Synthesis of Cell Adhesive Motif RGD Tripeptide by a Novel Chemical Method and Its Purification

IntroductionArg-Gly-Asp(RGD),a characteristic tripeptidesequence found within fibronectin and other related ad-hesion molecules in extracellular matrices(ECM),hasattracted much attention because it has been proved tobe a recognition site for cellular adhe…     

Synthesis of cyclicβ-silylenones via oxidative rearrangement of tertiaryα-hydroxy allylsilanes with PCC

An oxidative rearrangement of cyclic tertiary a-hydroxy allylsilanes has been carried out in refluxing ClCH₂CH₂Cl with pyridinium chlorochromate（PCC）.The reaction provides a convenient method to synthesize cyclicβ-silylenones in modest to excellent yields.     

ABA型聚L-丙氨酸-聚乙二醇嵌段共聚物的合成及其表征

利用L-α-丙氨酸和三聚光气反应制备了N-羧基-α-丙氨酸-环内酸酐(NCA).以聚乙二醇(PEG)为原料.制备了端氨基聚乙二醇(PEG-NH₂),并以此作为引发剂,引发NCA开环聚合.合成了不同组成和分子量的聚L-丙氨酸-聚乙二醇(PLAA-PEG-PLAA)嵌段共聚物.利用IR、¹H NMR、DSC、WAXD、CD等方法对共聚物结构进行了表征.结果表明,PEG-NH₂引发NCA开环聚合得到的是嵌段共聚物,通过¹H NMR谱得到共聚物组成及数均分子量;引入PEG的结果使聚L-丙氨酸的亲水性有所改善;CD测诚结果表明共聚物在水溶液中主链主要以α-螺旋构象存在.     

The Practical Asymmetric Syntheses of Key Chiral Intermediates of Chiral Drug from Four-Carbon Chiral Pool

(S)-or (R)-2-Amino-4-phenylbutyric acid and (S)-or (R)-2-hydroxy-4-phenylbutyric acid and their ethyl esters are key chiral intermediates for the preparation of angiotensin converting enzyme inhibitors (ACEI) and other chiral drugs. Their practically asymmetric synthetic methods in large scale from four-carbon chiral pool, commercially available L-aspartic acid and L-malic acid, will be presented (as scheme). (S)-2-Amino-4-phenylbutyric acid and its ethyl ester hydrochloride were prepared from the easily available L-aspartic acid via activation by forming anhydride hydrochloride, Friedel-Crafts reaction with benzene, hydrogenolysis and esterification with ethanol in the presence of thionyl chloride in overall yield of 80% and 73.6% respectively with 99% ee. We first used amino acid anhydride hydrochloride as the acylating agent in Friedel-Crafts reaction without racemization. [1]     

Preparation of certain chloromethyl- and dichloromethyl-substituted chlorodisilanes and their behavior toward aluminum halides

Four new (chloromethyl)disilanes, (ClCH₂)Cl₂SiSiCl₂Me (I), (Cl₂CH)Cl₂SiSiCl₂Me(II), (ClCH₂)MeClSiSiClMe₂(III) and (ClCH₂)Me₂SiSiCl₃(IV), have been prepared and studied as to their attitude toward intramolecular rearrangement with aluminum chloride. The reactivity decreases in the order: (III) > (IV) > (II) (I). Similar reactivity to rearrangement of Me₃SiSiMe₂(CH₂Br)(V), ClMe₂SiSiMe₂(CH₂Br) (VI) and Me₃SiSiMeCl(CH₂Br) (VII) in the presence of aluminum bromide has been found to decrease in the order: (V) > (VI) > (VII). The results are discussed in terms of a mechanism favoring initial rate-determining step of ionization of the carbon-halogen bond in which the migrating group plays a minor role, if any, followed by migration of a silyl group from silicon to carbon. Disilanes (I) and (II) enter into the Friedel-Crafts reaction with benzene to give, after methylation, PhCH₂SiMe₂SiMe₃ and Ph₂CHSiMe₂SiMe₃, respectively.     

