Chemical Synthesis of Chiral Bioactive Molecules

手性生物活性分子的化学合成

• 批准号: 10645231
• 负责人: Sarah Elizabeth Reisman
• 金额: $ 59.46万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645231
• 关键词: Academia; Acceleration; Address; Adopted; Alkenes; Area; Biological; Carbon; Carboxylic Acids; Chemicals; Chemistry; Complex; Coupling; Development; Diterpenes; Lead; Logic; Medicine; Methods; Natural Products; Organic Chemistry; Outcomes Research; Pharmaceutical Chemistry; Pharmacologic Substance; Postdoctoral Fellow; Preparation; Reaction; Research; Research Personnel; Training; catalyst; chemical reaction; chemical synthesis; design; graduate student; human disease; invention; programs; small molecule; theories; tool

Project Summary To enable the preparation of bioactive molecules with increased complexity, it is imperative to develop both the synthetic logic (the design concepts) and the synthetic tools (the chemical reactions) to assemble molecules with chiral centers and polycyclic frameworks. The proposed research program seeks to address this need through chemical research in two general areas. The first research area will focus on the synthesis of complex, highly oxidized, biologically active diterpenes. These total synthesis efforts inspire the invention of new reactions and investigate the ability of existing reactions to solve strategic bond constructions in complex settings. Synthetic access to these natural products will transform our ability to use them and their synthetic derivatives as biological probes or as lead compounds for the development of new medicines. The second research area will focus on the development of new Ni-catalyzed cross-electrophile coupling reactions. These reactions have emerged as versatile methods for carbon–carbon bond formation that are increasingly being adopted by chemists in academia and the pharmaceutical sectors. Despite recent advances, several challenges remain, particularly with respect to the development of catalyst-controlled stereoselective cross-electrophile coupling. To address these challenges, this research seeks to 1) identify new modes of electrophile activation to broaden the scope of products that can be prepared by Ni-catalyzed cross-electrophile coupling; 2) develop stereoselective cross-electrophile coupling reactions of small rings for medicinal chemistry and natural product synthesis; and 3) develop enantioselective CEC reactions of feedstock building blocks such as carboxylic acids and olefins. The expected outcomes of this research program are two-fold: it will provide new reactions and strategies for preparing complex polycyclic molecules, and it will provide access to medicinally relevant natural products and their derivatives. This research will be carried out by a team composed of the PI, four chemistry graduate students and one postdoctoral researcher. As part of this project, the graduate students and postdoctoral researchers will receive rigorous training in the theory, methods, and strategies of organic chemistry. The successful execution of this research will provide new tools to enable the synthesis of small molecules for the study and treatment of human disease.

项目摘要 为了能够制备具有增加的复杂性的生物活性分子，必须开发 合成逻辑（设计概念）和合成工具（化学反应） 具有手性中心和多环骨架的分子。拟议的研究计划旨在解决 这需要通过两个一般领域的化学研究来实现。第一个研究领域将集中在综合 复杂的高度氧化的生物活性二萜这些全面的综合努力激发了 发明新的反应，并研究现有反应解决战略键结构的能力 在复杂的环境中。人工合成这些天然产物将改变我们使用它们的能力， 合成衍生物作为生物探针或作为开发新药的先导化合物。的 第二个研究领域将集中在新的镍催化交叉亲电偶联的发展 反应.这些反应已经成为碳-碳键形成的通用方法， 越来越多地被学术界和制药行业的化学家采用。尽管最近 尽管取得了一些进展，但仍存在一些挑战，特别是在开发催化剂控制的 立体选择性交叉亲电偶联。为了应对这些挑战，本研究旨在1）确定 新的亲电试剂活化模式，以拓宽可通过Ni催化的 交叉亲电偶联; 2）发展小环的立体选择性交叉亲电偶联反应， 药物化学和天然产物合成; 3）发展手性CEC反应， 原料结构单元如羧酸和烯烃。本研究的预期结果 该计划是双重的：它将提供新的反应和制备复杂的多环分子的策略， 它将提供与医学相关的天然产品及其衍生物。这项研究将是 由PI、四名化学研究生和一名博士后研究员组成的团队进行。 作为该项目的一部分，研究生和博士后研究人员将接受严格的培训 有机化学的理论、方法和策略。这项研究的成功实施将提供 新的工具，使小分子的研究和治疗人类疾病的合成。

项目成果

A copper-catalyzed asymmetric oxime propargylation enables the synthesis of the gliovirin tetrahydro-1,2-oxazine core.

• DOI: 10.1039/d0sc04802j
• 发表时间: 2020-10-15
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Cowper NGW;Hesse MJ;Chan KM;Reisman SE
• 通讯作者: Reisman SE

Synthesis of Complex Diterpenes: Strategies Guided by Oxidation Pattern Analysis.

• DOI: 10.1021/acs.accounts.0c00858
• 发表时间: 2021-03-16
• 期刊: ACCOUNTS OF CHEMICAL RESEARCH
• 影响因子: 18.3
• 作者: Dibrell, Sara E.;Tao, Yujia;Reisman, Sarah E.
• 通讯作者: Reisman, Sarah E.

Enantioselective Synthesis of N-Benzylic Heterocycles by Ni/Photoredox Dual Catalysis.

• DOI: 10.1021/jacs.2c07917
• 发表时间: 2022-11-09
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Lacker, Caitlin R.;DeLano, Travis J.;Chen, Emily P.;Kong, Jongrock;Belyk, Kevin M.;Piou, Tiffany;Reisman, Sarah E.
• 通讯作者: Reisman, Sarah E.

Nickel-catalyzed asymmetric reductive cross-coupling of α-chloroesters with (hetero)aryl iodides.

• DOI: 10.1039/d1sc00822f
• 发表时间: 2021-04-26
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: DeLano TJ;Dibrell SE;Lacker CR;Pancoast AR;Poremba KE;Cleary L;Sigman MS;Reisman SE
• 通讯作者: Reisman SE

Nickel-Catalyzed Asymmetric Reductive Cross-Coupling To Access 1,1-Diarylalkanes.

• DOI: 10.1021/jacs.7b01705
• 发表时间: 2017-04-26
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Poremba KE;Kadunce NT;Suzuki N;Cherney AH;Reisman SE
• 通讯作者: Reisman SE