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

在这个由化学系化学合成计划资助的项目中，佐治亚理工学院的斯特凡·弗兰斯教授正在开发合成天然产品的新方法，天然产品是由活体自然产生的有机化合物。这个研究项目的特别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合成具有广泛生物活性的复杂天然产品。这些天然产物可以作为开发新药物的先导化合物。通过这一研究项目，法兰西教授也在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加外联活动，以扩大未被充分代表的群体在科学领域的参与，包括参加NOBCChE并担任佐治亚理工学院Face研究员的导师。杂芳基稠合七元环存在于在药物发现领域发挥重要作用的各种天然产品中。尽管这种分子结构在天然产物中无处不在，但由于这些化合物中显示出巨大的骨架多样性，有效地构建七元体系仍然是一个合成方法学挑战。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是非常重要的。法国教授正在研究如何开发杂芳基α-亚烷基-1，3-二酮基衍生物与烯烃的正式[5+2]环加成反应，以生成(杂芳基)稠环庚基环。为了证明[5+2]环加成方法的整体效用，法兰西教授将新开发的方法应用于几个有代表性的天然产物合成中。正在进行的三个合成是：1)用N-吲哚基烷基丙二酰胺合成氮杂并[1，2-a]吲哚；2)用吲哚基α-亚烷基β-酮酯合成环七[b]吲哚；3)用呋喃/苯并呋喃基α-亚烷基β-酮酯合成环七[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.