Catalytic Anhydride Desymmetrization as a Route to Polypropionate Synthons

拟议研究的中心主题是开发快速获取聚酮类天然产物片段的方法，这是一个具有生物活性的靶标家族，是其他天然产物家族的五倍。这些立体化学复杂结构的组装以前是使用固有的迭代策略进行的，这必然需要许多步骤和非常熟练的双手。本文详述的方法的不同之处在于，这门科学使用铑催化的酸酐脱对称，从商业上可用的原料中组装这些天然产物的重要部分。这一关键步骤提供了天然产物的6-11个碳部分，而不是更典型的2-4个碳部分，同时还控制了过程中的立体化学。在化学合成项目的支持下，科罗拉多州立大学化学系的Tomislav Rovis教授将开发快速获取聚酮类天然产物片段的方法。这些聚酮具有多种活性，包括抗生素、抗癌和血管生成抑制，这些治疗药物目前是全球卫生领域的重大挑战。这项研究计划的目标是填补这一科学领域的一个明显的深洞；也就是组装这个家族非常复杂的结构的能力。Rovis研究小组是唯一有资格做这件事的人，因为他们之前的贡献。一旦这个空白被填满，它将使有机和药物化学家、生物化学家、生物学家和微生物学家能够产生和筛选这些复杂分子亚段的生物功效，这些分子是药物化学中的特权结构。除了跨学科的影响和潜力之外，对本科生、研究生和博士后的教育效益也有更广泛的影响，他们成为独立科学家的培训和指导也得到了促进。此外，这些资金还将使代表性不足群体的两名成员能够参与研究（一名妇女和一名土著美国人，都是研究生）。

The central theme in the proposed research is to develop rapid access to fragments of polyketide natural products, a family of targets that are five times as likely to have biological activity as other natural product families. Assembly of these stereochemically complex structures has previously taken place using inherently iterative strategies that, by necessity, require many steps and very skilled hands. The approach detailed herein differs in that this science assembles significant subsections of these natural products from commercially available starting materials using a Rh-catalyzed anhydride desymmetrization. This one key step delivers 6-11 carbon sections of natural products, instead of the more typical 2-4 carbon sections, while also controlling stereochemistry in the process. With the support of this award from the Chemical Synthesis Program, Professor Tomislav Rovis of the Chemistry Department at Colorado State University will develop rapid access to fragments of polyketide natural products. These polyketides have diverse activity, including antibiotic, anticancer and angiogenesis inhibition, therapeutics that are currently a significant challenge in global health. The goal of this research program is to fill a deep apparent hole in this area of science; that is, the ability to assemble very complex structures of this family. The Rovis research group is uniquely qualified to do this because of their prior contributions. Once the hole is filled, it will enable organic and medicinal chemists, biochemists, biologists and microbiologists to generate and screen the biological efficacy of subsections of these complex molecules, privileged structures in medicinal chemistry. Beyond the interdisciplinary impact and potential, there is also the broader impact in educational benefit to undergraduates, graduates and postdoctoral fellows, whose training and instruction in becoming independent scientists is facilitated. Furthermore, these funds will also enable the participation of two members of underrepresented groups in research (one woman and one Native American, both graduate students).