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

在化学系化学合成计划的支持下，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学和药物化学中可能有用的生物活性物质的化学合成。具体来说，这项工作将集中在精神活性剂衍生物的制备上，这些精神活性剂最初是在属于Galblulimima属的热带雨林树木的树皮中发现的。为此目的而开发的方法是基于使用不含贵金属的试剂，并且预期它们不仅能够简洁地合成Galblulimima生物碱衍生物，而且还能够合成同样含有所谓的“附环”基序的其他复杂靶分子。将评价制备的化合物的生物活性，特别是阿片受体拮抗作用。资助项目的更广泛的影响将扩展到社会的利益，因为PI和Shenvi研究小组的其他成员参与了广泛的教育和推广活动，涉及从小学到大学的学生，无论是在美国境内还是境外。这些努力的很大一部分集中在属于传统上在STEM（科学、技术、工程和数学）领域代表性不足的群体的个人。sp2-sp2连接环的模块化合成，例如在联芳基系统中发现的那些，可以通过过渡金属介导的交叉偶联容易地完成。相比之下，通过sp2-sp3和sp3-sp3键连接来连接环状亚结构仍然是一个挑战。联芳基的四面体等价物的合成由于连接两个环的键的空间位阻增加、需要导航点手性立体选择性问题以及偶尔的化学不稳定性而变得复杂。因此，嵌入天然产物支架内的连接环通常是间接合成的：通过最初生成邻接键，然后通过环化事件形成所需的新环。Shenvi研究小组最近发现了一种附加环Galblimima生物碱，它可以有效地，但非选择性地拮抗两种与人类精神活动有关的受体。发现了由Ni和Mn共同介导的配体控制的交叉亲电偶联过程，其提供了一种以必要的对比（内面）非对映选择性安装所连接的环的方法。这个奇怪的过程可能提供了一个一般的方法来安装连接环，但它目前知之甚少，特别是关于立体选择性的起源。资助项目的目标有两个方面。首先，不寻常的配体控制的立体反转附着环交叉耦合，位置一个片段上的阻碍，内面的合作伙伴，将被优化和探索其范围。预计在这些研究过程中产生的Galblulimima生物碱类似物将在两种靶阿片受体之间及其更大的蛋白质超家族中显示出不同的选择性特征。其次，所取得的研究结果将扩展到配体控制的交叉偶联的广义模型，这将填补合成天然产物样连接环系统的方法中的一个重大空白。迄今为止，对含有这种基序的分子的研究很少，预计将从中产生有用的新基础知识。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.