New Approaches for Stereoselective Formation of Quaternary Carbon Stereocenters and Fragment Coupling

化学部的化学合成项目支持Overman教授的项目。Overman教授是加州大学欧文分校化学系的教员。他建议开发连接复杂分子片段的新方法，以制备高价值的有机分子。通过独立构建一个分子的复杂片段，然后在合成结束时将它们耦合在一起，可以避免一次一步构建整个结构的低效线性序列。正在开发的方法尤其令人印象深刻，因为它以一比一的比例组合了复杂的片段。因此，它避免了由于过量使用其中一个复杂碎片而浪费宝贵材料的更常见的需要。在这些研究中，Overman教授和他的同事使用光氧化还原催化偶联反应。这种转变是有吸引力的，因为它们使用可见光作为能量来源来形成新的化学键。这种使用可持续能源的反应有助于将其对环境的影响降到最低。涉及光催化、机械和定向合成目标的广泛研究范围非常适合各级科学家的教育。奥弗曼教授的小组长期以来一直为同事提供最高水平的教育和培训，包括那些在科学领域代表性不足的同事。这些学生中的许多人现在在学术界和制药行业都担任领导职务。双分子化学反应，结合复杂的片段，以良好的产量，并在重要的地方，具有高立体控制，是实施会聚合成策略的基础。当在片段耦合步骤中连接的原子是手性的时，这种结合特别具有挑战性。Overman教授实验室的最新发现表明，结构复杂的叔碳自由基和缺电子烯烃的双分子反应可以通过使用等摩尔（或接近等摩尔）量的两个偶联伙伴形成新的键，以高产量和高立体控制的方式连接复杂的片段。这种化学转化目前还不是有机合成中常见的部分，但在解决构建复杂有机分子的艰巨挑战方面具有令人兴奋的潜力。本研究明确了半草酸叔醇前体形成叔自由基的机理，优化了叔自由基的生成和偶联，探索了1,6-碳自由基在亲电二烯上的加成，并开发了多组分自由基-阴离子交叉反应。并定义了叔自由基片段偶联策略在含二氧双环[3.3.0]辛酮片段和对-烯二萜的结构精细二萜的对映选择性全合成中的应用。这些有机反应对制药工业具有重要的技术和广泛的影响。

The Chemical Synthesis Program of the Chemistry Division supports the project by Professor Overman. Professor Overman is a faculty member in the Department of Chemistry at the University of California, Irvine. He proposes to develop new ways to join complex molecular fragments to prepare high-value organic molecules. By building complex pieces of a molecule independently and then coupling them together at the end of a synthesis, inefficient linear sequences that build the entire structure one step at a time can be avoided. The method under development is particularly impressive in that it combines the complex fragments in a one to one ratio. Thus, it avoids the more common need to waste valuable material by using one of the complex fragments in excess. In these studies, Professor Overman and his coworkers employ photoredox catalysis for the coupling reactions. Such transformation are attractive because they use visible light as the energy source for making new bonds. This use of sustainable energy for the reactions help to minimize their environmental impact. The broad scope of the research involving photocatalysis, mechanistic and target-directed synthesis objectives is well suited for the education of scientists at all levels. Professor Overman's group has a long established record of providing the highest level of education and training for coworkers including those underrepresented in science. Many of these students now hold leading positions in both academics and the pharmaceutical industry. Bimolecular chemical reactions that combine complex fragments in good yield, and, where important, with high stereocontrol, are fundamental for implementing convergent synthetic strategies. When the atoms joined in a fragment-coupling step are chiral, this union is particularly challenging. Recent discoveries from Professor Overman's laboratories show that bimolecular reactions of structurally elaborate tertiary carbon radicals and electron-deficient alkenes can join complex fragments by forming new bonds in high yields and high stereocontrol using equimolar (or nearly equimolar) amounts of the two coupling partners. Such chemical transformations are not currently a common part of the repertoire of organic synthesis, yet hold exciting potential to solve formidable challenges in constructing complex organic molecules. The proposed studies define the mechanism and optimize the generation and coupling of tertiary radicals formed from tertiary alcohol hemioxalate precursors, explore 1,6-additions of carbon radicals to electrophilic dienes and develop multicomponent radical-anionic crossover reactions, and define the utility of tertiary-radical fragment coupling strategies in the enantioselective total synthesis of structurally elaborate diterpenoids harboring dioxobicyclo[3.3.0]octanone fragments and ent-kaurene diterpenoids. These organic reactions have important technical broader impacts on the pharmaceutical industry.