学校编码：10384 分类号 密级

学号：20520120153488 UDC

博 士 学 位 论 文

肽基 N-酰胺基硫脲的转角结构、手性传递及相

关应用研究

Turn Structure, Chirality Transfer and Applications of

Peptide-Based N-Amidothioureas

严 小 胜

指导教师姓名： 江 云 宝 教授

专 业 名 称： 分 析 化 学

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评 阅 人：

2016 年 5 月

厦门大学博硕士论文摘要库

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厦门大学博硕士论文摘要库

目 录

目 录

中文摘要……………………………………….…….……................……………....i

英文摘要……………………………..……………………………………………..iv

第一章 前言……………………….........................….…...........…......………….1

1.1 手性简介….……………………………………………………...…………..1

1.2 氮杂多肽及 β-转角简介……….….….….…..…………....…………………3

1.3 多肽及其衍生物的手性传递研究………………………..……..…...….......6

1.3.1 多肽及其衍生物分子内手性传递研究…………………………….......6

1.3.2 多肽及其衍生物分子间手性传递研究…………………….………....13

1.4 多肽合成中的手性选择性……………………………..…....…..…...….....17

1.4.1 二肽的手性选择性合成……….……………………………………....18

1.4.2 基于螺旋结构的多肽手性选择性合成.…...……………….………....18

1.4.3 分子间作用诱导的多肽手性选择性合成………...……….…..……...20

1.5 手性放大机制研究……………………………..…....…..…...………….....24

1.5.1 不对称自催化反应机制……….……………………………………....24

1.5.2 结晶-溶解过程中的手性放大.…...……………….…………………...29

1.5.3 其他手性放大机制………...……….…..……………………………...33

1.6 论文设想…………………...…………………………………………...…..36

1.7 参考文献…………………...…………………………………………...…..40

第二章 基于甘氨酰苯丙氨酸N-酰胺基硫脲的β-转角结构研究…...54

2.1 前言…………………………………………………………..…..............…54

2.2 药品试剂、仪器表征、化合物的合成及表征...……………………..……55

2.3 结果与讨论………….…………………………………………………...…62

厦门大学博硕士论文摘要库

目 录

2.3.1 F和GF的吸收与CD光谱研究……………………...………..…..…..62

2.3.2 GF分子内氢键模式研究……………………………………...…..…..63

2.3.3 阴离子诱导手性传递…………………...........................................…..66

2.3.4 硫脲/脲/多肽之分子内氢键对比研究………………….………....…..68

2.3.5 N-端保护基的影响………………………………………….……..…..71

2.4 结论………….…………………………………………………..……….…72

2.5 附图………….…………………………………………………..……….…73

2.6 参考文献…………………...…………………………………………...…..81

第三章 二肽基N-酰胺基硫脲的 β-转角和手性传递研究……….....…83

3.1 前言………………………………………………………………………....83

3.2 药品试剂、仪器表征、硫脲分子的合成及表征………………………..…85

3.3 结果与讨论……………………………………………………………...…93

3.3.1 β-转角结构研究…………………….…………........………….….…...93

3.3.2 CD光谱之手性传递研究..................................................…….….…...97

3.3.3 阴离子结合物的 CD光谱研究.........…………........………….….….101

3.4 结论……………………………………………….…………………….....105

3.5 附图…………………………………...……………………………….......106

3.6 参考文献…………………...………………………………………….......120

第四章 双边 N -酰胺基硫脲的手性选择性及手性放大应用研

究…………….……………………………………………………………………..122

4.1 前言………………………………………………………………..………122

4.2 药品试剂、仪器表征、化合物的合成与表征……………………………..123

4.3 结果与讨论………………………………………………………………..134

4.3.1 β-转角及手性传递研究....…………………………………………....134

4.3.2 异手性选择性研究…………..…..…………………………...…..…..140

4.3.3 异手性选择性诱导手性放大…………………………...………..…..144

厦门大学博硕士论文摘要库

目 录

4.3.4 异手性选择性机理探讨……………………………………………...147

4.3.5 双边脲/硫脲反应体系的对比研究…...……………………………...157

4.4 结论…………………………...…………………………..………...……..163

4.5 附图…………………………...………………………………….....……..164

4.6 参考文献…………………...………………………………………….......180

第五章 多肽基硫脲化合物之超分子螺旋聚合物的构建………..…183

5.1 前言……………………………………………………………………......183

5.2 药品试剂、仪器表征、化合物的合成及表征……………………………185

5.3 结果与讨论……………..………………………..…...…..…...….….……188

5.3.1 OcFTU2之单体结构特征…………………..………….…...………..188

5.3.2 水溶液中超分子螺旋聚合物的构建……………………..………….189

5.3.3 固相中的超分子螺旋结构………………………………………..….195

5.3.4 聚集作用力及模式探讨…………………………………………..….197

5.3.5 自发拆分性质研究…………………………………………………...199

5.4 结论…………………….……………………...…………………….....….203

5.5 附图…………………….……………………...…………………….....….204

5.6 参考文献…………………...………………………………………….......213

附录…………………………………...………………………………………...….216

论文创新点…...…………………………………..………………..……..…….216

本文涉及的符号和缩略语……………………………………………….....….218

攻读博士学位期间所获奖项………………………………………………......220

攻读博士学位期间发表和交流的论文……………………………………......221

致谢……………………………………………………………………………..223

厦门大学博硕士论文摘要库

Contents

CONTENTS

Abstract in Chinese………………………………….……................……………...i

Abstract in English………………..…...…………………………………………..iv

Chapter 1 Introduction..............................................................................……1

