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%。     

天冬酰胺丙酮叉在多肽合成中的应用

L-天冬酰胺(Asn)与丙酮在KOH的甲醇溶液中反应得到具有丙酮叉结构的环化天冬酰胺[cAsn(acetone)]。该化合物在缩合剂1-乙基-3-(3′-二甲氨基丙基)碳化二亚胺盐酸盐(EDC I)和1-羟基苯并三氮唑(HOB t)存在下,与芴甲氧羰基(Fmoc)保护的酪氨酸(Fmoc-Tyr(B zl)-OH)、苯丙氨酸(Fmoc-Phe-OH)和丙氨酸(Fmoc-A la-OH)在二氯甲烷和N,N-二甲基甲酰胺溶液中反应得到新的二肽Fmoc-Tyr(B zl)-cAsn(acetone)-OH、Fmoc-Phe-cAsn(acetone)-OH和Fmoc-A la-cAsn(acetone)-OH,收率分别为35%、30%和30%。其中Fmoc-Tyr(B zl)-cAsn(acetone)-OH与苯丙氨酸二肽酰胺(H-Phe-Phe-NH2)在相同的缩合条件下反应生成四肽Fmoc-Tyr(B zl)-cAsn(acetone)-Phe-Phe-NH2,收率为70%。乙酸中Pd-C催化加氢可同时脱去酪氨酸残基上的芴甲氧羰基和苄基(B zl)保护基,首次得到内吗啡肽-2(endomorph in-2,H-Tyr-Pro-Phe-Phe-NH2)的环化天冬酰胺类似物H-Tyr-cAsn(acetone)-Phe-Phe-NH2,收率为60%。应用核磁共振、红外、质谱和高分辨质谱测试技术对目标产物和中间体的结构进行了表征。小鼠醋酸扭体法对类似物的镇痛活性进行了初步的研究。结果表明,当剂量为2.4×10-5g/Kg时,镇痛抑制率为45%。     

基于配合共保护策略合成γ-L-谷氨酰二肽的新方法

提出了一种采用谷氨酸席夫碱Ni(II)配合物共保护L-谷氨酸的α-氨基和α-羧基合成γ-L-谷氨酰二肽的新方法. 首先由手性助剂——2-[N-(N-苄基-脯氨酰)氨基]二苯甲酮(1)、六水合氯化镍和L-谷氨酸反应, 得到谷氨酸席夫碱Ni(II)配合物2, 产率为98.2%; 进而采用二异丙基碳二亚胺(DIC)/1-羟基-苯并三唑(HOBt)复合缩合剂法分别与L-氨基酸3a～3h反应, 得到相应的γ-L-谷氨酰二肽席夫碱Ni(II)配合物4a～4h, 产率为93.1%～99.0%; 最后稀酸水解配合物, 得到γ-L-谷氨酰二肽5a～5h, 产率为73.0%～86.4%, 高收率(92.2%～97.4%)回收手性助剂. 中间产物和终产物的结构经由旋光, 1H NMR, 13C NMR和HRMS表征.     

N-叔丁氧羰基-β-环己基天冬氨酸苄酯的合成

天冬氨酸侧链环己酯Boc Asp(OcHex) OBzl(Ⅰ)较苄基酯对酸稳定10倍以上,适于长链肽的合成;且可用甲磺酸温和脱除(0℃/1h);可承受温和的皂化、肼解及氢解反应;可显著降低含有天冬氨酸序列(如Asp Gly、Asp Ser等)的肽在合成过程中形成天冬酰亚胺(aspartimide)(即β 肽)的可能性[1]。我们从价廉易得的L Asp出发,经环己基化和Boc酰化制得Ⅱ[2],将Ⅱ苄基化,得到目标分子Ⅰ[1～6]。Ⅲ的酰化,用四氢呋喃(THF)、水为反应溶剂;Ⅱ的苄基化,试用过(1)PhCH2Br/THF/TEA/10～19℃(2)hCH2Br/EtOAc/TEA/reflux(3)PhCH2OH/DCC/HOBt/T…     

