Pilot-Scale Heterocyclic and Carbocyclic Libraries for High Throughout Screening

描述（由申请人提供）：爱荷华州州立大学的Larock小组将为高通量筛选大量杂环和碳环文库做准备，这些文库预计将表现出广泛的生物活性。将采用主要在Larock组中开发的三种非常通用的合成方法。(1)炔、二烯、烯烃和芳炔的Pd催化的环化将用于制备吲哚、苯并呋喃、苯并吡喃、香豆素、异香豆素、苯酞、吡喃酮、2-喹诺酮、吡啶、异喹啉-1-酮、异吲哚啉-1-酮、异喹啉、咔啉、异吲哚并[2，1-a]吲哚、咔唑、二苯并呋喃和各种其它杂环的特别多样的库，加上茚酮、茚、芴-9-酮和9-亚烷基-9H芴。(2)通过卤素、硫、硒和有机钯亲电试剂环化容易获得的官能取代的炔将用于制备医学上感兴趣的吲哚、苯并呋喃、香豆烷、色酮、苯并噻吩、苯并硒吩、苯酞、异香豆素、异色烯、异喹啉、喹啉、呋喃、异恶唑和各种螺三烯酮的文库。(3)芳炔环化将用于制备氧杂蒽酮、噻吨酮和吖啶酮。含卤素的杂环和碳环将通过众所周知的Pd催化方法进一步加工成更多样化的文库。该方法是非常有效的，耐受几乎所有重要的有机官能团，在温和的反应条件下进行，提供高收率的非常纯的化合物，并使用容易获得的起始材料，试剂和催化剂。由20-100种新颖的、小的、密集官能化的、特别多样化的化合物组成的库将通过这种在Larock组中已经研究出的非常通用的溶液和固相化学来制备。外消旋混合物将由德克萨斯州的阿姆斯特朗小组分离，分子建模将由堪萨斯大学的卢欣顿小组进行。将使用标准实验室技术和（如有必要）PI可通过堪萨斯大学化学方法学和文库开发卓越中心获得的高通量纯化技术将所得文库纯化至通常>95%的纯度。该方法将被广泛发表，并将产生的文库捐赠给NIH分子图书馆小分子库和分子图书馆筛选中心网络。

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.