Connective Stereospecific Generation of Alkenes Continued

在化学系化学合成计划的支持下，俄勒冈州立大学的保罗·布莱克莫尔教授正在研究一种通用的方法来制备一类重要的分子，即烯烃。烯烃广泛存在于天然和人造化学物质中，具有医药、工程、农业、电子和材料科学等方面的价值。用于生成烯烃的方法与传统方法的不同之处在于，分子直接由两个所谓的类卡宾构建块组成，这两个构建块以如此精确的方式组装，潜在的任何类型的烯烃都可以完全控制结构而成为靶标。在这一新的支持期内将制备的分子包括维生素D2，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病)的D维生素D2家族的代表性成员，以及来自热带青蛙物种的防御生物碱PumilioToxin251D，以及具有强心作用的相关化合物。该资助项目的更广泛影响延伸到为社会带来的利益，因为首席研究员和他的研究团队在俄勒冈州立大学STEM学院的赞助下为高中生提供暑期研究体验。这一教育和推广计划促进了一系列不同的年轻学习者对科学和工程的兴趣，它包括旨在促进传统上代表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用于碳-碳双键合成的类卡宾消除交叉偶联(CEXc)概念。与传统的连接烯合成方法不同，CEXc不依赖取代基效应来控制立体化学结果；相反，在两个立体定义的SP3杂化卡宾底物中编码的绝对立体化学信息完全通过三阶段立体专一性机制(形成络合物、1，2-金属酸重排和β-消除)决定烯烃产品的相对构型。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)，它包括使用更具活性的卡宾类型(例如，α-氯代烷基锂和-硼酸盐)和新的反应模式(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：围绕中心烯烃组装共轭三烯，通过生成C7-C8双键(远端键断开)半合成维生素D2，以及通过亚砜-金属交换引发的分子内CEXc形成大环苯乙烯。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效应的具有挑战性的目标，包括：手性4-环己烯、同分异构烯和短链毒素251D。对重点研究议程的追求预计将导致手性碳离子化学和用于控制分子构型的先进立体消融合成技术的实践的基础和广泛适用的进展。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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 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.