Strategic Formal [5+2]-Cycloadditions Toward Heteroaryl-fused Seven-membered Rings

在这个由化学系化学合成项目资助的项目中，格鲁吉亚理工学院的Stefan France教授正在开发合成天然产物的新方法，天然产物是由生物体自然产生的有机化合物。 这个研究项目的具体目标是开发一个化学反应工具箱，从而有效地构建包含七个原子环的分子。 法国教授正在将这些方法应用于具有各种生物活性的复杂天然产物的合成。 这些天然产物可作为开发新药的先导化合物。 通过这一研究项目，法国教授还为本科生和研究生提供高水平的教育和培训。 他和他的研究小组还积极参与外展活动，以扩大在科学中代表性不足的群体的参与，包括参加NOBCChE和担任格鲁吉亚技术FACES研究员的导师。杂芳基稠合七元环存在于各种各样的天然产物中，在药物发现领域发挥着重要作用。尽管这种分子结构在天然产物中普遍存在，但由于这些化合物中表现出巨大的骨架多样性，七元系统的有效构建仍然是合成方法学的挑战。因此，以简洁、区域和立体控制的方式合成这些基序的能力对有机化学家来说非常重要。 France教授正在研究开发杂芳基α-亚烷基1，3-二羰基衍生物与烯烃的正式[5+2]环加成以生成（杂）芳基稠合环庚基环的方法。为了证明[5+2]环加成方法的总体效用，France教授正在将新开发的方法应用于几个有代表性的天然产物合成。正在进行的三种合成是：1）使用N-吲哚基亚烷基丙二酰胺合成氮杂卓并[1，2-a]吲哚; 2）使用吲哚基α-亚烷基β-酮酯合成环庚并[B]吲哚;和3）使用呋喃基/苯并呋喃基α-亚烷基β-酮酯合成环庚并[B]呋喃。

In this project funded by the Chemical Synthesis Program in the Division of Chemistry, Professor Stefan France of the Georgia Institute of Technology is developing new approaches to synthesize natural products, which are organic chemical compounds that are naturally produced by living organisms. The particular goal of this research project is to develop a toolbox of chemical reactions that lead to the efficient construction of molecules that contain rings of seven atoms. Professor France is applying these methods toward the synthesis of complex natural products that have a wide variety of biological activities. These natural products may serve as lead compounds for the development of new pharmaceuticals. Through this research project, Professor France is also providing high-level education and training for undergraduate and graduate students. He and his research group are also active in outreach activities to broaden the participation of underrepresented groups in science, including participating in NOBCChE and acting as a mentor for Georgia Tech FACES fellows.Heteroaryl-fused seven-membered rings are present in a large variety of natural products that play an important role in the field of drug discovery. Despite the ubiquity of this molecular structure in natural products, the efficient construction of seven-membered systems remains a synthetic methodology challenge due to vast skeletal diversity exhibited in these compounds. Consequently, the ability to synthesize these motifs in a concise, regio- and stereocontrolled manner is of high importance to organic chemists. Professor France is studying ways to develop formal [5+2] cycloadditions of heteroaryl alpha-alkylidene 1,3-dicarbonyls derivatives with alkenes to generate (hetero)aryl-fused cycloheptyl rings. To demonstrate the overall utility of the [5+2] cycloaddition approaches, Professor France is applying the newly developed methodologies in a few representative natural product syntheses. Three of the syntheses being pursued are: 1) the synthesis of azepino[1,2-a]indoles using N-indolyl alkylidene malonamides; 2) the synthesis of cyclohepta[b]indoles using indolyl alpha-alkylidene beta-ketoesters; and 3) the synthesis of cyclohepta[b]furans using furyl/benzofuryl alpha-alkylidene beta-ketoesters.