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）：该程序的广泛目标是开发新的，有效的合成方法，用于合成具有独特结构特征的生物活性肽天然产品。我们选择的作为建立该程序的载体的靶标是Celogentin C，Celogentin C是一种双环八肽，它是由于其抑制小管蛋白的抑制作用而成为有效的抗魔法剂。 Celogentin C的不寻常的分子结构包括在吲哚侧链的C-2和C-6上取代的色氨酸残留物，一个双型型系统的特征是吲哚和咪唑基团之间的C-N键，以及beta-辅助氨基酸之间的biarel-type系统，是由the-subsubsented氨基酸之间的，这是由Thepthan和Leucine sane sane Chine inther-ink-subs-Susted氨基酸的。我们提出了三种新型的合成方法，用于构建这些有趣的结构。取代的中央色氨酸将通过将相转化催化的不对称烷基化化学融合到库克色氨酸合成中来制备。这项工作还将导致新型金chona生物碱衍生的相位转移催化剂的发展，用于烷基化和醛醇反应。后一个过程将提供β-羟基氨基酸。吲哚 - 咪唑连接将通过铜或钯催化的芳基胺化反应形成。我们的目的是以分子内的方式进行这种反应，以开发用于肽环化的替代肽的替代方法。最后，将通过手性刘易斯酸促进共轭物添加亲核自由基在不饱和硝基酯或酰胺中促进结合添加的β氨基酸系统。这些底物在中间体制备氨基酸方面具有巨大的潜力。但是，它们尚未用于合成，这可能是由于对所得α-蛋白酶的酸度的担忧。在使用模型底物完全开发了新方法之后，我们将将它们应用于Celogentin C的总合成。除了这些方法外，我们将在总合成中探索的区域包括精氨酸保护组和分子内knoevenagel凝结。该合成的设计方式可以轻松制定用于结构活性研究的新型类似物。因此，通过产生具有潜在药用价值的化合物并促进适用于多种生物活性肽的合成方法的发明，该程序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.