A strategy for the asymmetric aminohomologation of alpha, beta-dihydroxy aldehydes: application to the synthesis of the southwest tripeptide segment of echinocandin B

The synthesis of the (2S,3S,4S)-3,4-dihydroxyhomotyrosine amino acid segment, present in echinocandin B, in its activated form ready for peptide coupling is described. The key steps of the approach are the enantioselective AD reaction of 4-methoxycinnamic acid methyl ester, a completely diastereoselective [2 + 2] hydroxyketene-imine cycloaddition, and the TEMPO-assisted cycloexpansion of the resulting 3-hydroxy beta-lactam to the corresponding alpha-amino acid N-carboxy anhydride (NCA). The smooth opening of the latter upon treatment with L-Thr(OSi(t)BuPh(2))OMe and further acylation with the N-Cbz protected L-4-tert-butyldiphenylsilyloxy proline rendered the southwest portion of echinocandin B.     

Influence of extreme thermodynamic conditions and pyrite surfaces on peptide synthesis in aqueous media

Free energy landscapes and reaction mechanisms underlying the synthesis of diglycine in water were studied computationally. It was found that amino acid activation by carbonyl sulfide, leading to the formation of a cyclic alpha-amino acid N-carboxyanhydride (NCA, or Leuchs anhydride), preferentially follows an indirect pathway that involves an isocyanate intermediate. Extreme temperature and pressure conditions accelerate peptidization greatly compared to the ambient bulk water environment and are shown to favor, in general, concerted versus stepwise mechanisms. Finally, a pyrite surface, FeS2 (001), is found to lower reaction barriers further by decreasing fluctuations and by assisting the preformation of the cyclic five-membered NCA ring due to scaffolding.     

Synthesis of Vinyl Polymer—Poly (α-Amino Acid) Block Copolymers by End-Reactive Oligomers

In order to synthesize block copolymers consisting of segments having dissimilar properties, vinyl polymer - poly (α-amino acid) block copolymers were synthesized by two different methods. In the first method, the terminal amino groups of polysarcosine, poly(γ-benzyl L-glutamate), and poly(γ-benzyloxycarbonyl-L-lysine) were haloacetylated. The mixture of the terminally haloacetylated poly (α-amino acid) and styrene or methyl methacrylate was photoirradiated in the presence of Mo (CO)₆ or heated with Mo(CO)₆, yielding A-B-A-type block copolymers consisting of poly(α-amino cid) (the A component) and vinyl polymer(the B component). The characterization of block copolymers revealed that the thermally initiated polymerization of vinyl compounds by the trichloroacetyl poly(α-amino acid)/Mo(CO)₆ system was most suitable for the synthesis of vinyl polymer - poly-(α-amino acid) block copolymers. In the second method, poly (methyl methacrylate) and polystyrene having a terminal amino group were synthesized by the radical polymerization in the presence of 2-mercaptoethylammonium chloride. Using these polymers having a terminal amino group as an initiator, the block polymerizations of γ-benzyl L-glutamate NCA and e-benzyloxycarbonyl-L-lysine NCA were carried out, yielding A-B-type block copolymer. By eliminating the protecting groups of the side chains of poly(α-amino acid) segment, block copolymers such as poly(methyl methacrylate) with poly(L-glutamic acid) or poly(L-lysine) and polystyrene with poly(L-glutamic acid) and poly(L-lysine) were successfully synthesized.     

Solution-phase synthesis of a hindered N-methylated tetrapeptide using Bts-protected amino acid chlorides: efficient coupling and methylation steps allow purification by extraction

N-Benzothiazole-2-sulfonyl (Bts)-protected amino acid chlorides were used to prepare the hindered cyclosporin 8-11 tetrapeptide subunit 1. The synthesis was performed via 3a and the deprotected amines 5a, 13, and 19, including three repeated cycles involving N-methylation using iodomethane/potassium carbonate, deprotection of the Bts group, and N-acylation with a N-Bts-amino acid chloride such as 9b or 9c. Among three Bts cleavage methods compared (H3PO2/THF; NaBH4/EtOH; PhSH/K2CO3), the third gave somewhat higher overall yields. N-Acylation of 5a with the Bts-protected N-methylamino acid chloride 10b followed by deprotection was also highly efficient and could be used as an alternative route to 11. Each of the deprotected amines was isolated without chromatography using simple extraction methods to remove neutral byproducts. The tetrapeptide 1 was obtained in analytically pure form as the monohydrate.     