1.1 Introduction of Chirality……………..………………………...…………..1

1.2 Introduction of Azapeptides and β-Turn……....……………………….…3

1.3 Chirality Transfer in Peptides and Their Derivatives...…….………….…6

1.3.1 Intramolecular Chirality Transfer in Peptides and Their Derivatives.......6

1.3.2 Intermolecular Chirality Transfer in Peptides and Their Derivatives….13

1.4 Chiral Selectivity in Peptide Synthesis…………………………......….....17

1.4.1 Chiral Selectivity in Dipeptide Synthesis...........................…..………...18

1.4.2 Helix Based Chiral Selectivity in Peptide Synthesis……….………...18

1.4.3 Intermolecular Interactions Based Chiral Selectivity in Peptide

Synthesis………………………………………………………….….…20

1.5 Research of Mechanism for Chiral Amplification……..………......….....24

1.5.1 Asymmetric Autocatalysis Mechanism..............................…..………...24

1.5.2 Chiral Amplification in Crystal-Solution Process...…………….……...29

1.5.3 Other Mechanism for Chiral Amplification…………...……….….…33

1.6 Objectives of the Dissertation…………….............…………………...…..36

1.7 References……………………………...….............…………………...…..40

Chapter 2 β-Turn Structure in Glycinylphenylalanine Dipeptide

Based N-Amidothioureas…………..…..………………………………………54

2.1 Introduction……………..…………………………………..…..............…54

厦门大学博硕士论文摘要库

Contents

2.2 Reagents, Apparatus, Synthesis and Characterizations…………...……55

2.3 Results and Discussion………….……….……………………………...…62

2.3.1 Absorption and CD Spectra of F and GF……………………………....62

2.3.2 Intramolecular Hydrogen Bonding in GF………...…………....…..…..63

2.3.3 Chirality Transfer Induced by Anion.…..………………..………....…..66

2.3.4 Comparison of Intramolecular Hydrogen Bonds in Thiourea, Urea and

Peptide………………………………………………………………….68

2.3.5 Role of N-Terminal Protecting Group…………………….........…..…..71

2.4 Conclusions………….…………...……………………………..……….…72

2.5 Appended Figures………….……...…….……………………..……….…64

2.6 References……………………………...….............…………………...…..81

Chapter 3 β-Turn and Chirality Transfer in Dipeptide Based

N-Amidothioureas……………………………..……………………...…………83

3.1 Introduction………..……………………………………………………....83

3.2 Reagents, Apparatus, Synthesis and Characterizations…………...……85

3.3 Results and Discussion…………………..……………………………...…93

3.3.1 Study of β-Turn Structure…………….……………………….........…..93

3.3.2 Study of Chirality Transfer Based on CD Spectra……….....….….…...97

3.3.3 CD Spectra of Anion Complex……………………………………...101

3.4 Conclusions……………………………………….…………………......105

3.5 Appended Figures…………………...……………………………….…..106

3.6 References…………………………..…...….............………………...…..120

Chapter 4 Chiral Selectivity in Bilateral N-Amidothioureas and

Application of Chiral Amplification……………………….…….…...……122

4.1 Introduction……………..………………………………………..……..122

