also by the nitrogen atom on the nucleobase leading to intramolecular phosphoryl group migration. It was found that the sodium ion having multidentate binding ability played an essential role in this characteristic rearrangement. The proposed mechanisms were supported by the MS/MS study, deuterium-labeled experiments, high-resolution tandem mass spectrometry and moderate calculations at the B3LYP/6-31G* level. The characteristic fragmentation patterns of α-amino acyl phosphates and amino acid phosphoramidates allows identification of stereoisomers when either the phosphorylation is at the N-terminus or C-terminus of amino acids.     

5-(2-羧基苯基)-10,15,20-三苯基卟啉对氨基酸酯的分子识别模型研究

对氨基酸及其衍生物的分子识别一直是仿生化学领域中的重要课题.以金属卟啉配合物作为主体分子对氨基酸酯的分子识别是最近几年来的热点之一^[15].氨基酸是蛋白质的主要组成部分,在蛋白质合成过程中,对氨基酸及其衍生物的识别是关健的一步.     

R(-)四氢噻唑-2-硫酮-4-羧酸对D,L-氨基酸酯拆分的研究

以新手性拆分试剂R(-)四氢噻唑-2-硫酮-4-羧酸[简称R(-)TTCA]对D,L-氨基酸酯进行手性拆分,分别得到(R)TTCA氨基酸酯盐1a_1f([α]_D²⁰＝-30.40°～-42.70°)及光学活性氨基酸酯2a-2f,其光学纯度为35.4%～75.8%.由1a_1f在碱存在下分解出2a-2f的对映体3a-3f,光学纯度为39.50%～69.10%.用半经验的量子化学PM3方法研究了氨基的碱性、中间产物铵盐生成热和稳定性.     

Stereoselective analysis of D and L dansyl amino acids as the mixed chelate copper(II) complexes by HPLC

This paper reviews the mixed chelation approach to resolution of the optical isomers of D and L dansyl amino acids by high performance liquid chromatography. The use of eluants containing Cu(II) complexes of L-proline, L-arginine, L-histidine, and L-histidine methyl ester effected the separation of many D and L amino acids, including those with aliphatic, polar, and aromatic substituents. The mechanism of separation, which is based on the preferential ternary complex formation of the analyte amino acid and the chiral chelate with Cu(II) in the mobile phase, is discussed. The stereoselectivity depends mainly on the different steric interactions between the alkyl side chains of the amino acid analytes and the chiral ligands coordinating around Cu(II), although such parameters as pH, temperature, organic modifier, and concentration of the chiral additive also affect the chromatographic separation. Among the chiral ligands studied, L-histidine methyl ester is unique in that it possesses both achiral selectivity for the dansyl amino acids and chiral selectivity for the respective D and L enantiomers. With a mobile phase gradient of acetonitrile in a buffer containing Cu(II) L-histidine methyl ester complex, a stereoselective procedure was devised for the analysis of D and L amino acid enantiomers, achieving the separation that the current amino acid analyzer could not perform. Finally, the use of the mixed chelation approach in two biomedical studies is described. In the first application, the histidine methyl ester gradient was adapted for analyzing amino acids in cerebrospinal fluid; in the second, an L-aspartame Cu(II) complex eluant was developed for measuring the urine concentration of D and L pipecolic acid (piperidine-2-carboxylic acid), a metabolite of lysine.     

Complete NMR Elucidation of Two N-Protected Trishomocubane Hydantoins and the Ethyl Ester of the Corresponding Amino Acid

In an attempt to resolve a racemic mixture of a trishomocubane hydantoin, the synthesis of a pair of novel diastereomers was obtained by protecting the racemic hydantoin with chlorocarbonic acid-(–)(R)-sec-butyl ester. An achiral i-propyl ester was first used to establish the procedure. The NMR elucidation of both the chiral and achiral N-protected hydantoins is described. Some proton and carbon NMR shifts on the cage are reversed when relative small changes on the protection group are introduced. The chiral centre on the protective group induced splitting of some carbon signals in the ¹³C spectrum on the cage skeleton, but effective separation of the diastereomers could not be obtained. In a further attempt to demonstrate the potential use of the trishomocubane amino acid in peptide synthesis, the ethyl ester of the cage amino acid was synthesised. The structures of the amino acid derivatives were elucidated with 2D NMR techniques and the assignment of the NMR data is presented.     

Preparation and characterization of phosphorus‐containing Mannich‐type bases as curing agents for epoxy resin

Two novel phosphorus‐containing Mannich‐type bases, [(2‐{[(diethoxy‐phosphoryl)‐phenyl‐methyl]‐amino}‐ ethylamino)‐phenyl‐methyl]‐phosphonic acid diethyl ester (PEDA) and ({2‐[2‐(2‐{[(diethoxy‐phosphoryl)‐phenyl‐methyl]– amino}‐ethylamino)‐ethylamino]‐ethylamino}‐phenyl‐methyl)‐phosphonic acid diethyl ester (PTTA) were prepared and employed as curing agents in an attempt to prepare flame retardant epoxy systems. Through a curing reaction, phosphorus was incorporated in the backbone of the epoxy polymer. The processing characteristic of these systems was studied in terms of gel time at different temperatures. Thermal and flame retardancy properties of the cured epoxy thermosets were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and flammability test. The degradation activation energy was calculated by Kissinger's model. The results showed that the gel time of the phosphorus‐containing epoxy systems was prolonged; the glass transition temperature (T_g) was increased due to the introduction of phosphorus and the initial degradation activation energy of phosphorus‐containing epoxy systems was lower than phosphorus‐free epoxy systems. High char yield (23–27 wt%) and limiting oxygen index (LOI) values of 28–30 were observed for the phosphorus‐containing epoxy thermosets, indicating their improvement in flame retardancy. Copyright © 2008 John Wiley & Sons, Ltd.     

