Pilot-Scale Heterocyclic and Carbocyclic Libraries for High Throughout Screening

描述（申请人提供）：爱荷华州立大学Larock小组将准备高通量筛选大量杂环和碳环文库，这些文库有望表现出广泛的生物活性。将采用Larock小组主要开发的三种非常一般的合成方法。(1)炔、二烯、烯烃和芳烃的pd催化环化将用于制备特别多样化的化合物库，包括吲哚、苯并呋喃、苯并吡喃、香豆素、异香豆素、酞、吡咯酮、2-喹诺酮、吡啶、异喹啉-1- 1、异喹啉-1- 1、异喹啉、碳啉、异吲哚[2,1-a]吲哚、咔唑、二苯并呋喃和其他各种杂环化合物，以及茚酮、茚酮、芴-9- 1和9-烷基芴。(2)利用卤素、硫、硒和有机钯亲电试剂对易获得的功能化取代炔进行环化，可制备具有药用价值的吲哚、苯并呋喃、库美司丹、铬酮、苯并噻吩、苯并噻吩、邻苯酞、异香豆素、异铬烯、异喹啉、喹啉、呋喃、异恶唑和各种螺三烯酮文库。(3)炔环酮可用于制备山酮类、硫山酮类和吖啶酮类。含卤素杂环和碳环将通过众所周知的pd催化过程进一步阐述为更多样化的文库。这种方法非常有效，几乎可以耐受所有重要的有机官能团，在温和的反应条件下进行，提供非常纯的化合物的高产量，并使用现成的起始材料、试剂和催化剂。由20-100种新颖的、小的、密集功能化的、特别多样化的化合物组成的文库将由Larock小组已经研究出的这种非常通用的溶液和固相化学制备出来。外消旋混合物将由德克萨斯州的阿姆斯特朗小组分离，分子模型将由堪萨斯大学的卢辛顿小组进行。最终的文库将使用标准实验室技术纯化到大约95%的纯度，如有必要，PI可以通过堪萨斯大学化学方法和文库开发卓越中心使用高通量纯化技术。该方法将被广泛发表，并将结果文库捐赠给NIH分子文库小分子库和分子文库筛选中心网络。

DESCRIPTION (provided by applicant): The Larock group at Iowa State University will prepare for high throughput screening a large number of libraries of heterocycles and carbocycles expected to exhibit a wide range of biological activity. Three very general synthetic methods primarily developed in the Larock group will be employed. (1) The Pd-catalyzed annulation of alkynes, dienes, alkenes and arynes will be employed to prepare specially diverse libraries of indoles, benzofurans, benzopyrans, coumarins, isocoumarins, phthalides, pyrones, 2-quinolones, pyridines, isoquinolin-1-ones, isoindolin-1-ones, isoquinolines, carbolines, isoindolo[2,1-a]indoles, carbazoles, dibenzofurans and various other heterocycles, plus indenones, indenes, fluoren-9-ones and 9-alkylidene-9Hfluorenes. (2) The cyclization of readily available, functionally-substituted alkynes by halogen, sulfur, selenium and organopalladium electrophiles will be utilized to prepare libraries of medicinally interesting indoles, benzofurans, coumestans, chromones, benzothiophenes, benzoselenophenes, phthalides, isocoumarins, isochromenes, isoquinolines, quinolines, furans, isoxazoles and various spirotrienones. (3) Aryne annulations will be used to prepare xanthones, thioxanthones and acridones. Halogen-containing heterocycles and carbocycles will be further elaborated to more diverse libraries by well known, Pd-catalyzed processes. This methodology is very efficient, tolerates virtually all important organic functional groups, proceeds under mild reaction conditions, affords high yields of very pure compounds, and uses readily available starting materials, reagents and catalysts. Libraries consisting of (20-100 novel, small, densely functionalized, specially diverse compounds will be prepared by this very versatile solution and solid phase chemistry already worked out in the Larock group. Racemic mixtures will be separated by the Armstrong group in Texas and molecular modeling will be carried out by the Lushington group at Kansas University. The resulting libraries will be purified to generally >95% purity using standard laboratory techniques and, if necessary, the high throughput purification techniques available to the PI through the Kansas University Center of Excellence in Chemical Methodologies and Library Development. This methodology will be widely published and the resulting libraries donated to the NIH Molecular Libraries Small-Molecule Repository and the Molecular Libraries Screening Center Network.