Attached-Ring Cross-Coupling to Explore Chemical Space and Receptor Selectivity

附着环交叉偶联探索化学空间和受体选择性

基本信息

批准号：
2155228
负责人：
Ryan Shenvi
金额：
$ 52.5万
依托单位：
The Scripps Research Institute
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2155228&HistoricalAwards=false
关键词：
Attached Ring Cross Coupling Explore

项目摘要

With the support of the Chemical Synthesis program in the Division of Chemistry, Professor Ryan Shenvi of The Scripps Research Institute is studying a series of unusual processes that will facilitate the chemical synthesis of bioactive substances of possible utility in chemical biology and medicinal chemistry. Specifically, the work will focus on the preparation of derivatives of psychoactive agents that were originally discovered in the bark of rainforest trees belonging to the genus Galbulimima. The methods being developed for this purpose are based on the use of non-precious metal-containing reagents and they are anticipated to enable not only concise syntheses of Galbulimima alkaloid derivatives, but also other complex target molecules that likewise contain so-called 'attached-ring' motifs. The prepared compounds will be evaluated for biological activity, specifically opioid receptor antagonism. The broader impacts of the funded project will extend to the benefits accrued to society as the PI and other members of the Shenvi research group engage in a broad range of educational and outreach activities involving students from elementary school through college level, both within the US and beyond its borders. A significant portion of these efforts focus on individuals belonging to groups traditionally underrepresented in STEM (science, technology, engineering and mathematics) fields.Modular syntheses of sp2–sp2 attached-rings, such as those found in biaryl systems, can be readily accomplished via transition metal-mediated cross-coupling. By contrast, the attachment of cyclic substructures by sp2–sp3 and sp3–sp3 bond linkages remains a challenge. The synthesis of tetrahedral equivalents of biaryls is complicated by increased steric encumbrance about the bond linking the two rings, the need to navigate point-chiral stereoselectivity issues and, occasionally, chemical instability. As a consequence, attached rings embedded within natural product scaffolds are typically synthesized indirectly: by initial generation of the adjoining bond and then a cyclization event to form the desired new ring. The Shenvi group recently identified an attached-ring Galbulimima alkaloid that potently, yet non-selectively, antagonizes two receptors involved in psychotropic activity in humans. A ligand-controlled cross-electrophile coupling process co-mediated by Ni and Mn was discovered that offers a means to install the attached ring with the necessary contrasteric (endo face) diastereoselectivity. This curious process may offer a general approach for the installation of attached rings, but it is currently poorly understood, and especially with regard to the origin of stereoselectivity. The objectives of the funded project are two-fold. First, the unusual ligand-controlled stereo-invertive attached-ring cross-coupling that positions one fragment onto the hindered, endo-face of its partner, will be optimized and its scope explored. It is anticipated that the Galbulimima alkaloid analogues generated during the course of these studies will show different selectivity profiles between two target opioid receptors and across their larger protein superfamily. Second, the findings made will be extended to a generalized model of ligand-controlled cross-coupling that will fill a significant gap in methods to synthesize natural product-like attached-ring systems. Molecules containing such motifs have been hitherto little investigated and useful new fundamental knowledge is anticipated to emerge from this endeavor.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学合成计划中的支持下，斯克里普斯研究所的Ryan Shenvi教授正在研究一系列不寻常的过程，这些过程将促进化学生物活性物质在化学生物学和医学化学中的生物活性物质。具体而言，这项工作将集中于最初在属于Galbulimima属的雨林树皮中发现的精神活性药物的衍生物。为此目的开发的方法基于使用非含有金属的试剂的使用，预计它们不仅可以简洁的Galbulimima生物碱衍生物的合成，而且还可以使其他复杂的靶标分子，也可以使所谓的“附着”托曲序相同。制备的化合物将用于生物学活性，特别是阿片类受体拮抗作用。随着PI和Shenvi Research Group的其他成员从事各种教育和外展活动，涉及来自小学到大学范围内的学生，包括在美国境内和边界以外的学生。这些努力的很大一部分集中在传统上属于STEM（科学，技术，工程和数学）领域的群体的个人。SP2-SP2附加环的模块化合成（例如在Biaryl系统中发现的）可以通过过渡金属介导的交叉介导的交叉介导。相比之下，SP2 -SP3和SP3 – SP3键连接的循环子结构的附着仍然是一个挑战。双面双体等效物的综合因与连接这两个环的键的空间负担增加，需要驾驶点性直立定位性问题以及有时是化学不稳定性。结果，嵌入自然产物支架内的附着环通常是间接合成的：通过初始生成相邻的键，然后是一个环化事件，形成所需的新环。 Shenvi组最近确定了一个附着的Galbulimima生物碱，该生物碱有可能但非选择性地拮抗参与人类精神活性的两个受体。发现了由Ni和MN共同介导的配体控制的跨电量耦合过程，该过程提供了一种以必要的对比（Endo Face）映射的方式安装连接环的手段。这个奇怪的过程可能会为安装附件的环提供一种通用的方法，但目前对立体选择性的起源尤其是较少的理解。资助项目的目标是两个方面。首先，不寻常的配体控制的立体声互换环耦合耦合将一个碎片定位在其伴侣的阻碍的，内face上，并将得到优化，并探索其范围。可以预料，在这些研究过程中产生的galbulimima生物碱类似物将显示两个靶阿片类药物接收器和较大的蛋白质超家族之间的选择性不同。其次，所做的发现将扩展到配体控制的交叉偶联的广义模型，该模型将填补合成类似天然产品的附属环系的方法的显着空白。含有此类主题的分子很少被隐藏起来，预计有用的新基本知识将从这项努力中脱颖而出。该奖项反映了NSF的法定任务，并通过使用该基金会的智力优点和更广泛的影响来审查标准来通过评估来获得支持。