4.2 Reagents, Apparatus, Synthesis and Characterizations…..……...…..123

厦门大学博硕士论文摘要库

Contents

4.3 Results and Discussion………….……………………………………....134

4.3.1 Study of β-Turn and Chirality Transfer…..…………………………...134

4.3.2 Study of Heterochiral Selectivity………...……..…………….…..…..140

4.3.3 Chiral Amplification Induced by Heterochiral Selectivity……..……..144

4.3.4 Mechanism of Heterochiral Selectivity……………….……….……...147

4.3.5 Comparison of Bilateral Thioureas and Ureas......................................157

4.4 Conclusions………………...…………………………..………...……..163

4.5 Appended Figures…………...………………………………….....……..164

4.6 References……………………………...….............……………….....…..180

Chapter 5 Construction of Supramolecular Helical Polymers by

Using of Peptide Based Thioureas…….……………………………………183

5.1 Introduction……..……………………………………………………......183

5.2 Reagents, Apparatus, Synthesis and Characterizations….……………185

5.3 Results and Discussion..…………….…………..…...…..…...….….……188

5.3.1 Monomers of OcFTU2……………………………………………...188

5.3.2 Construction of Supramolecular Helical Polymers in Water….……...189

5.3.3 Supramolecular Helical Structures in Solid State………………....….195

5.3.4 Discussion of Driving Forces and Model for Aggregation…..…....….197

5.3.5 Study of Self-Sorting……...……………………....……...…………...199

5.4 Conclusions………….……………...………...…………………….....….203

5.5 Appended Figures………………….………...…………………….....….204

5.6 References……………………………...….............……………….....…..213

Appendixes…………………………….………………………………….......….216

Innovations of the Dissertation Researches……..……..……………..………….216

Abbreviations…………………………………………………………………...….218

Awards and Honors……………..……………………………………………...….220

厦门大学博硕士论文摘要库

Contents

Publications……………………….…………………...……………………..….....221

Acknowledgements………………….………………...……………………..….....223

厦门大学博硕士论文摘要库

中 文 摘 要

i

摘 要

多肽是重要的生命基础物质之一，其作用涉及生命活动的各个环节。多肽具

有丰富的手性源，系因其氨基酸结构单元绝大部分为手性的。通过分子内手性传

递，单个氨基酸残基的手性可影响整条肽链分子结构及功能，而分子间手性传递

则于肽链与底物分子间的特异性识别和结合过程中扮演重要角色，因此多肽及其

衍生物的手性传递特征备受重视，对拟肽类药物分子及不对称有机催化剂的设计

合成、生物分子间相互作用的研究等具有重要指导意义。

同手性起源是手性科学研究的热点及难题，它作为生命科学领域的重要研究

内容而备受关注，科学家们通过几十年的研究虽已窥得冰山一角，然其神秘面纱

仍未揭开。以多肽及其衍生物为考察对象，构建手性选择性、手性放大及超分子

螺旋聚合物等研究体系，可系统地加深对原始地球同手性起源问题的理解，有助

于手性化合物的合成纯化，并可应用于新型仿生材料的构筑等研究领域。

本论文以 N-酰胺基硫脲为结构骨架，通过引入短肽单元，设计合成了一系

列含 β-转角结构的氮杂多肽分子，并成功地应用于分子内及分子间手性传递、手

性选择性及手性放大、超分子螺旋聚合物等研究体系中。

论文共分五章，包括如下内容：

第一章为前言部分，首先对手性、氮杂多肽及 β-转角进行了简介，然后分别

概述了多肽及其衍生物的手性传递、多肽合成中的手性选择性、手性放大机制的

研究进展，最后提出本论文的设计思路和研究内容。

第二章设计合成了基于甘氨酰苯丙氨酸的 N-酰胺基硫脲分子 GF，其可视为

氮杂多肽的硫代酰胺衍生物。GF 存在分子内十元环氢键，即 β-转角结构，并诱

导了自苯丙氨酸残基至硫脲生色团的分子内手性传递，于 270 nm 显示特征 CD

信号峰，反之，该特征 CD 信号亦可应用于判断 β-转角结构存在与否。基于变构

效应，GF 与阴离子有极强的结合能力，并伴随着分子内及分子间手性传递。与

厦门大学博硕士论文摘要库

中 文 摘 要

ii

传统氮杂多肽分子对比，GF 中 NH 质子酸性更强，维系 β-转角结构的氢键强度