Synthesis of pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5-ones. Cyclization reaction of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid with acetic anhydride

Treatment of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid (X) with acetic anhydride under refluxing conditions afforded 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]-pyrimido[4,5-d]pyrimidin-5-one acetate (IX). The intermediate X was prepared from 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (V). The reaction of V with the sodium salt of 2-amino-3-hydroxypyridine at room temperature gave 4-(2-amino-3-pyridyloxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (VI). Treatment of VI with a hot aqueous sodium hydroxide solution and subsequent acidification gave X. Involvement of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecaroboxylic acid ethyl ester (VIII) (Smiles rearrangement product) as an intermediate in the above alkaline hydrolysis reaction of VI to X was demonstrated by the isolation of VIII and its subsequent conversion into X under alkaline hydrolysis conditions. Acetylation of VIII with acetic anhydride in pyridine solution gave 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester acetate (XI), which afforded IX on fusion at 220°. This alternative synthesis of IX from XI supported the structural assignment of IX. Fusion of VI gave 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]pyrimido]4,5-d]pyrimidin-5-one (VII). The latter was also obtained when VIII was fused at 210°. Acetylation of VII with acetic anhydride afforded IX.     

叔丁氧羰基单端基保护己二胺的合成

以己二胺为原料，叔丁氧羰基酸酐(Boc2O)为保护剂，合成了Boc单端基保护己二胺。并用IR和^1H NMR对产物进行了表征。该化合物可用作氨基酸的N-羰基环内酸酐(NCA)开环聚合法合成结构明晰的两嵌段聚氨基酸的引发剂，因而具有良好的应用前景。     

基于β-环糊精的多肽支臂星状聚合物的制备及性能

以β-环糊精(β-CD)为起始原料, 通过磺酰化及乙二胺基取代等过程, 制备具有端氨基的中间体β-环糊精(6-en-β-CD); 再以6-en-β-CD为引发剂, 通过赖氨酸N-羧基环内酸酐(Lys-NCA)和谷氨酸N-羧基环内酸酐(Glu-NCA)的混合开环聚合(ROP)和脱苄氧羰基(Cbz)保护等反应, 制备了以β-CD为核、 混聚多肽为支臂的星状聚合物[6-聚(谷氨酸-赖氨酸)-β-CD]. 以基质辅助激光解吸电离飞行时间质谱(MALDI-TOF-MS)、 核磁共振波谱(NMR)和傅里叶变换红外光谱(FTIR)等对星状聚合物及中间体结构进行表征; 同时采用圆二色光谱(CD)和噻唑蓝(MTT)法对该聚合物的二级结构和体外毒性进行了考察. 结果表明, 所得星状聚合物的重均分子量(M_w)为4626, 多分散系数(PDI)为1.10, 平均聚合度(DP)为27.1; 在水溶液中星状聚合物的二级结构是无规则线团; 在5 mg/mL浓度下, 细胞存活率可达到94%以上, 没有呈现明显体外细胞毒性, 具有潜在的药用前景.     

靶向iNOS的雷公藤甲素氨基酸前药的合成

雷公藤甲素(TL)是从卫矛科雷公藤中提取的环氧二萜内酯,具有显著的抗炎和免疫抑制活性,但TL本身毒性较大、水溶性差、治疗窗窄,极大地限制其在临床上的应用.以炎症部位过度表达的诱导型一氧化氮合酶(iNOS)为靶点,在TL结构中引入iNOS底物及其类似物设计合成系列雷公藤甲素氨基酸前药,提高其水溶性和靶向性.雷公藤甲素氨基...     

