Methods for Chemo- and Site-Selective C-O activation in Bioactive Natural Products

生物活性天然产物中化学和位点选择性 C-O 活化的方法

• 批准号: 10246926
• 负责人: MICHEL R GAGNE
• 金额: $ 30.37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246926
• 关键词: Acids; Amides; Antifungal Agents; Boranes; Chemistry; Cleaved cell; Complex; Cyclic Peptides; Cyclosporine; Data; Development; Drug Kinetics; Environment; Goals; Intercept; Ions; Lead; Libraries; Methodology; Methods; Modification; Natural Products; Outcome; Peptides; Property; Reaction; Reagent; Reducing Agents; Scheme; Silanes; Site; Structure; Techniques; Testing; Work; analog; base; bioactive natural products; c new; catalyst; enolate; functional group; high throughput screening; improved; innovation; novel; tool

Abstract Late stage functionalization (LSF) is a synthetic strategy to derivatize medicinally interesting compounds to optimize key properties such as bioactivity, pharmacokinetics, etc. The challenge to the synthetic methodology for doing so is one of chemo- and site-selectivity as most such species are multi-functional, and even display multiple copies of a target functional group. We outline an approach that utilizes oxophilic silylium and borenium ions to target for subsequent derivatization, the C–O bonds common in bioactive natural products (NPs), all under catalyst or reagent control. The methods to be investigated first heterolytically cleave Si–X and B–X bonds (X= H, allyl, N3, etc), and then sequences their reactivity to achieve the C–O activation/functionalization goal. Fluoroaryl borane Lewis acids such as B(C6F5)3, BCF, are effective catalysts for generating the key reactive ion pairs and they will be optimized via high throughput screening techniques.

摘要 后期功能化(LSF)是一种衍生医学趣味的综合策略 化合物优化生物活性、药代动力学等关键性能的挑战 对合成方法学来说，这样做是化学和位置选择性之一，就像大多数这样 物种是多功能的，甚至显示一个目标官能团的多个拷贝。我们 概述一种利用亲氧硅和硼离子作为后续目标的方法 衍生化，生物活性天然产物(NPs)中常见的C-O键，均在催化剂或 试剂控制。首先要研究的方法是异质裂解Si-X和B-X键 (X=H、烯丙基、N3等)，然后对它们的反应性进行排序以获得C-O 激活/功能化目标。氟芳基硼烷路易斯酸，如B(C6F5)3，BCF，是 生成关键反应离子对的有效催化剂，将通过高效率进行优化 吞吐量筛选技术。