Connective Stereospecific Generation of Alkenes Continued

烯烃的连接立体定向生成（续）

• 批准号: 2247031
• 负责人: Christopher Beaudry
• 金额: $ 48.17万
• 依托单位: Oregon State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2247031&HistoricalAwards=false
• 关键词: Connective; Stereospecific; Generation; Alkenes; Continued

With the support of the Chemical Synthesis Program in the Division of Chemistry, Professor Paul Blakemore of Oregon State University is studying a versatile method for the preparation of an important class of molecules called alkenes. Alkenes are widespread among natural and artificial chemical substances with properties of value to medicine, engineering, agriculture, electronics, and materials science. The method being used to generate alkenes differs from traditional approaches in that the molecule is formed directly from two so-called 'carbenoid' building blocks, which assemble in such a precise fashion that potentially any kind of alkene can be targeted with complete control of structure. Molecules to be prepared during this renewed period of support include vitamin D2, a representative member of the D vitamin family with a range of therapeutic indications (e.g., cancer, osteoporosis, and Alzheimer's disease), and pumiliotoxin 251D, a defense alkaloid from a tropical frog species, and related compounds with cardiotonic properties. The broader impacts of the funded project extend to benefits accrued to society as the principal investigator and his research team provide summer research experiences for high school students under the auspices of the STEM academy at Oregon State University. This education and outreach program promotes interest in science and engineering from a diverse array of young learners and it includes mechanisms designed to foster participation from individuals belonging to traditionally underrepresented groups.The award supports continued research and development of the carbenoid eliminative cross-coupling (CEXc) concept for carbon-carbon double bond synthesis. By contrast to conventional methods for connective alkene synthesis, CEXc does not rely on substituent effects to control stereochemical outcome; rather, absolute stereochemical information encoded in two stereodefined sp3-hybridized carbenoid substrates wholly determines the relative configuration of the alkene product via a three-stage stereospecific mechanism (ate-complex formation, 1,2-metalate rearrangement, and beta-elimination). The funded research focuses on extending the concept of CEXc to classes of targets not previously investigated (cyclic styrenes, conjugated trienes, and non-conjugated alkenes) and it encompasses the use of more reactive types of carbenoids (e.g., alpha-chloroalkyl-lithiums and -boronates) and new reaction modalities (e.g., intramolecular). In the context of conjugated alkene synthesis (research thrust 1), specific goals are: assembly of conjugated trienes about the cental olefin, semi-synthesis of vitamin D2 via generation of the C7-C8 double bond (distal bond disconnection), and formation of macrocyclic styrenes by intramolecular CEXc triggered by sulfoxide-metal exchange. The work on non-conjugated alkenes (research thrust 2) focuses on generating challenging targets with subtle stereogenicity, including: chirotopic 4-cyclohexylidenes, isotopomeric olefins, and pumiliotoxin 251D. Pursuit of the highlighted research agenda is anticipated to lead to fundamental and broadly applicable advances both to chiral carbanion chemistry and to the practice of advanced stereoablative synthetic techniques for the control of molecular configuration.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.

在化学系化学合成项目的支持下，俄勒冈州州立大学的保罗·布莱克摩尔教授正在研究一种制备一类重要分子（称为烯烃）的通用方法。烯烃广泛存在于天然和人工化学物质中，具有对医学、工程、农业、电子和材料科学有价值的性质。用于生成烯烃的方法与传统方法不同，因为分子直接由两个所谓的“类卡宾”构建单元形成，它们以精确的方式组装，从而可以完全控制结构，从而潜在地靶向任何种类的烯烃。在这一新的支持期内要制备的分子包括维生素D2，它是D维生素家族的代表性成员，具有一系列治疗适应症（例如，癌症、骨质疏松症和阿尔茨海默氏病），以及来自热带青蛙物种的防御生物碱pumiliotoxin 251 D，以及具有强心特性的相关化合物。资助项目的更广泛的影响延伸到社会的利益，因为主要研究者和他的研究团队在俄勒冈州州立大学的STEM学院的赞助下为高中生提供暑期研究经验。该教育和推广计划旨在促进各种年轻学习者对科学和工程的兴趣，并包括旨在促进传统上代表性不足的群体的个人参与的机制。该奖项支持继续研究和开发碳碳双键合成的类卡宾消除交叉偶联（CEXc）概念。与传统的连接烯烃合成方法相比，CEXc不依赖于取代基效应来控制立体化学结果;相反，编码在两个立体定向的sp3-杂化类卡宾底物中的绝对立体化学信息通过三阶段立体特异性机制（酯络合物形成，1，2-金属酯重排和β-消除）完全决定了烯烃产物的相对构型。资助的研究重点是将CEXc的概念扩展到以前没有研究过的目标类别（环苯乙烯，共轭三烯和非共轭烯烃），并且它包括使用更具反应性的类卡宾（例如，α-氯烷基-锂和-硼酸盐）和新的反应形式（例如，分子内）。在共轭烯烃合成（研究重点1）的背景下，具体目标是：共轭三烯的组装中心烯烃，维生素D2的半合成通过生成的C7-C8双键（远端键断开），和形成大环苯乙烯的分子内CEXc触发亚砜-金属交换。关于非共轭烯烃的工作（研究重点2）侧重于产生具有微妙立体性的具有挑战性的靶标，包括：手性4-环己叉基，同位素烯烃和pumiliotoxin 251 D。追求突出的研究议程，预计将导致基本的和广泛适用的进步，手性碳负离子化学和先进的立体烧蚀合成技术的控制分子configure.This奖项反映了NSF的法定使命的做法，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。