Tuning the conformation of synthetic co‐polypeptides of serine and glutamic acid through control over polymer composition

Ring opening polymerization (ROP) of N‐carboxy anhydride (NCA) amino acids presents a rapid way to synthesize high molecular weight polypeptides with different amino acid compositions. The compositional and functional versatility of polypeptides make these materials an attractive choice for biomaterials. The functional performance of polypeptide materials is equally linked to their conformation which is determined by the amino acid sequence in the polymer chains. Here, the interplay between composition and conformation of synthetic polypeptides obtained by NCA polymerization was explored. Various copolypeptides from Glu(Bzl) and Ser(Bzl) were prepared to investigate how polypeptide composition affected the conformation of the resulting copolymer. Polymerization kinetics indicated that the copolymerization of Glu(Bzl) and Ser(Bzl) preferentially yielded alternating copolymers. Both the polydispersity and the conformation of the polypeptides were dependent on the Ser(Bzl) content in the polymer, demonstrating that polypeptide functionalities could be tuned directly by altering the relative amounts of amino acids in the chain. This work presents the first step toward an improved understanding and control over polypeptide conformation through modulating the amino acid composition of the material. Understanding this sequence–functionality relationship is essential to advancing the use of ROP as a technique to design smart polypeptide based materials with specific functions. © 2016 The Authors. Journal of Polymer Science Part A: Polymer Chemistry Published by Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 2331–2336     

固相合成胸腺五肽(TP5)

采用Fmoc固相多肽合成中的活化酯方法和2,6-二氯苯甲酰氯(DCB)混合酸酐法, 对Fmoc-Tyr(t-Bu)-OH与Wang树脂反应中的反应级数和表观活化能进行了研究, 并采用常规方法和微波强化方法分别进行了胸腺五肽的合成. 实验结果表明, 活化酯方法的反应级数为1.855, 表观活化能15.24 kJ/mol, 混合酸酐法的表观活化能为35.14 kJ/mol. 与传统方法相比, 微波将缩合反应速率提高了30倍以上, 氨基酸过量倍数也从传统的三倍降低到两倍.     

Chemoenzymatic Synthesis of Cellular Adhesion Tripeptide RGD Precursor in Organic Media

IntroductionA characteristic tripeptide sequence Arg-Gly-Asp(RGD) that is found within fibronectin and other rela-ted adhesion molecules in extracellular matrices(ECM)has received considerable attention from researcherssince it was proved to be a recognit…     

Zinc(II) perchlorate as a new and highly efficient catalyst for formation of aldehyde 1,1-diacetate at room temperature and under solvent-free conditions

Zinc(II) perchlorate efficiently catalysed the conversion of aromatic, heteroaromatic, and aliphatic aldehydes to 1,1-diacetates under solvent-free conditions at room temperature. It was compatible with other functional groups (e.g., ether, ester, nitro, and cyano) likely to interfere by complex formation with the catalyst. Other anhydrides such as isobutyric, pivalic, and benzoic anhydrides afforded the corresponding 1,1-dicarboxylates and established the generality. The reaction rate was influenced by the steric and electronic nature of the anhydride. The rate of 1,1-dicarboxylate formation was found to follow the order Ac₂O > (i-PrCO)₂O > (t-BuCO)₂O > (PhCO)₂O and no 1,1-dicarboxylate formation took place with (ClCH₂CO)₂O, and (F₃CO)₂O. During inter- and intra-molecular competition between a ketone and an aldehyde group with Ac₂O, 1,1-diacetate formation took place exclusively with the aldehyde group. An 88:12 selectivity was observed for 1,1-diacetate formation in favour of 1-naphthaldehyde during competition with 2-methoxy-1-naphthaldehyde.     

