Synthesis of sterically-hindered peptidomimetics using 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methyl-morpholinium chloride

Our study demonstrated that 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methyl-morpholinium chloride (DMTMM) is a versatile coupling reagent for the synthesis of sterically-hindered peptidomimetics. It is superior to HBTU/HOBt and CDMT in controlling racemization and N-arylation, respectively.     

Synthesis of benzoic acids and polybenzamides containing tertiary alkylamino functionality

The high-yielding and easily scalable synthesis of a number of benzoic acids bearing a tertiary alkylamino functionality has been achieved. The flexible synthesis began from readily available aminobenzoic acids or terephthaloyl chloride and requires almost no chromatography. Coupling of the synthesised amino acids to a range of substituted anilines was achieved when utilizing a specific combination of DIC, HOBt and DMAP.     

HOBt,HOOBt, HOSu与惰性氯代烷溶剂之间的反应及其对 多肽合成影响的研究

HOBt,HOSu,HOOBt是多肽合成中常用的试剂,它们常被用作羧基活化试剂和消旋抑制剂。首次发现HOBt,HOSu,HOOBt在碱的存在下可与氯代烷烃溶剂发生反应,并系统地研究了不同的反应条件对产率的影响和对多肽合成的影响。发现反应的产率与碱的用量,反应温度,反应物等因素有关,碱性越强,反应速度越快产率越高,HOBt较易反应,HOSu较为稳定,二氯甲烷易生成双取代产物,1,2-二氯乙烷易生成单代产物,所有产物均经硅胶柱层析分离纯化,共合成8个经合物并通过光谱鉴定。虽然在模型二肽BocAlaPheOCH3合成反应中检测到少量副产物的产生,但二肽的产率>82%。     

Oxyma: An Efficient Additive for Peptide Synthesis to Replace the Benzotriazole‐Based HOBt and HOAt with a Lower Risk of Explosion[1]

Oxyma [ethyl 2‐cyano‐2‐(hydroxyimino)acetate] has been tested as an additive for use in the carbodiimide approach for formation of peptide bonds. Its performance in relation to those of HOBt and HOAt, which have recently been reported to exhibit explosive properties, is reported. Oxyma displayed a remarkable capacity to inhibit racemization, together with impressive coupling efficiency in both automated and manual synthesis, superior to those of HOBt and at least comparable to those of HOAt, and surpassing the latter coupling agent in the more demanding peptide models. Stability assays showed that there was no risk of capping the resin under standard coupling conditions. Finally, calorimetry assays (DSC and ARC) showed decomposition profiles for benzotriazole‐based additives that were consistent with their reported explosivities and suggested a lower risk of explosion in the case of Oxyma.     

Naphthyl-l-α-amino acids via chemo-enzymatic dynamic kinetic resolution

A double catalyst system (protease + base) was applied to the dynamic kinetic resolution (DKR) of isomeric 1- and 2-α-naphthyl-glycines and -alanines exploiting the in situ racemization of their thioesters. Due to the different C-acidity of the two sets of compounds, different experimental conditions have been devised to perform the simultaneous resolution/racemization process.In all cases, the racemic N-Boc-thioesters were converted into the aminoacids with an l-configuration almost quantitatively and with complete enantioselectivity.     

Novel immonium type peptide coupling reagent: 5‐(1H‐benzotriazol‐1‐yloxy)‐3,4‐dihydro‐1‐methyl 2H‐pyrrolium hexachloroantimonate (BDMP® )

A novel immonium type coupling reagent, 5‐(1H‐benzotriazol‐1‐yloxy)‐3,4‐dihydro‐1‐methyl 2H‐pyrrolium hexachloroantimonate (BDMP) has been designed, synthesized and utilized to synthesize oligopeptides and biologically active peptide both in solution and solid phase with satisfactory yield, low racemization and fast reaction rate. The estimation of racemization and the influence of several reaction parameters were studied by HPLC method using the model reaction: Z‐Gly‐Phe‐OH + Val‐OMe·HCl·Z‐Gly‐D/L‐Phe‐Val‐OMe. It was shown that the reactivity of BDMP was much higher and the racemization was much lower than those of HOBt‐based ‘onium’ reagents, even though its analogues BOMI. To further verified me effectiveness of BDMP, Leu‐enkephalin was synthesized both in solution and solid phase using BDMP as coupling reagent. The proposed mechanism was also speculated.     

Energy barriers to rotation in axially chiral analogues of 4-(dimethylamino)pyridine.