提升，同时显著增强了与阴离子的结合能力。该实验结果体现了 C-末端酰胺基

硫脲基团的结构及功能优势，提供了优越的 β-转角结构模板，有利于新型拟肽类

药物分子、生物探针及不对称有剂催化剂的设计合成。

第三章构造了一系列二肽基 N-酰胺基硫脲化合物，即氮杂三肽分子，其中

二肽结构单元中两个氨基酸残基或均为手性，或一个为手性一个为非手性。该系

列氮杂三肽分子中均存在 β-转角结构，且其类型依赖于是否存在与 β-转角连锁

的分子内五元环氢键。氮杂三肽分子于 270 nm 处显示源于硫脲生色团的特征 CD

信号，系 β-转角结构诱导的分子内手性远程传递所致，可资分子内手性传递研究。

该 CD 信号可近似于二肽结构单元中两个氨基酸残基贡献值的线性叠加结果。这

一线性加和方式亦适用于阴离子与氮杂三肽分子的结合物，但两个氨基酸残基的

贡献比例发生变化，系氢键网络模式变化所致。该实验结果阐述了氮杂多肽分子

及其与阴离子结合物于氢键介导下手性沿肽链自 N-端至 C-端传递的特征。硫脲

基团可视为药物分子的作用位点，而阴离子则类似于底物分子，因此该研究对手

性短肽类药物分子的设计合成具有重要指导意义。

第四章主要以短肽类手性酰肼分子AcFN2H3与非手性化合物Ph(NCS)2构造

了双边对称反应体系。实验结果表明该体系存在异手性选择性，且可诱导手性放

大效应，即当向一定 ee 值的酰肼分子中加入少量非手性化合物 Ph(NCS)2 时，反

应结束后剩余酰肼分子之 ee 值得以提升。β-转角及其诱导的手性传递现象为两

手性氨基酸间的远程空间联系搭建桥梁，同手性/异手性双边硫脲之分子间作用

力的区别引起溶解度差异，进而影响反应速率常数。分子内和分子间氢键作用共

同驱动异手性选择性及其手性放大效应。双边硫脲为尾-尾连接模式的氮杂多肽

分子，其异手性选择性与头-尾连接模式的自然多肽之同手性特征具异曲同工之

妙；同手性和异手性双边硫脲产物中，分子间氢键作用均存在于同手性部分，这

些均有利于对生命起源之同手性多肽分子形成过程的理解。高温有利于异手性选

择性及手性放大效应，因此这一过程可能存在于生命起源之地-深海的热液喷口。

此外，该实验结果亦指示双边对称反应可建立同手性与异手性间的联系，并可能

于同手性起源过程中扮演一定角色。

厦门大学博硕士论文摘要库

中 文 摘 要

iii

第五章设计合成了具长烷基链的多肽基硫脲分子 OcFTU2，其分子内存在 β-

转角结构。OcFTU2 对映体可在水溶液中借助多重分子内和分子间氢键、π-π 堆

积以及疏水作用，以“头-尾”连接方式有序排列并形成高稳定性超分子螺旋聚

合物。相反螺旋方向的聚合物水溶液混合时存在自发拆分行为，即使经热处理也

不能破坏，系螺旋聚合物的耐高温性所致。对映体之单体混合物于水溶液中共聚

时可得到左手和右手螺旋状聚合物，亦存在自发拆分行为。该实验结果丰富了稳

定螺旋聚合物的种类及其制备方法，有效地模拟了蛋白质/多肽中的螺旋结构，

有助于同手性起源，尤其是蛋白质/多肽的同手性特性研究，并对新型仿生材料

的构筑具启示意义。

关 键 词

酰胺基硫脲；氮杂多肽；β-转角；氢键；手性传递；阴离子；异手性选择性；手

性放大；超分子螺旋聚合物；自发拆分

厦门大学博硕士论文摘要库

英 文 摘 要

iv

Abstract

Peptide is one important basic substance of life, involving in every aspect of life

activity. Most of the structural units in peptides are chiral amino acids, causing their

abundant chiral resources. With intramolecular chirality transfer, the asymmetrical

information of individual amino acid residue can influence the structure and function

of the whole peptide chain, while intermolecular chirality transfer plays a key role in

the specific recognition and binding process between peptides and their substrates.

Thus the character of chirality transfer in peptides and their derivatives is focused,

which is instructive for the designing of peptide-based drugs, asymmetric

organocatalysts as well as the interactions between biological molecules.

The origin of homochirality is one hotspot and challenge in chirality science, which

is concerned as one important issue in life science and has been debated for decades,

but without consensus till now. Constructing chiral selectivity, chiral amplification

and supramolecular helical polymers research systems by taking use of peptides or

peptidomimetics can deepen the understanding of the origin of homochirality in

prebiotic earth as well as guide the synthesis and purification of chiral compounds,

and also can be applied in developing novel biomimetic materials.