具有抗糖尿病活性（拟）二肽分子的设计、合成及生物活性

采用液相缩合法,保护的苯丙氨酸衍生物和氨基葡萄糖衍生物分别与Fmoc氨基酸偶联,简便地得到9个未见报道的L-对硝基苯丙氨酸二肽衍生物4a～i和4个2-氨基-β-D-葡萄糖拟二肽衍生物8a～d,收率为52．4％～88．1％．4a～i选择性碱性水解,得到9个对应的水解产物5a～i,收率为64．4％-90．4％．产物的化学结构经1HNMR,13CNMR和HRMS表征及证实．体外抗糖尿病活性测试结果表明,某些化合物具有很强的抗糖尿病活性,其中化合物4c和8b的过氧化物酶体增殖物激活受体反应元件（PPRE）相对激动活性分别达到150．59％和185．23％,EC50分别为1．37uM和0．64uM,作为新型抗糖尿病先导分子值得进一步研究．     

苯甲酸阿格列汀的合成

本文以邻溴甲苯为原料,经催化偶联,自由基反应,烷基化反应,取代,成盐5步制得二肽基肽酶IV(DPP-IV)抑制剂苯甲酸阿格列汀,所得目标化合物经质谱,核磁共振氢谱确认,总收率达31.5%。     

基于2-(4-二羟基硼烷)苯基喹啉-4-羧酸的二硼酸化合物的合成

以4-溴苯乙酮、靛红及常见试剂为起始原料,通过Pfitzinger reaction、羧基酯化、钯催化、水解等反应合成2-(4-二羟基硼烷)苯基喹啉-4-羧酸(PBAQA).二胺化合物经二碳酸二叔丁酯单保护、酰胺缩合、盐酸脱保护基,再与另一端苯基硼酸化合物酰胺缩合,合成了3个含有PBAQA结构的二硼酸新化合物,考察了溶剂选择、反应温度、活化反应时间以及反应中羧基化合物与1,3-二环己基碳化二亚胺(DCC)和1-羟基苯并三唑(HOBT)物质的量之比对二硼酸类化合物收率的影响.通过IR、~1H NMR、~(13)C NMR、HRMS对新化合物的结构进行表征.结果表明最佳反应条件为以N,N-二甲基甲酰胺(DMF)作溶剂,反应温度20℃,活化反应60 min,反应中羧基化合物与DCC和HOBT的物质的量之比在1∶20∶20的条件下,收率可达82%,纯度90%.该合成路线具有操作步骤简便,经济适用,副产物少易于纯化等特点,对二硼酸化合物衍生化研究具有重要实用和经济价值.     

手性芳基膦-噁唑啉的简便合成

膦-噁唑啉化合物作为一类“优势配体”,自发现以来就引起化学家们的广泛关注。 现有合成方法存在路线长、收率低、分离困难等问题。 本研究发展了一种合成手性芳基膦-噁唑啉(PHOX)的简单高效方法。 在1-羟基苯并三唑(HOBt)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)作用下,2-(二苯基膦基)苯甲酸与多种光学纯的氨基醇发生缩合反应,高收率获得酰胺基醇类化合物;之后酰胺基醇经三苯基膦/三乙胺/四氯化碳体系处理完成噁唑啉环的构建,以64%86%的总收率得到膦-噁唑啉化合物。 随后,合成的化合物(S)-t-BuPHOX被应用于钯催化β-酮酯的脱羧Tsuji烯丙基化反应,得到了80%的收率和84%的ee值。 该新方法具有原料易得、条件温和、收率高等优点。     

两个α-氨基酸类二肽肽酶Ⅳ抑制剂的合成

以2,4,5.三氟苯甲酸为原料,经还原、溴代、烷基化、脱羧、脱乙酰基保护、上Boc-保护、酯水解、偶联、脱Boc-保护和成盐十步反应,合成了两个α-氨基酸类二肽肽酶Ⅳ抑制剂,α-氨基酸类衍生物,总收率23%,其结构经<'1>H NMR,<'13>C NMR和MS表征.     

2-(2-(5-氟尿嘧啶-1-基)乙酰氨基)丙酸的合成及表征

以5-氟尿嘧啶-1-基乙酸为原料,N,N-二异丙基碳二亚胺(DIC)/1-羟基苯并三氮唑(HOBt)为缩合剂,分别与L-丙氨酸甲酯和D-丙氨酸甲酯通过液相偶联合成了(S)-和(R)-2-(2-(5-氟-2,4-二氧-3,4-二氢嘧啶-1(2H) -基)乙酰氨基)丙酸甲酯对映体,收率分别为82％和80％;室温下将化合物水...     

