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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（由申请人提供）：化学中一直需要开发新的合成方法，以合成大量结构多样的化合物，这些化合物在自然界中仅少量产生，或者有效地制备用于药物发现的小分子文库。该建议概述了两种新的策略，用于合成对映体富集的 α，α-二取代的内酯和内酰胺，利用前手性或外消旋化合物在手性布朗斯台德酸催化剂存在下的不同环化速率该项目的第一个目标（Aim 1）是开发手性布朗斯台德酸催化的氨基或羟基二酯的去对称化。在这个目标中，α，α-二取代内酯将通过开发前手性羟基酯的去对称化来制备。随后将扩展去对称化工艺，包括保护的氨基二酯，以产生α，α-二取代内酰胺。该提案的第二个目标（目标2）是建立手性布朗斯台德酸介导的动态动力学拆分。这里，外消旋混合物的两种对映异构体的快速外消旋化与外消旋混合物的对映异构体的优选环化的组合将使反应漏斗化以形成单一环状产物。探索的DKR将利用氧碳正离子中间体。该项目的第三个目标（Aim 3）是将不对称方法应用于新型杂环核的形成。在本节中，开发的合成方法将用于形成具有潜在强效抗菌或细胞毒性特性的新型杂环支架（如螺环和新型β-内酰胺支架）的文库。