The barriers to enantiomerization of a series of axially chiral biaryl analogues of 4-(dimethylamino)pyridine (DMAP) 1-10 were determined experimentally by means of dynamic HPLC measurements and racemization studies. The barriers to rotation in derivatives 1-6 (based on the bicyclic 5-azaindoline core) were lower than those in the corresponding derivatives 7-10 (based on the monocyclic DMAP core). Semiempirical (PM3), ab initio Hartree-Fock (HF/STO-3G), and density functional theory (DFT/B3LYP/6-31G*) calculations reveal that these differences in barriers to rotation are the result of differing degrees of hybridization of the non-pyridyl nitrogen in the enantiomerization transition states (TSs). The importance of heteroatom hybridization as a factor in determining nonsteric contributions to barriers to rotation in azabiaryls of this type is discussed.     

Synthesis of heptapeptides and analysis of sequence by tandem ion trap mass spectrometry

Two heptapeptides have been prepared by Fmoc methodology using Wang resin as solid support. For attachment of the first amino acid, several coupling systems were evaluated, and DIC/DMAP system could give yields of >99% and low levels of racemization. The selection of scavenger combination to deprotect side chains revealed that H₂O/p-cresol was good at scavenging trityl and 1,2-ethanedithiol was highly efficient for scavenging t-butyl. Through shortening the preactivation time to 5 min, the racemization which occurred during formation of amide bonds coupled by HBTU was minimized. The crude peptides were characterized by RP-HPLC and MS, and sequenced by MS/MS to acquire reliable amino acid sequence information.     

新型一枝蒿酮酸异噁唑衍生物的合成及其抗A,B型流感病毒活性研究

为了提高一枝蒿酮酸的生物活性,以一枝蒿酮酸和3-取代苯基-5-氨甲基-异噁唑为原料,在偶合试剂DCC,HOBt/DMAP的作用下,合成了6个未见文献报道的含异噁唑的一枝蒿酮酸酰胺衍生物3a～3f.所合成的化合物均经过IR,1H NMR,13C NMR,ESI-MS等分析方法表征及初步体外抗A(H3N2,H1N1)型和B型流感病毒活性研究.初步实验结果表明:化合物3c同时具有抗A(H3N2)型和B型流感病毒活性,化合物3c和3e表现出比母体化合物强的抗B型流感病毒活性.     

一枝蒿酮酸酰胺衍生物的合成和抗A3, B型流感病毒和 单纯I, II型疱疹病毒活性研究

从新疆一枝蒿中分离得到了单体化合物一枝蒿酮酸, 然后以一枝蒿酮酸和有机胺为原料, 在偶联剂DCC, HOBt/DMAP的作用下, 合成了13种未见文献报道的一枝蒿酮酸酰胺衍生物2a～2m. 所合成的化合物经过IR, 1H NMR, ESI-MS等分析方法进行了表征, 并对化合物2a～2m进行初步的体外抗A3, B型流感病毒和单纯I, II型疱疹病毒活性研究. 初步试验结果表明化合物2a同时具有抗A3, B型流感病毒活性, 而且抗B型流感病毒活性比母体化合物的活性较高. 化合物2d的抗B型流感病毒活性比母体化合物高16倍, 化合物2e同时具有较强的抗单纯I, II型疱疹病毒活性.     

Synthesis and conformation of n-trityl dipeptide derivatives

N-Tritylamino acids activated with DCC/HOBt, were coupled with various amino acid derivatives without racemization. The trityl group was split off quantitatively in 10% CCl₃COOH monohydrate or CH₂ClCOOH in CH₂Cl₂. Under these conditions detritylation of N-Trt-Trp-Gly-NH₂ proceeds without formation of an oxindole derivative and side alkylation products, even in the absence of a scavenger. Dipeptide derivatives 1 and 2 exhibited magnetic asymmetry, attributed to steric factors.     

The total synthesis of bistratamides F-I

The total synthesis of bistratamides F-I (2-5) have been achieved in overall yields of 3, 10, 13, and 27%, respectively. The thiazole substructure was prepared utilizing a MnO₂ oxidation of a thiazoline, synthesized from a Val-Cys dipeptide using bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate. The serine-based oxazole substructure was prepared from a Val-Ser dipeptide using literature methods. The threonine-derived oxazole substructure was synthesized from a ketoamide dipeptide using the bisphosphonium salt employed for thiazoline preparation. Most of the amide bonds were formed using HBTU and HOBt in the presence of DIEA. The final macrocyclization step was accomplished efficiently by PyBOP and DMAP in all cases.     