Screening of N-Alkyl-Cyanoacetamido Oximes as Substitutes for N-Hydroxysuccinimide

Peptide-bond formation is a pivotal process in the synthesis of peptide oligomers. Among the various coupling methodologies described, carbodiimides combine strong acylation potency and smooth reaction conditions, and they are commonly used in the presence of N-hydroxylamine additives. In recent years, acidic oxime templates, mainly ethyl 2-cyano-2-(hydroxyimino) acetate (Oxyma), have emerged as highly reactive alternatives to the classic and explosive-prone benzotriazolic additives, 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt). However, to achieve certain biochemical targets, less reactive species, such as N-hydroxysuccinimide (HOSu) esters, are often required to obtain stability under aqueous conditions. In the present study, we report on a new family of water-soluble N-alkyl-cyanoacetamido oximes, most of which have proven useful in the construction of active carbonates for the introduction of fluorenylmethoxycarbonyl (Fmoc) with minimal impact of dipeptide impurities. We performed a direct comparison of these new N-alkyl-cyanoacetamido oximes with HOSu in order to evaluate their capacity to retain optical purity and their coupling efficiency in the assembly of bulky residues.     

Amino acids and peptides. XXIII. Synthesis of N alpha-protected amino acid 6-chloro-2-pyridyl esters and their evaluation for peptide synthesis

6-Chloro-2-pyridyl esters (OPyCl) of N alpha-benzyloxycarbonyl and tert-butyloxycarbonylamino acids were synthesized by the N,N'-dicyclohexylcarbodiimide (DCC) method from the acids and 6-chloro-2-hydroxypyridine in dimethylformamide (DMF). The reactivity of the 6-chloro-2-pyridylester with amino group is much higher than that of the corresponding 2-pyridyl ester (OPy) and p-nitrophenyl esters (ONp) in dioxane and DMF, and a peptide bond is formed without acylation at the side chain hydroxyl group of amino acids. Z-Asp(OBzl)-OPyCl reacted with amino acid methyl esters in dioxane to give the corresponding dipeptide without any detectable aspartimide formation.     

Solid-phase synthesis of a farnesylated CaaX peptide library: inhibitors of the Ras CaaX endoprotease

A solid-phase method, based on Kaiser's p-benzophenone oxime resin, was developed for the synthesis of a series of N-acetyl-S-(E, E-farnesylated) Ca(1)a(2)X tetrapeptides as potential inhibitors of recombinant Ras and a-factor converting enzyme (RCE). N-Acetyl-S-(E, E-farnesyl)-L-cysteine was coupled to resin-bound a(1)a(2) dipeptide using HOBt/DCC activation in conjunction with N-BOC chemistry. The protected farnesylated tripeptide was cleaved from the resin with simultaneous addition of the X residue by treating the resin-bound farnesylated Ca(1)a(2) tripeptide with L-amino acid benzyl ester tosylates under mildly acidic conditions. The benzyl ester was saponified, and the resulting carboxylate precipitated by ether to afford a library of tetrapeptides as a mixture of diastereomers at the cysteine center. The peptides were evaluated as inhibitors of recombinant yeast RCE endoprotease (yRCE) to obtain information about the affinity of the enzyme for the a(1)a(2)X portion of the Ca(1)a(2)X moiety.     

4个新型有机磷缩合试剂的合成及其在生物活性肽合成中的应用

报道了4个新型有机磷化合物：N-二乙氧基磷酰苯并唑酮(DEPBO)、N－(2-氧-1,3,2-二氧杂磷杂环乙烷基)-苯并唑酮(DOPBO)、3－(2'-氧-1',3',2'-二氧杂磷杂环己烷基)-氧-1,2,3-苯共三嗪-4(3H)-酮(DOPBT)和3－(二乙氧基磷酰基)-氧-1,2,3-苯并三嗪-4(3H)-酮(DEPBT)的合成,并研究了它们作为缩会试剂在多肽合成中的应用. 研究结果表明,它们可以成功地用于固相法和溶液法合成多肽,其中DEPBT还可用于环肽的合成. 应用DEPBO和DEPBT合成了促睡眠肽的类似物及从云南中草药繁缕中分离鉴定的一个环七肽等生物活性肽.     

