Chemical Synthesis of Chiral Bioactive Molecules

手性生物活性分子的化学合成

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要为了使生物活性分子的复杂性增加，必须发展合成逻辑（设计概念）和合成工具（化学反应）都需要组装具有手性中心和多环形框架的分子。拟议的研究计划旨在解决通过在两个一般领域进行化学研究的需求。第一个研究领域将重点放在合成上复杂，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反应并研究现有反应解决战略键结构的能力在复杂的设置中。综合使用这些天然产品将改变我们使用它们及其使用的能力合成衍生物作为生物学问题或新药物开发的铅化合物。这第二研究领域将重点介绍新的NI催化跨电动耦合的发展反应。这些反应已成为碳 - 碳键形成的多功能方法越来越多地被学术界和药品领域的化学家采用。尽管最近进步，仍然存在一些挑战，特别是关于催化剂控制的发展立体选择性跨电动耦合。为了应对这些挑战，本研究试图1）确定新型的电生物激活模式以扩大可以通过Ni催化制备的产品范围交叉噬菌体耦合； 2）开发小环的立体选择性跨电动耦合反应药物化学和天然产物合成； 3）开发对映选择性CEC的反应原料构建块，例如羧酸和烯烃。这项研究的预期结果程序是两个方面：它将提供新的反应和策略来制备复杂的多环分子，即它将提供获得与药物相关的天然产品及其衍生产品的访问权限。这项研究将是由由PI组成的团队，四个化学研究生和一名博士后研究员组成的团队。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。这项研究的成功执行将提供新工具可以使小分子合成人类疾病的研究和治疗。

项目成果

期刊论文数量（27）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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.

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.

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.