Mécanisme de la racémisation des chlorosilanes. Étude cinétique: Détermination de l'ordre et de l'entropie d'activation

The solvent-induced racemization of chlorosilanes takes place by an increase in coordination of the silicon atom. The rate-equation and activation parameters have been determined in a kinetic study: the equation is first order in chlorosilane and second order in solvent.The results obtained suggest that pseudo-rotation of a pentacoordinated intermediate does not take place, but they do not allow distinction between two other possible intermediates: a hexacoordinated octahedral intermediate or a pentacoordinated bipyramidal siliconium ion.     

Kinetics of amide formation through carbodiimide/N-hydroxybenzotriazole (HOBt) couplings

The kinetics of formation of amide, 4, from the corresponding carboxylic acid by reaction with the isopropyl ester of methionine (MIPE), mediated by carbodiimide EDCI, 1, and HOBt, 2, have been studied in 1-methyl-2-pyrrolidinone (NMP) using reaction calorimetry. The reaction rates have been found to be independent of the concentration of HOBt, showing that the rate-determining step is the reaction between the carboxylic acid and EDCI to give the corresponding O-acylisourea. The pH dependence of the observed rate constants for O-acylisourea formation is consistent with a second-order reaction between doubly protonated EDCI (EDCIH2(2+), 6) and the carboxylate group. The observed rate constants fall sharply at high pH, as the fraction of EDCI as EDCIH2(2+) continues to fall strongly, whereas the carboxylic acid group is already fully ionized. The rate constant, kP, for reaction between the carboxylate group of acid, 3, and EDCIH2(2+) has a value of kP = 4.1 x 10(4) M(-1) s(-1) at 20 degrees C, some 10(5) times higher than similar rate constants measured in water. The subsequent catalytic cycle, involving reaction of O-acylisourea with HOBt to give HOBt ester, which then reacts with the amine to give the amide with regeneration of HOBt, determines the product distribution. In the case of the amino acid, 3, reaction of the O-acylisourea with MIPE to give amide, 4, is increasingly favored at higher pH values over that with the less basic internal aromatic amine of 3 to give the diamide 5.     

Reactivity and spectroscopy of the {Ru(DMAP)5} fragment: an {Ru(NH3)5} analogue

Reaction of trans-Ru(DMSO)4Cl2 with DMAP (DMAP = 4-dimethylaminopyridine) yields the yellow [Ru(DMAP)6](2+) cation in good yield. The crystal and molecular structure of [Ru(DMAP)6]Cl2.6CH3CH2OH was determined by X-ray diffraction methods. The complex crystallizes in the trigonal R3 space group with a = b = 16.373(1), c = 20.311(1) A, gamma = 120 degrees , and Z = 3 molecules per unit cell. The reaction of [Ru(DMAP)6](2+) in aerobic water gives the red [Ru(III)(DMAP)5(OH)](2+) cation. This complex shows a chemical behavior similar to [Ru(III)(NH3)5Cl](2+) and allows the preparation of a family of [Ru(DMAP)5L](n+) complexes. Their electronic properties indicate that the {Ru(II)(DMAP)5} fragment is a weaker pi-donor than {Ru(II)(NH 3)5}. Our density functional theory (DFT) calculations show that in {Ru(II)(DMAP)5} the DMAP ligands can compete for the pi electron density of the ruthenium making the fragment a weaker pi-donor.     

全保护RGD三肽的合成方法研究

以两条路线、多种偶联试剂(DCC，EDCI，CDI，EEDQ)合成了全保护三肽Arg- Gly-Asp(RGD)．Boc-Arg(Tos)-OH经上述偶联剂短时活化，于合适条件下与Ts0H- G1y-OBzl缩合，均获得良好收率(43％-97％)．经Pd(OH)2／H2还原得到的Boc-Arg (Tos)-G1y-0H于22-27℃与HCl·Asp(OcHex)-OBzl偶联得到全保护三肽Boc-Arg (Tos)-Gly-Asp(OcHex)-OBzl(TM)，反应收率分别为76．4％(DCC／HOSu)，64．7％ -78．3％(DCC／HOBt)，66．7％-77．9％(EDCI／HOBt)．Boc-Gly-OH和HCl·Asp- (OcHex)-OBzl经DCC／HOBt或CDI活化，可得到碳端二肽Boc-Gly-Asp(OcHex)-OBzl (收率分别为81．2％，89．5％)，该二肽脱Boc后与Boc-Asp(Tos)-OH反应，经DCC ／HOBt，EDCI／HOBt，CDI，DCC／HOSu活化，均可生成目标分子TM，其反应收率分 别为40．4％，73．8％，67．8％，84．4％．     

Sulfonamide synthesis using N-hydroxybenzotriazole sulfonate: an alternative to pentafluorophenyl (PFP) and trichlorophenyl (TCP) esters of sulfonic acids

The N-hydroxybenzotriazole (HOBt) sulfonate esters undergo amidation under ambient conditions in the presence of di-isopropylethyl amine. This method can be applied to varieties of amines including sterically hindered amino acid esters in less time with reasonably good yields.HOBt ester of sulfonic acids can be a replacement for pentafluorophenyl and trichlorophenyl ester as well as chloride moiety of sulfonyl chloride for amidation.     