In this dissertation, a series of azapeptides containing β-turn structures are designed

and synthesized by taking C-terminal N-amidothiourea as structural motif and

introducing short-peptide unit, which are successfully applied in the research systems

of intramolecular and intermolecular chirality transfer, chiral selectivity, chiral

amplification and supramolecular helical polymers.

The dissertation consists of five chapters.

In Chapter 1, chirality, azapeptides and β-turn are introduced briefly at first, then

research progress of chirality transfer in peptides and their derivatives, chiral

selectivity in peptide synthesis and mechanism for chiral amplification are reviewed,

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and at last the design thoughts and research contents of this dissertation are presented.

Chapter 2 reports glycinylphenylalanice dipeptide based N-amidothiourea GF,

which can be regarded as thioamide of azapeptides and affords a new entry to β-turn

structural motif. The created β-turn structure can be readily identified by a CD signal

at 270 nm assigned to the achiral phenylthiourea chromophore, resulting from

chirality transfer induced by intramolecular hydrogen bonding. The β-turn structure in

GF is not only more stable than that in azapeptides, it is meanwhile more labile to

anion binding, both be attributed to the stronger acidity of thioureido NHs. These

observations together with the interesting chirality transfer in both the dipeptide based

N-amidothiourea and its anion binding complex may help guide the design of

peptidomimetic pharmaceuticals. It also establishes a new entry to chiral thioureas of

intensive current interest in organocatalytic asymmetric synthesis.

Chapter 3 describes a small library of the dipeptide based N-amidothioureas

(azatripeptides) containing β-turn structure, in which the two amino acid residues in

the dipeptide backbone being either both chiral or one achiral one chiral. Two types of

β-turn structure were identified, which are dictated by the existence or not of a

five-membered ring hydrogen bond between the two amino acid residues. All the

examined azatripeptides exhibit CD signal at 270 nm from the C-terminal achiral

phenylthiourea chromophore, which is approximatively a linear addition of the

individual contributions from the two chiral amino acid residues in the dipeptide

residue. This linear additivity is also operative in the acetate anion binding complexes

of these azatripeptides, despite with differed proportional coefficients. These

observations confirm the chirality transfer or conformation communication along the

backbone of the azatripeptides and their anion binding complexes, from the

N-terminus to the C-terminus and could be instructive in designing peptide-based

drugs as well as thiourea based asymmetric organocatalysts.

Chapter 4 presents heterochirality in the bilateral symmetrical reaction of racemic

N-acylamino acid based acylhydrazines with symmetric achiral Ph(NCS)2, which can

directly induce chiral amplification the acylhydrazines after treated with a certain

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amount of the achiral reactant Ph(NCS)2. Both inter- and intramolecular hydrogen

bonds are operative here for the appearance of heterochirality. The β-turn structures

establish asymmetric communication between the two distant chiral amino acid

residues in the reaction products. The stronger intermolecular hydrogen bonds

between homochiral portions in the heterochiral product cause its less solubility than

the homochiral ones, which provides the thermodynamic driving force for the

heterochirality, whilst the difference in the reaction rate constants shapes the reaction

kinetically. We believe that bilateral symmetrical reactions may have affected the

evolution of homochirality in a universe governed by symmetrical laws and our

findings provide a new perspective for the origin of homochirality of life under

prebiotic environments, especially in the ideal place for the origin of life, the

submarine hydrothermal vents that provide the high temperature condition.

Chapter 5 develops stable supramolecular helical polymers by peptide-mediated

thioureas containing β-turns. With inter- and intramolecular hydrogen bonds, π-π

stacking and hydrophobic interactions, the enantiomers can self-assemble to form

left-handed or right-handed supramolecular helical polymers in water, respectively.

These helical polymers are stable and insensitive to temperature, causing self-sorting

of the mixtures of polymer, even after annealing. Besides, the monomer mixtures can

also co-assemble in water to form helical polymers with self-sorting character. Hence

peptide-mediated supramolecular helical polymers in water with heat resisting

character are constructed to mimic the helical structures of peptides and proteins,

which are instructive for the preparation of stable helical polymers as well as for the

exploiting of novel biomimetic materials.

Keywords

Amidothiourea, Azapeptides, β-Turn, Hydrogen bonding, Chirality transfer, Anion,

Heterochiral selectivity, Chiral Amplification, Supramolecular helical polymers,

Self-sorting

厦门大学博硕士论文摘要库

Degree papers are in the “Xiamen University Electronic Theses and

Dissertations Database”.

Fulltexts are available in the following ways:

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厦门大学博硕士论文摘要库