Synthesis of Bioactive Natural Products

生物活性天然产物的合成

基本信息

批准号：
7743757
负责人：
Amos B Smith
金额：
$ 27.61万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-09-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7743757
关键词：
13-deoxytedanolide 3-hydroxybutanal Acetylene Achievement Acids Acyl Coenzyme A Acylation Address Aldehydes Alkaloids Alkenes Alkylation Ally Anions Antibiotics Antineoplastic Agents Architecture Area Attention Aziridines Binding Biological Biological Factors Biomimetics Calcineurin Carbon Cell Line Chemicals Chemistry Cholesterol Clinical Cobalt Collaborations Complex Cyclization DNA Sequence Rearrangement Dental crowns Development Dimensions Dimethyl Sulfoxide Diterpenes Enzymes Epoxy Compounds Esters Evaluation Evolution FK506 Family Felis catus Frustration Generations Goals Grant Hempa Human Hybrids Indoles Institutes Iodides Ions Japan Laboratories Licensing Macrolide Antibiotics Macrolides Marines Medical Medicine Methodology Methods Modeling Molecular Molecular Conformation Mus Nitrogen Octanes Outcome Oxygen Paclitaxel Pharmacologic Substance Phase I Clinical Trials Porifera Preparation Productivity Progress Reports Protocols documentation Publications Rana Reaction Reader Relative (related person)Reporting Research Resistance Route Scheme Series Sirolimus Skeleton Solutions Staging Structure-Activity Relationship System Time Tokyo Transferase Treatment Protocols Tumor Cell Line Update Work Workplace analog antineoplastic antibiotics antitumor agent avermectin base callystatin A clinically relevant college demethoxyrapamycin design discodermolide dithiane experience flasks flexibility improved inhibitor/antagonist innovation kendomycin macrosphelide A macrosphelide B member milbemycin milbemycins mycoticin A n-butyllithium nodulisporic acid A nodulisporic acid D nodulisporic acid F novel oligomycin sensitivity-conferring protein oxidation penitrem D professor programs rimocidin sorangicin A spirastrellolide A stereochemistry success targeted delivery tedanolide ylide

项目摘要

The principal goals for the 24-27 years update since July 2005 will now include: (A) development of an enantioselective total synthesis of the potent insecticidal agent (+)-nodulisporic acid A, (B) completion of the total synthesis of the challenging macrolide antibiotic (+)-sorangicin A; and (C) development of a viable enantioselective total synthesis of the architecturally complex marine antitumor macrolide spirastrellolide A. As in the past, each of these targets will require the development of as yet unforeseen new synthetic methodology to overcome unforeseen obstacles. This is indeed the excitement and frustration of target oriented total synthesis. In the area of new synthetic methods, we will: (D) develop the new modular indole synthesis comprising a sequential Stille and Buchwald-Hartwig cross-coupling union/cyclization tactic, devised in conjunction with the nodulisporic acid A synthetic venture; (E) expand and showcase the new concept of Anion Relay Chemistry (ARC), a powerful synthetic tactic introduced at the time of our previous renewal application, albeit without "proof of concept". Towards the latter end,we will explore a wide variety of nucleophiles, silyl linchpins possessing various anion stabilizing groups (ASG), and electrophiles to demonstrate the feasibility and rapid assembly of diverse, stereochemically complex oxygen and nitrogen substituted products in a single flask. Beyond these specific synthetic objectives, a general, long-range goal of this program is the identification of the molecular architecture responsible for biological activity. Thus, as we develop an approach to each target, we will also prepare model compounds designed to permit the elucidation of structure-activity relationships. Our experience with discodermolide gives us great confidence in this area.

自2005年7月以来24 - 27年更新的主要目标现在将包括：（a）开发有效杀虫剂的对映选择性总合成（+） - 结节酸A，（b）完成具有挑战性的大环内酯类抗生素（+） - 索兰吉蛋白A的总合成；（c）开发可行的结构复杂的海洋抗肿瘤大花环螺旋杆菌A的对映选择性总合成。与过去一样，这些目标中的每一个都需要开发尚无法预料的新合成克服不可预见的障碍的方法。这确实是目标的兴奋和沮丧定向总合成。在新合成方法的领域，我们将：（d）开发新的模块化吲哚合成由序列的Stille和Buchwald-Hartwig交叉耦合联盟/环保策略组成与结节酸合成企业的结合；（e）扩展和展示阴离子继电器化学（ARC），这是我们先前续订时引入的强大合成策略应用程序，尽管没有“概念证明”。朝后一端，我们将探索各种各样的亲核菌，具有各种阴离子稳定组（ASG）的甲硅烷基属蛋白和对展示了不同，立体化学复杂的氧和氮的可行性和快速组装用单个烧瓶取代产品。除了这些特定的合成目标之外，该程序的一般远程目标是识别负责生物活性的分子体系结构。因此，随着我们发展对每个目标的方法，我们还将准备旨在阐明的模型化合物结构活动关系。我们在dincodermolide方面的经验使我们对这一领域充满信心。