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New Methods for the Synthesis of Unusual Peptides

合成特殊肽的新方法

基本信息

批准号：
7390857
负责人：
STEVEN L CASTLE
金额：
$ 21.33万
依托单位：
BRIGHAM YOUNG UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7390857
关键词：
3-hydroxybutanal Acidity Acids Alkylation Amides Amination Amino Acids Anti-Inflammatory Agents Anti-inflammatory Antifungal Agents Antimitotic Agents Antiparasitic Agents Architecture Area Arginine Biological Assay Biological Factors Chemistry Cinchona Alkaloids Classification Complex Copper Coupling Cyclic Peptides Cyclization Development Esters Evaluation Facility Construction Funding Category Generations Goals Hand Health Histidine Human Imidazole Indoles Intention Lead Left Leucine Link Mediating Methods Modeling Modification Molecular Object Attachment Palladium Peptide Synthesis Peptides Phase Physical condensation Preparation Process Protons Range Reaction Reliance Research Research Personnel Route Side Solid Solutions Staging Structure System Techniques Testing Tryptophan Tubulin Work amino group analog base catalyst celogentin A celogentin C cooking crosslink design epimerization improved indole interest novel nucleophilic addition polymerization programs racemization

项目摘要

DESCRIPTION (provided by applicant): The broad goal of this program is to develop new, effective synthetic methods for the synthesis of bioactive peptide natural products with unique structural features. The target that we have chosen as a vehicle for establishing this program is Celogentin C, a bicyclic octapeptide which is a potent antimitotic agent by virtue of its inhibition of the polymerization of tubulin. The unusual molecular architecture of Celogentin C includes a tryptophan residue with substitution at C-2 and C-6 of the indole side chain, a biaryl-type system characterized by the C-N bond between the indole and imidazole moieties, and a beta-substituted amino acid that results from the cross-link between the tryptophan and leucine side chains. We propose three novel synthetic methods for the construction of these interesting structures. The substituted central tryptophan will be prepared via incorporation of phase-transfer-catalyzed asymmetric alkylation chemistry into the Cook tryptophan synthesis. This work will also lead to the development of novel Cinchona alkaloid derived phase- transfer catalysts for both alkylations and aldol reactions. The latter process will afford beta-hydroxy amino acids. The indole-imidazole linkage will be formed by means of a copper- or palladium-catalyzed aryl amination reaction. Our intention is to perform this reaction in an intramolecular fashion in order to develop alternatives to macrolactamization for the cyclization of peptides. Finally, the beta-substituted amino acid system will be constructed via the chiral Lewis acid promoted conjugate addition of nucleophilic radicals to unsaturated nitro esters or amides. These substrates have great potential as intermediates in the preparation of amino acids. However, they have not been utilized in synthesis, likely due to concerns about the acidity of the resulting alpha-proton. After we have fully developed our new methods with model substrates, we will apply them to the total synthesis of Celogentin C. In addition to these methods, areas we will explore in the total synthesis include arginine protecting groups and the intramolecular Knoevenagel condensation. The synthesis is designed in a manner that will allow easy preparation of novel analogues for structure-activity studies. Thus, by generating compounds with potential medicinal value and facilitating the invention of synthetic methods applicable to a wide range of bioactive peptides, this program will have a profound effect on human health.

描述（由申请人提供）：该项目的主要目标是开发新的、有效的合成方法来合成具有独特结构特征的生物活性肽天然产物。我们选择的目标作为建立这个程序的载体是Celogentin C，一种双环八肽，由于其抑制微管蛋白的聚合而成为一种有效的抗有丝分裂剂。Celogentin C不同寻常的分子结构包括在吲哚侧链的C-2和C-6取代的色氨酸残基，以吲哚和咪唑部分之间的C- n键为特征的双芳基型体系，以及色氨酸和亮氨酸侧链之间交联产生的β取代氨基酸。我们提出了三种新的合成方法来建造这些有趣的结构。取代的中心色氨酸将通过相转移催化的不对称烷基化化学加入到库克色氨酸合成中来制备。这项工作也将导致开发新的金鸡纳生物碱衍生的相转移催化剂，用于烷基化反应和醛醇反应。后一过程将提供-羟基氨基酸。吲哚-咪唑键可通过铜或钯催化的芳基胺化反应形成。我们的目的是在分子内进行这种反应，以开发替代肽环化的大内酰胺化反应。最后，通过手性路易斯酸促进的亲核自由基与不饱和硝基酯或酰胺的共轭加成，构建β取代氨基酸体系。这些底物作为氨基酸制备的中间体具有很大的潜力。然而，它们还没有被用于合成，可能是由于担心产生的α -质子的酸度。在我们用模型底物完全开发了我们的新方法之后，我们将把它们应用到Celogentin c的全合成中。除了这些方法之外，我们将在全合成中探索的领域包括精氨酸保护基团和分子内Knoevenagel缩合。该合成的设计方式将允许易于制备用于结构-活性研究的新型类似物。因此，通过生成具有潜在药用价值的化合物和促进适用于广泛生物活性肽的合成方法的发明，该计划将对人类健康产生深远的影响。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stereoselective additions of thiyl radicals to terminal ynamides.

DOI：
10.1021/ol1008679
发表时间：
2010-06-04
期刊：
ORGANIC LETTERS
影响因子：
5.2
作者：
Banerjee, Biplab;Litvinov, Dmitry N.;Kang, Junghoon;Bettale, Jennifer D.;Castle, Steven L.
通讯作者：
Castle, Steven L.

Enantioselective total synthesis of (-)-acutumine.