Asymmetric synthesis of highly functionalized lactones and lactams using a chiral Bronsted acid

使用手性布朗斯台德酸不对称合成高官能化内酯和内酰胺

基本信息

批准号：
8958040
负责人：
Kimberly Sue Petersen
金额：
$ 34.11万
依托单位：
UNIVERSITY OF NORTH CAROLINA GREENSBORO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8958040
关键词：
1-Propanol 3-Dimensional Acids Alcohols Applications Grants BINOL Biochemistry Biological Factors Biological Testing Biology Catalysis Chemistry Collaborations Complex Congenital Abnormality Cyclization Data Development Esters Ethanol Future Geometry Goals Handedness Health Housing Hydroxyl Radical Ions Kinetics Laboratories Laboratory Research Lactams Lactones Lead Libraries Mediating Medicine Methodology Methods Molecular Molecular and Cellular Biology Natural Products Chemistry Nature Nausea Paper Pharmaceutical Preparations Pharmacologic Substance Phosphoric Acids Preparation Process Property Protons Publishing Reaction Research Research Personnel Resolution Shapes Structure Students Sulfonamides Variant Work antimicrobial base beta-Lactams catalyst conformer cytotoxic cytotoxicity drug discovery enantiomer experience graduate student innovation novel novel strategies process repeatability racemization research study scaffold small molecule small molecule libraries undergraduate research

项目摘要

DESCRIPTION (provided by applicant): The development of new synthetic methods in order to synthesize the vast array of structurally diverse compounds that nature produces only in small quantities or to efficiently prepare libraries of small molecules for drug discovery is a constant need in chemistry. This proposal outlines two novel strategies for the synthesis of enantioenriched α,α-disubstituted lactones and lactams that take advantage of the different rates of cyclization of prochiral or racemic compounds in the presence of a chiral Brønsted acid catalyst The first goal of the project (Aim 1) is the development of a chiral Brønsted acid catalyzed desymmetrization of amino or hydroxyl diesters. In this aim, α,α-disubstituted lactones will be prepared through the development of a desymmetrization of prochiral hydroxy esters. This will be followed by the expansion of the desymmetrization process to include protected amino diesters to yield α,α-disubstituted lactams. The second objective of the proposal (Aim 2) is the establishment of a chiral Brønsted acid mediated dynamic kinetic resolution. Here, the rapid racemization of the two enantiomers of a racemic mixture in combination with the preferred cyclization of an enantiomer of the racemic mixture will funnel the reaction to the formation of a single cyclic product. The DKR explored will utilize an oxocarbenium ion intermediate. The third goal (Aim 3) of the project is the application of asymmetric methodologies to the formation of novel heterocyclic cores. In this section, the synthetic methods developed will be utilized in the formation of libraries of novel heterocyclic scaffolds such as spirocycles and new beta-lactam scaffolds with potentially potent antimicrobial or cytotoxic properties.

描述（由应用提供）：开发新的合成方法，以综合大自然仅少量产生的各种结构多样的化合物，或有效地准备小分子的库来发现药物发现是化学中持续需求的。该提议概述了对映体合成的两种新型策略在存在手性BrønstedAcid的情况下，利用α，α-脱取代的内酯和乳糖，利用了手术或外消旋化合物的不同速率，是该项目的第一个目标（AIM 1）是手势Brønsted酸催化了对氨基化的手势促进了对Amino或hysrys的抗体化。在此目的中，将通过开发对治疗羟基酯的去对称性化来制备α，α-二取代的内酯。随后将扩展去对称过程，以包括受保护的氨基二极管，以产生α，α-二取代的乳糖。该提案的第二个目标（AIM 2）是建立手性BrønstedAcid介导的动态动力学分辨率。在这里，外消旋混合物的两个对映异构体的快速种族化结合了对映异构体的首选循环化，这将使对单个环状产物形成的反应将反应引向反应。探索的DKR将利用氧化碳离子中间体。该项目的第三个目标（AIM 3）是将不对称方法应用于新型异环核的形成。在本节中，开发的合成方法将用于形成具有潜在潜在潜在抗菌或细胞毒性特性的新型杂环支架和新的β-内酰胺支架。