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Synthesis of Macrolides, Steroids, Cyclopentanoids, etc.

大环内酯类、类固醇、环戊烷等的合成

基本信息

批准号：
7433887
负责人：
BARRY M TROST
金额：
$ 58.9万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-07-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7433887
关键词：
3-hydroxybutanal Alcohols Aldehydes Alkenes Alkynes Anhydrides Anti-Inflammatory Agents Anti-inflammatory Architecture Award Benzomorphan Benzomorphans Biological Biological Factors Biological Phenomena Brefeldin A Catalysis Chemicals Complex Coupling Cyclization Cyclopropanes Development Evolution Facility Construction Funding Category Family Galantamine Grant Immunosuppressive Agents Ketones Laboratories Lead Ligands Macrocyclic Compounds Macrolides Metals Methodology Methods Molds Molecular Molecular Conformation Molecular Target Morphine Numbers Object Attachment One-Step dentin bonding system Operative Surgical Procedures Palladium Process Progress Reports Protocols documentation Pyrans Range Reaction Reagent Reporting Ruthenium Squalene Synthetase Staging Sterility Steroids Structure System Terpenes Therapeutic Agents Time Translating Work Zinc acetol base bryostatin bryostatin 7 butyrolactone catalyst concept cotylenin A cyclic compound cycloaddition cyclopropane design diene enol enolate guanacastepene improved inhibitor/antagonist insight interest ion channel blocker isomigrastatin member norcarane novel novel therapeutics paraherquamide programs research study rhodotoxin siccanin streptazolin vinylsilane

项目摘要

DESCRIPTION (provided by applicant): Exploring biological phenomena at a molecular level provides the basis of understanding from which new therapeutic agents derive. The ability to construct a defined molecular architecture requires highly selective reactions and reagents to permit the development of effective synthetic strategies. Cyclic compounds have biological activities across a broad spectrum. Furthermore, constraining conformations of mobile molecules by forming rings also frequently enhances biological potency. Thus, a concerted effort to apply new chemical principles being developed in these laboratories to the formation of rings becomes an important objective. Two new methods for accessing pyrans by simple one operation cycloaddition - like strategy relying on palladium and / or ruthenium catalysis may lead to biologically active targets containing such subunits illustrated by dactyolide and the bryostatins. Unprecedented cycloadditions of norcarane type substrates will be a major focus that may lead to a structural motif so common to a great number of bioactive molecules ranging from ion channel blockers like grayanotoxin to anti-inflammatories like ramaswaralide. Cascade reactions involving creation of three rings in one step can provide rapid entry to complex targets like guanacastepene. The reactivity and selectivity of palladium complexes of chemically reactive intermediates to form odd membered rings including five, seven and even nine members can lead to strategies to families of compounds possessing powerful antihelmintic and antinematodol mold metabolites ranging to squalene synthase and Ras farnesyl transfer inhibitors. A new concept for the synthesis of macrocyclic compounds at high concentrations will be examined in the context of the antitumor amphidinolide and the immunosuppressive ushikulide families. These new synthetic methods apply to many structural types beyond those illustrated and constitutes a significant to gain access to complex molecular targets more easily.

描述(由申请人提供)：在分子水平上探索生物现象为理解新的治疗药物的来源提供了基础。构建确定的分子结构的能力需要高度选择性的反应和试剂，以允许开发有效的合成策略。环状化合物具有广泛的生物活性。此外，通过形成环来限制可移动分子的构象也经常增强生物效力。因此，共同努力将这些实验室正在开发的新化学原理应用于环的形成成为一个重要的目标。两种基于钯和/或Ru催化的简单一步环加成类策略来获得吡喃的新方法可能会导致含有Dactyolide和Bryostins所示亚基的生物活性靶标。前无古人的降冰片烷型底物的环加成反应将是一个主要焦点，它可能导致大量生物活性分子共同的结构基序，从离子通道阻滞剂(如灰霉毒素)到抗炎药物(如雷马斯瓦里德)。一步生成三个环的级联反应可以快速进入复杂的目标，如鸟嘌呤。化学活性中间体的钯配合物形成包括五个、七个和偶数九个成员的奇数环的反应性和选择性可以导致具有强大的抗蠕虫和抗霉菌代谢产物的化合物家族的策略，包括角鲨烯合成酶和RAS法尼基转移抑制剂。在抗肿瘤的两面体内酯和免疫抑制的乌什库里内酯家族的背景下，将研究在高浓度下合成大环化合物的新概念。这些新的合成方法适用于许多结构类型，而不是那些所示的类型，并且构成了更容易获得复杂分子靶标的重要手段。