Carbon-Heteroatom Bond-Forming Reactions

碳-杂原子键形成反应

• 批准号: 7826732
• 负责人: VALERY V FOKIN
• 金额: $ 37.6万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-05 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7826732
• 关键词: Accounting; Affect; Autoimmune Diseases; Azides; Azoles; Be++ element; Beryllium; Biocompatible Materials; Biological; Biological Factors; Biological Phenomena; Biology; Carbohydrates; Carbon; Chemicals; Chemistry; Communities; Complex; Cyclopropanes; Development; Diagnostic Neoplasm Staging; Dyes; Environment; Event; Family; Foundations; Goals; Heterocyclic Compounds; Imidazole; Imidazole-Pyrazole; Inflammation; Investigation; Isoxazoles; Ligands; Light; Lipids; Methodology; Methods; Modification; Molecular; Molecular Probes; Molecular Structure; Nitrogen; Organism; Organometallic Chemistry; Pattern; Peptides; Pharmaceutical Chemistry; Pharmacologic Substance; Physiological; Planets; Plastics; Play; Process; Property; Proteins; Publications; Publishing; Pyrazoles; Pyrimidine; Pyrimidines; Pyrroles; Quinazolines; Reaction; Research; Resistance; Rhodium; Role; Ruthenium; Scientist; Structure; Surveys; System; Thiazoles; Time; Triazoles; biological systems; catalyst; chemical reaction; cycloaddition; cyclopropane; directed evolution; drug candidate; drug market; in vivo; interest; novel; progenitor; programs; public health relevance; pyridine; research and development; scaffold; small molecule; sound; tool

DESCRIPTION (provided by applicant): Nitrogen heterocycles are ubiquitously present both in natural products and in the man-made bioactive compounds. Despite of the diversity of known heterocyclic systems, it is remarkable how few of them are routinely used in medicinal chemistry. Part of the reason is that practical methods leading to these heterocycles are either absent altogether or lacking the generality required for their widespread utilization. Development of such methods is the main goal of the current proposal. We begin with cycloaddition processes for the synthesis of azoles. 1,2,3-Triazoles have witnessed a resurgence of interest during the last several years. Nevertheless, in the vast majority of publications they remain reactivity cul-de-sacs: permanent, inert connectors that unite molecular fragments with a desired function. This is not surprising when one takes into account the exceptional stability of these nitrogen heterocycles: they are exceedingly resistant to thermal degradation and are not affected by severe hydrolytic, reductive, and oxidative conditions. However, the few notable exceptions to this general truth provide unique opportunities for exploration of synthetic transformations which utilize 1,2,3-triazoles themselves as energetic, but reasonably stable progenitors of reactive intermediates which give rise to a plethora of different heterocyclic compounds. In addition to developing synthetic methodologies, we will develop methods for studying biological systems using organic azides. We will endeavor to develop new bioorthogonal catalytic transformations through studies in organometallic chemistry and chemical biology. Ultimately, we hope to give the synthetic organic, biological, and materials chemistry communities a range of tools for creating functional structures. PUBLIC HEALTH RELEVANCE: We propose to develop novel chemical reactions for synthesis of heterocyclic compounds with biological activity. We will also develop chemical transformations that are compatible with physiological conditions and allow tracking of biological molecules in living systems in order to study in vivo chemical events, such as modification of complex biomolecules (proteins, lipids, and carbohydrates), which are often a hallmark of the earliest stages of cancer, inflammation, and autoimmune diseases.

描述（由申请人提供）：氮杂环普遍存在于天然产物和人造生物活性化合物中。尽管已知的杂环系统的多样性，但值得注意的是，它们中很少有常规用于药物化学。部分原因是导致这些杂环的实际方法要么完全不存在，要么缺乏广泛利用所需的一般性。制定这些方法是本提案的主要目标。我们开始与环加成过程的唑类化合物的合成。1，2，3-三唑在过去几年中再次引起人们的兴趣。然而，在绝大多数出版物中，它们仍然是反应性死胡同：永久的，惰性的连接器，将分子片段与所需的功能结合起来。当考虑到这些氮杂环的特殊稳定性时，这并不奇怪：它们对热降解具有极强的抵抗力，并且不受严重的水解，还原和氧化条件的影响。然而，这一普遍真理的几个显着的例外提供了独特的机会，探索利用1，2，3-三唑本身作为充满活力的合成转化，但相当稳定的反应性中间体，产生了过多的不同的杂环化合物的祖先。除了开发合成方法，我们还将开发使用有机叠氮化物研究生物系统的方法。通过有机金属化学和化学生物学的研究，奋进开发新的生物正交催化转化。最终，我们希望为合成有机，生物和材料化学社区提供一系列用于创建功能结构的工具。 公共卫生相关性：我们建议开发新的化学反应，用于合成具有生物活性的杂环化合物。我们还将开发与生理条件兼容的化学转化，并允许跟踪生命系统中的生物分子，以研究体内化学事件，例如复杂生物分子（蛋白质、脂质和碳水化合物）的修饰，这通常是癌症、炎症和自身免疫性疾病最早阶段的标志。