Exploiting Unconventional Building Blocks in Chemical Synthesis

在化学合成中利用非常规构件

• 批准号: 10330994
• 负责人: NEIL K GARG
• 金额: $ 58.23万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330994
• 关键词: Alkynes; Amides; Area; Catalysis; Chemical Structure; Complex; Development; Intercept; Lead; Medicine; Methodology; Methods; Molecular; Natural Products; Nickel; Organic Synthesis; Periodicity; Preparation; Research; Structure; Variant; chemical synthesis; functional group; novel therapeutics; propadiene; scaffold; small molecule; tool

Project Summary/Abstract The central objective of this application is to harness unconventional synthetic building blocks for the development of new, reliable, and efficient, methodologies. These methodologies are intended to enable the construction of stereochemically rich scaffolds, including those seen in naturally occurring small molecules and medicines. The development of new methods and the syntheses of complex small molecules continues to be vital areas of research. Most medicinal agents on the market are prepared by organic synthesis, including the large majority of all new drugs that have become available over the past three decades. The chemical structures of new drug entities are becoming increasingly complex, now often bearing sp3 centers rather than “flat” structures. This has led to an increased need for chemists to develop new methods that can reliably build intricate structures. The two unconventional building blocks we seek to harness in the proposed studies are amides and strained cyclic alkynes and allenes. Regarding amides, the C–N bond of amides has long been viewed as stable, such that synthetic methodologies that rely on C–N bond cleavage have remained limited. We seek to develop methods that utilize nickel catalysis to harness amide functional groups as synthons. We propose to assemble important linkages with defined stereocenters, including quaternary stereocenters, using catalysis and chemoenzymatic methods. These efforts provide new opportunities in the area of strong bond activation by nickel catalysis, along with new tools for the manipulation of amides via C–N bond cleavage. With regard to strained cyclic alkynes and allenes, we seek to intercept these transient, highly reactive species to efficiently build complex molecular scaffolds. Such methods should allow for the establishment of scaffolds bearing two new bonds and three sp3 centers. Enantiospecific and catalytic enantioselective variants will be targeted. Our methodologies will be evaluated in the context of several synthetic endeavors. The results of our studies should lead to powerful new strategies and tools for accessing various molecules of importance, including natural products and medicines.

项目总结/文摘