4‐(N,N‐Dimethylamino)pyridine‐Embedded Nanoporous Conjugated Polymer as a Highly Active Heterogeneous Organocatalyst

We report herein for the first time the incorporation of a versatile organocatalyst, 4‐(N,N‐dimethylamino)pyridine (DMAP), into the network of a nanoporous conjugated polymer (NCP) by the “bottom‐up” approach. The resulting DMAP‐NCP material possesses highly concentrated and homogeneously distributed DMAP catalytic sites (2.02 mmol g^?1). DMAP‐NCP also exhibits enhanced stability and permanent porosity due to the strong covalent linkage and the rigidity of the “bottom‐up” monomers. As a result, DMAP‐NCP shows excellent catalytic activity in the acylation of alcohols with yields of 92–99 %. The DMAP‐NCP catalyst could be easily recovered from the reaction mixture and reused in at least 14 consecutive cycles without measurable loss of activity. Moreover, the catalytic acylation reaction could be performed under neat and continuous‐flow conditions for at least 536 h of continuous work with the same catalyst activity.     

有抗病毒活性的苯并咪唑苯氧乙酸乳糖酯的催化合成

苯并咪唑及其衍生物在应用上有许多报道,是广泛使用的驱虫剂、杀真菌剂、植物病毒抑制剂、农用杀菌剂（如多菌灵）,作为医药也有许多报道。芳氧羧酸类化合物是医药、农药、染料的中间体,其中一些还具有杀虫、杀菌、除草和植物激素等多方面的生物活性。     

Base-induced dismutation of POCl3 and POBr3: synthesis and structure of ligand-stabilized dioxophosphonium cations

The interaction between POCl(3) or POBr(3) and pyridine or DMAP has been reinvestigated to clarify the discrepancies between previously published results concerning the Lewis acidity of phosphoryl halides and their behavior toward pyridine bases. The obtained results show that POCl(3) virtually does not react with pyridine, while it does with 4-(dimethylamino)pyridine (DMAP), even in SO(2) solution, to yield an ionic compound [(DMAP)(2)PO(2)]Cl.3SO(2) (1.3SO(2)). Its recrystallization from acetonitrile gives [(DMAP)(2)PO(2)]Cl.CH(3)CN (1.CH(3)CN). The POBr(3) reacts readily with both DMAP and pyridine forming the analogous tribromides, [(DMAP)(2)PO(2)]Br(3) (2) and [(py)(2)PO(2)]Br(3) (3), respectively. Treatment of 3 with Me(3)SiOSO(2)CF(3) in acetonitrile solution led to [(py)(2)PO(2)][CF(3)SO(3)].CH(3)CN (4), while the reaction between 1.CH(3)CN and Me(3)SiOPOF(2) gave [(DMAP)(2)PO(2)][PO(2)F(2)] (5). The crystal structures of 1.CH(3)CN, 1.3SO(2), 2, and 4 revealed that all four compounds are ionic containing the distorted tetrahedral cations [(DMAP)(2)PO(2)](+) and [(py)(2)PO(2)](+). Both ions represent a donor-stabilized form of the so far unknown cation [PO(2)](+). The geometry of [(DMAP)(2)PO(2)](+), optimized by density functional calculations at the B3LYP/6-31G(d,p) level, is in good agreement with X-ray structural data. The NBO analysis of natural atomic charges shows an extensive delocalization of the [PO(2)](+) intrinsic positive charge and indicates a contribution of the electrostatic attraction to the formation of N-P donor-acceptor bonds. According to a (31)P NMR study, the reactions of both phosphoryl halides with DMAP proceed via successive formation of the intermediates [(DMAP)POX(2)](+) and (DMAP)PO(2)X to give an equimolar mixture of [(DMAP)(2)PO(2)](+) and PX(5) (X = Cl, Br) as the end products. The NMR spectroscopic identification of the cations [(DMAP)POX(2)](+) and [(DMAP)(2)PO(2)](+) was supported by ab initio calculations of their chemical shifts.