Synthesis and structure of preorganized,C(3)-symmetric trilactam scaffolds with convergently oriented (S)-acetylthiomethyl appendages

[reaction: see text] Efficient modular synthesis of conformationally preorganized, C(3)-symmetric trilactams is reported. The allyl acetate cyclization substrate was synthesized in five steps from Garner's L-serine-derived aldehyde. After chiral ligand-mediated palladium cyclization, the resulting vinyl hydropyran was transformed into the orthogonally protected amino acids for iterative coupling. The final macrolactamization was accomplished using EDCI/HOBt or HATU/HOAt under high dilution conditions.     

Multigram Solution‐Phase Synthesis of Three Diastereomeric Tripeptidic Second‐Generation Dendrons Based on (2S,4S)‐, (2S,4R)‐, and (2R,4S)‐4‐Aminoprolines

Three diastereomeric second‐generation (G2) dendrons were prepared by using (2S,4S)‐, (2S,4R)‐, and (2R,4S)‐4‐aminoprolines on the multigram scale with highly optimized and fully reproducible solution‐phase methods. The peripheral 4‐aminoproline branching units of all the dendrons have the 2S,4S configuration throughout, whereas those units at the focal point have the 2S,4S, 2S,4R, and 2R,4S configurations. These latter configurations led to the dendrons being named (2S,4S)‐ 1 , (2S,4R)‐ 1 , and (2R,4S)‐ 1 , respectively. The 4‐aminoproline derivatives used in this study are new, although many closely related compounds exist. Their syntheses were optimized. The dendron assembly involved amide coupling, the efficiency of which was also optimized by employing the following well‐known reagents: EDC/HOBt, DCC/HOSu, TBTA/HOBt, TBTU/HOBt, BOP/HOBt, pentafluorophenol, and PyBOP/HOBt. It was found that the use of PyBOP is by far the best for dendrons (2S,4S)‐ 1 and (2R,4S)‐ 1 , and pentafluorophenol active ester is best for (2S,4R)‐ 1 . Because of their multigram scale, all couplings were done in solution instead of by solid‐phase procedures. Purifications were, nevertheless, easy. The optical purities of the key intermediates as well as the three G2 dendrons were analyzed by chiral HPLC analysis. These novel, diastereomeric second‐generation dendrons have a rather compact and conformationally highly rigid structure that makes them interesting candidates for applications, for example, in the field of dendronized polymers and in organocatalysis.     

细胞粘附肽RGD的液相合成

精氨酸-甘氨酸-天冬氨酸(RGD)是近年来发现的具有较高应用价值的生物活性短肽,可抑制肿瘤细胞与内皮细胞和基底膜的粘附,加速肿瘤细胞脱附,阻止肿瘤细胞滞留,从而抑制肿瘤细胞的转移。研究RGD序列肽的合成具有重要意义。本文以氯乙酰氯和天冬氨酸为原料经缩合、胺化合成GD二肽,其纯度为98.6%,产率约为84.8%。然后采用液相N-羧基内酸酐化学法合成了游离的RGD三肽,其纯度为94.2%,产率约为71.4%。采用红外光谱、质谱、高效液相色谱等手段对中间产物及RGD三肽进行了表征和分析,证实产物结构正确。     

Solid-phase synthesis and spectroscopic studies of TRH analogues incorporating cis- and trans-4-hydroxy-L-proline.

An efficient solid-phase synthesis of the TRH analogue Glp-His(Nim-Trt)-Hyp-OH is described. Na-Fmoc protected amino acids and DCC/HOBt activation were employed. The bulky and mild-acid-sensitive 2-chlorotrityl resin, utilised as the solid support, completely suppressed dioxopiperazine formation. The tripeptide is a key intermediate in the synthesis of TRH analogues incorporating cis- and trans-4-hydroxy-L-proline. The tripeptide was converted, with inversion of configuration at C-4 of the Hyp residue, to Glp-His(Nim-Trt)-cHyp lactone in the presence of triphenylphosphine-diethyl azodicarboxylate (TPP-DEAD). One-pot MeOH-TPP-DEAD transesterification of the lactone, followed by Nim-detritylation, provided Glp-His-cHyp-OMe. This ester gave the corresponding amide and acid on ammonolysis and saponification, respectively. A high-field 1H NMR investigation of Glp-His-cHyp-OH and its diastereomer Glp-His-Hyp-OH, obtained by Nim-detritylation of the key tripeptide, showed that the configuration at C-4 of the prolyl residues is critical for the determination of the preferred three-dimensional structure of the molecules.