Synthesis of Sequential Polypeptides Containing O‐Phospho‐L‐Serine

The chemistry of phosphoserine [Ser(P)] containing peptides and polypeptides was extensively investigated to explore a new biomineralization material science. The selective cleavage of the O,O′‐diphenyl phospho‐protecting groups of Ser(PO₃Ph₂) was examined using hydrogenolysis catalysts. Among the catalysts examined, only PtO₂ in 50% trifluoroacetic acid (TFA)/AcOH successfully cleaved the protecting group of Ser(PO₃Ph₂) to give Ser(P). Based on these characteristic new findings, Ser(P)‐containing dipeptides such as Gly‐Ser(P), Ala‐Ser(P), Ser‐Ser(P), Asp‐Ser(P), Glu‐Ser(P), and Lys‐Ser(P), and tetrapeptide [Asp‐Ser(P)]₂ were synthesized by a facile method. When we used the Ser(PO₃Ph₂) residues at the C terminals, the amino functional groups of amino acids and peptides can be coupled by the unsymmetric mixed anhydride using isobutyl chloroformate but cannot be by the symmetric anhydride method using dicyclohexylcarbodiimide. Neither unsymmetric mixed anhydride nor symmetric anhydride can be coupled with p‐nitrophenol at their C terminals. High‐molecular‐weight sequential polypeptides containing Ser(P) such as poly[Ser(P)‐Xaa] (Xaa: Gly, Ala, Ser, Lys, Asp, Glu) and poly[Gly‐Ser(P)‐Gly] were first synthesized by the polycondensation of the di‐ and tripeptide p‐nitrophenyl active esters, followed by the quantitative elimination of the diphenyl protecting groups by PtO₂ in TFA/AcOH. The new strategy to synthesize Ser(P)‐containing peptides and model proteins may help the development of hybrid formulations of marine and biomimetic protein minerals.

     

超临界二氧化碳中亚胺类共价有机骨架材料COF-LZU1的合成与表征

研究了超临界流体技术在共价有机骨架材料（COF）合成中的应用,以均苯三甲醛和对苯二胺为原料,N,N-二甲基甲酰胺为共溶剂,醋酸为催化剂,在超临界二氧化碳（scCO₂）中合成了亚胺类共价有机骨架材料COF-LZU1.考察了共溶剂、反应温度、反应压力、反应时间、醋酸含量和反应物摩尔比对COF-LZU1材料的晶体结构和微观形貌的影响.实验结果表明,反应温度的升高有利于提高scCO₂的传质速率及增加反应物在scCO₂中的溶解度,从而促进反应的进行;反应时间的延长有利于晶体的成熟和结晶度的提高;醋酸不仅是反应催化剂,还具有形貌导向剂的作用,通过改变醋酸用量分别获得了球状、块状和棒状形貌的COF-LZU1;反应物中对苯二胺含量过高会干扰反应过程中醛基与氨基的有序结合,导致结晶度的降低以及形貌规整程度的下降.在反应温度为60℃,反应压力为20 MPa,反应时间为6 h,均苯三甲醛与对苯二胺摩尔比为1：1.5,醋酸（3 mol/L）与N,N-二甲基甲酰胺体积比为1：1的条件下,制备的COF-LZU1呈现截面直径为80 nm的纳米棒形貌,具有良好的结晶度和优异的热稳定性,热分解温度高达550℃.本文首次在超临界环境中制备了COFs材料,为COFs的绿色合成提供了新途径.     

Synthesis and conformational studies of peptidomimetics containing a new bifunctional diketopiperazine scaffold acting as a beta-hairpin inducer

A practical synthesis of a new bifunctional diketopiperazine (DKP) scaffold 1, formally derived from the cyclization of L-aspartic acid and (S)-2,3-diaminopropionic acid, is reported. DKP-1 bears a carboxylic acid and an amino functionalities in a cis relationship, which have been used to grow peptide sequences. Tetra-, penta-, and hexapeptidomimetic sequences were prepared by solution-phase peptide synthesis (Boc strategy). Conformational analysis of these derivatives was carried out by a combination of 1H NMR spectroscopy, IR spectroscopy, CD spectroscopy, and computer modeling, and reveals the formation of beta-hairpin mimics involving 10-membered and 18-membered H-bonded rings and a reverse turn of the growing peptide chain.