Discovery of carboxypeptidase Y as a catalyst for the incorporation of sterically demanding α-fluoroalkyl amino acids into peptides

The first example of a direct enzymatic coupling of two different, sterically demanding C^α-fluoroalkyl amino acids to amino acid nucleophiles is reported. N-Protected Ala methyl ester derivatives bearing a methyl-, difluoromethyl-, or trifluoromethyl group, respectively, instead of the α-proton were accepted as substrates by carboxypeptidase Y and could, therefore, be coupled directly to various nucleophiles.     

Crystallization-controlled dynamic self-assembly and an on/off switch for equilibration using boronic ester formation

Macrocyclic boronic esters of different sizes can be prepared selectively from the same starting diboronic acid and 1,2-diol by means of an interesting dynamic self-assembly phenomena. More specifically, two kinds of macrocyclic boronic esters could be formed diastereoselectively and nearly quantitatively under neutral conditions by the addition of an appropriate guest molecule that acts as a template. Although a mixture of tetrol 1 and di(boronic acid) 2 in methanol gave only insoluble polymeric boronic esters, a soluble macrocyclic boronic ester, homo-[2+2], was obtained selectively in the presence of toluene as a guest molecule. Furthermore, when benzene was employed as a guest molecule, the selective formation of another macrocyclic boronic ester, hetero-[3+3], occurred. Interestingly, each of these macrocycles could be converted into the other in the presence of methanol and the appropriate guest molecule; however, under aprotic conditions, guest molecules encaged by the macrocyclic boronic ester could be exchanged without affecting its structure. Thus the presence or absence of a protic solvent could be used as a regulator to switch on or off the dynamic equilibrium of the system. In addition, investigation of the effect of reaction time, direct observation of the reaction mixture by NMR spectroscopy, and carrying out the reaction using optically active tetrol suggested that precipitation plays an essentially important role in the selective formation of the macrocyclic boronic esters. Thus, although both of [2+2] and [3+3] were present as solutes in the reaction mixture, the type of added guest molecule induced the selective precipitation of only one form of macrocyclic boronic ester, hence displacing the equilibrium of the system.     

An Efficient Synthesis of 3-Alkyl-2-alkyliminooxazolidin-4-one via a Domino Reaction

3‐Alkyl‐2‐alkyliminooxazolidin‐4‐ones were prepared from a copper‐catalyzed domino intermolecular nucleophilic addition of α‐hydroxy‐(or mecapto) carboxylic acid ester to carbodiimide and a followed nucleophilic substitution of the formed amino group to carboxylic acid ester. The reactions could be performed under convenient conditions and good yields were achieved in most cases.     

Substituted Esters of Coumarin-3-phosphonic Acid—Linear-Polarized IR-Spectroscopic Elucidation

Correlation between the structure and IR-spectroscopic properties of two halogen and one amino substituted esters of coumarin-3-phosphonic acid has been studied by means of linear-polarized IR-spectroscopy of oriented colloid suspensions in nematic host. The influence of the ester group on the peak positions of the IR-characteristic bands of these derivatives and in particular, on phosphorus group is investigated by a comparison with the data for corresponding coumarin-3-phosphonic acids. Theoretical quantum chemical DFT calculations (B3LYP/6-311++G??) are carried out, thus supporting the experimental assignment of the IR-bands and predicting the electronic structure of all of the compounds studied.     

Solid products from thermal decomposition of polyethylene terephthalate: Investigation by CP/MAS 13C-NMR and fourier transform-IR spectroscopy

The solid reaction products from pyrolysis of polyethylene terephthalate in the presence and absence of red phosphorus were characterized by CP/MAS ¹³C-NMR, FR-IR, and MAS ³¹P-NMR spectroscopy. Over the temperature range of 300–400°C, polyethylene terephthalate was converted in a sealed vial to a highly crosslinked polymer of terephthalic acid. Pyrolysis in the presence of red phosphorus, which functions as a flame retardant by increasing the amount of char, yielded an intractible polyaromatic phosphate ester. After thermal cleavage of polyethylene terephthalate with formation of free carboxyl and vinyl ester groups, there are two competing reaction pathways. The smaller molecular weight fragments may enter the vapor phase where they undergo further degradation primarily to CO₂, CO, and acetaldehyde, as described by others. However, if volatilization of the oligomeric fragments is inhibited, an alternate reaction pathway gives rise to the formation of highly crosslinked char. Red phosphorus decreases the volatility of the oligomeric fragments by converting them to phosphates and thereby enhances char formation.     

Development of a stereoselective practical synthetic route to indolmycin, a candidate anti-H. pylori agent.

A stereoselective practical synthetic route to indolmycin is described. The route is composed of the regioselective coupling of indolyl magnesium halide with a trans-epoxy ester, diastereoselective oxazolone ring formation with guanidine and amine exchange reaction with methylamine. In the coupling step, use of dichloromethane as co-solvent and conversion of the resulting hydroxy ester to the hydroxy acid for purification, make this process efficient and practical. The oxazolone ring is formed in good yield without epimerization at the C5 position by treatment with guanidine and potassium tert-butoxide in tert-butanol at room temperature. In the final step, the amino group is efficiently converted to the methylamino group in aqueous methylamine solution at 5 degrees C. After examination of the route with racemates, indolmycin was synthesized stereoselectively in 22% total yield from optically active trans-epoxy ester. This route was applied to the preparation of the metabolites of indolmycin.