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首页> 外文学位 >Constrained beta-prolines. (I) Methanopyrrolidine beta-amino acids: Synthesis and chracterization of novel C6-substituted analogues and peptide oligomers. (II) Synthesis of 2,2-disubstituted pyrrolidine-3-carboxylic acids.
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Constrained beta-prolines. (I) Methanopyrrolidine beta-amino acids: Synthesis and chracterization of novel C6-substituted analogues and peptide oligomers. (II) Synthesis of 2,2-disubstituted pyrrolidine-3-carboxylic acids.

机译：受约束的β-脯氨酸。 （I）甲基吡咯烷β-氨基酸：新型C6取代的类似物和肽低聚物的合成和表征。 （II）2，2-二取代的吡咯烷-3-羧酸的合成。

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摘要

In the study of structurally restricted cyclic beta-amino acids and peptides, methanopyrrolidine-5-carboxylic acids (MetPyr-5-acids), or 5-syn-carboxy-2-azabicyclo[2.1.1] hexanes, and derivatives were investigated. MetPyr-5-acids are a series of highly conformationally constrained beta-proline derivatives, which belong to a novel category of beta-amino acids utilized as building blocks for the synthesis of beta-peptides. These beta-peptides lack the backbone hydrogen bonds necessary for folding in the usual manner. Substituents and functional groups in this ring system were envisioned to impact the folding properties and functionalities of the corresponding beta-peptides. In the present study, the analogues of MetPyr-5-acids with C6- substitutions were prepared, and the folding properties of their peptides were explored. To introduce different functionalities at C6 in MetPyr-5-acids, 6-syn-hydroxymethyl substituted derivatives were synthesized and were used as key intermediates. In the synthesis of this core structure, the major steps in their preparation included the Michael addition of benzyloxymethyl allyl amine to 3-butynone, followed by UV light irradiation of the diene to afford 5-acetyl-6-benzyloxymethyl-2-azabicyclo[2.1.1]hexane. Haloform (Br2/NaOH) oxidation of the acetyl group leads to the 6-substituted MetPyr-5-acid. Resolution of the racemate was achieved either by resolving (+/-)-6-syn-benzyloxymethyl-MetPyr-5-acid via a classical crystallization resolution method using (S)-(-)-beta-methylbenzylamine, or by chiral preparative HPLC separation of (+/-)-6-syn-benzyloxymethyl-MetPyr-5-acid methyl ester. The absolute stereochemistry was confirmed by X-ray crystallography of a derivative. Novel analogs with a range of functionalities incorporated at the C6 position in MetPyr-5-acid were synthesized from 6-syn-hydroxymethyl-MetPyr-5-acid methyl ester, and include hydrophilic groups such as hydroxyl, amino, methyl ether, and hydrophobic groups, such as substituted phenyl groups and triazole. From the protected C6-substituted analogs of MetPyr-5-acids, peptide oligomers of C6-benzyloxymethyl-2,4-methanopyrrolidine-beta-amino acid were prepared up to the length of octomer in high yields. This series of oligomers were characterized by circular dichroism (CD) and indicated enhanced order of folding uniformity for the tetramer and up, with increasing ordered folding for longer oligomers. The octomer exhibited minimal solvent effects, and was stable with increasing temperature up to 80 °C. Analysis by NMR of the iso-butyric amide capped monomer indicated a mixture of cis/trans conformation favoring the cis conformation. This was slightly different from the C6 unsubstituted iso-butyric amide derivative, which favored the trans conformation. For the dipeptide, the C6-benzyloxymethyl substitution increased the percentage of cis conformation of the dipeptide amide bond, but the major peptide had the trans conformation. This demonstrated that C6 substitutions could shift the cis/trans equilibrium towards the cis conformation. Longer oligomers showed ordered secondary folding structure as demonstrated by the increase in ellipticity per amino acid unit, but was too complicated to be determined by NMR analysis. Both the CD patterns and molecular model calculation predicted that the longer oligomers (tetramer and above) favor the trans conformation. This preference was driven by the backbone dipole effect. II. SYNTHESIS OF 2,2-DISUBSTITUTED PYRROLIDINE-3-CARBOXYLIC ACIDS Due to the perceived steric influence of 2,2-disubstitution in the pyrrolidine-3-carboxylic acid, it is believed that the adjacent amide/peptide bonds should result in a trans amide bond conformation. Because of the difficulty in introducing disubstitution at the hindered C2 position, the synthesis of such derivatives has not been successful. For this reason a new method was introduced to prepare novel derivatives, at the N- and C- termini of protected 2,2-dimethyl pyrrolidine-3-carboxylic acid, i.e., benzyloxycarbonyl protected 2,2-dimethylpyrrolidine-3-carboxylate. This procedure included the Michael addition of 2-nitropropane to dimethyl fumarate, followed by ring closure of the amino ester derived from reduction of the nitro ester providing the pyrrolidinone. Reduction of the pyrrolidinone to the pyrrolidine with borane finished 2,2-dimethylpyrrolidine-3-carboxylate in moderate overall yield. A preliminary set of two amides, iso-butyric amide and 3,5-dichlorobenzamide of this 2,2-dimethylpyrrolidine-3-carboxylate, were also prepared. NMR analysis of this pyrrolidine derivative suggested the amide bonds adopted the trans conformation. It was concluded that steric bulk of the 2,2-disubstitution favorably influenced the trans amide conformation. This demonstrated that trans amide conformation control of a beta-proline amide was possible.
机译：在结构受限的环状β-氨基酸和肽的研究中，研究了甲吡咯烷-5-羧酸（MetPyr-5-酸）或5-syn-羧基-2-氮杂双环[2.1.1]己烷及其衍生物。 MetPyr-5-酸是一系列高度构象受限的β-脯氨酸衍生物，属于一类新型的β-氨基酸，用作合成β-肽的基础。这些β-肽缺乏以常规方式折叠所需的主链氢键。设想该环系统中的取代基和官能团会影响相应β肽的折叠特性和功能。在本研究中，制备了具有C6-取代的MetPyr-5-酸类似物，并探索了其肽的折叠特性。为了在MetPyr-5-酸中的C6处引入不同的官能团，合成了6-syn-羟甲基取代的衍生物并将其用作关键中间体。在此核心结构的合成中，制备这些化合物的主要步骤包括将苄氧基甲基烯丙基胺迈克尔加成至3-丁炔酮，然后用紫外线照射二烯，得到5-乙酰基-6-苄氧基甲基-2-氮杂双环[2.1]。 .1]己烷。乙酰基的卤仿（Br2 / NaOH）氧化可生成6位取代的MetPyr-5-酸。外消旋体的拆分是通过使用（S）-（-）-β-甲基苄基胺的经典结晶拆分方法拆分（+/-）-6-syn-苄氧基甲基-MetPyr-5-酸或通过手性制备型HPLC来实现的分离（+/-）-6-顺式苄氧基甲基-MetPyr-5-酸甲酯。通过衍生物的X射线晶体学证实了绝对立体化学。由6-syn-羟甲基-MetPyr-5-酸甲酯合成了在MetPyr-5-酸的C6位引入了一系列功能的新型类似物，并包含亲水基团，例如羟基，氨基，甲基醚和疏水基团基，例如取代的苯基和三唑。从MetPyr-5-酸的被保护的C6-取代的类似物，以高收率制备直至八聚体长度的C6-苄氧基甲基-2,4-甲氧基吡咯烷-β-氨基酸的肽低聚物。该系列低聚物的特征在于圆二色性（CD），并表明四聚体和更高分子量的折叠均匀性增强，而较长的低聚物的折叠性增大。八聚体表现出最小的溶剂作用，并且在高达80°C的温度下稳定。通过NMR对异丁酰胺封端的单体进行的分析表明，顺式/反式构象的混合物有利于顺式构象。这与C6未取代的异丁酰胺衍生物略有不同，后者有利于反式构象。对于二肽，C6-苄氧基甲基取代增加了二肽酰胺键的顺式构象的百分比，但是主要肽具有反式构象。这表明C6取代可以使顺式/反式平衡朝着顺式构象移动。更长的低聚物显示出有序的二级折叠结构，如每个氨基酸单位的椭圆率的增加所证明的那样，但是太复杂了，无法通过NMR分析确定。 CD模式和分子模型计算都预测较长的低聚物（四聚物及以上）有利于反式构象。这种偏好是由主干偶极效应引起的。二。 2，2-二取代的吡咯烷-3-羧酸的合成由于在吡咯烷-3-羧酸中感觉到的2，2-二取代的空间影响，因此认为相邻的酰胺/肽键应产生反式酰胺键构象。由于难以在C2位阻位引入破坏性，这种衍生物的合成没有成功。由于这个原因，引入了一种新方法来制备在受保护的2，2-二甲基吡咯烷-3-羧酸的N-和C-末端，即苄氧羰基保护的2，2-二甲基吡咯烷-3-羧酸酯的新型衍生物。该方法包括将2-硝基丙烷迈克尔加成到富马酸二甲酯中，然后将由还原硝基酯得到的吡咯烷酮衍生的氨基酯闭环。用硼烷将吡咯烷酮还原成吡咯烷以适中的总产率完成2，2-二甲基吡咯烷-3-羧酸酯。还制备了该2，2-二甲基吡咯烷-3-羧酸酯的两种酰胺的初步组，即异丁酰胺和3，5-二氯苯甲酰胺。对该吡咯烷衍生物的NMR分析表明酰胺键采用了反式构象。结论是2，2-二取代的空间体积有利地影响反酰胺构象。这表明控制β-脯氨酸酰胺的反酰胺构象是可能的。

著录项

  • 作者

    Hu, Zilun.;

  • 作者单位

    Temple University.;

  • 授予单位 Temple University.;
  • 学科 Analytical chemistry.;Organic chemistry.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 198 p.
  • 总页数 198
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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