Skeletal Diversity Employing Scaffold Rearrangements, Annulations & Cycloaddition

使用支架重新排列、成环的骨骼多样性

• 批准号: 7695405
• 负责人: JOHN A PORCO
• 金额: $ 29.84万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7695405
• 关键词: Acids; Alkenes; Amino Alcohols; Attention; Breathing; Cations; Characteristics; Chemicals; Complex; Computer software; Copper; Custom; Cyclopropanes; DNA Sequence Rearrangement; Development; Dimerization; Diversity Library; Electrostatics; Elements; Ethers; Ethyl Ether; Facility Construction Funding Category; Fingerprint; Flavones; Generations; Goals; Incentives; Libraries; Mediating; Methodology; Molecular; Oxepins; Pathway interactions; Positioning Attribute; Preparation; Process; Production; Pyrans; Pyrrolidines; Reaction; Reagent; Relative (related person); Research; Research Personnel; Resources; Route; Score; Shapes; Skeletal system; Structure; System; Technology; Three-dimensional analysis; base; chemical reaction; cycloaddition; cyclopropane; design; flavone; ionization; member; novel; pyrrolidine; pyrroline; scaffold; small molecule libraries; stereochemistry

Introduction. The synthesis of focused, chemical libraries provides incentive and inspiration for the discovery of novel chemical reactions. Scaffold rearrangement is an attractive approach for library development due to the rigid structures that scaffolds can possess and the stereochemical diversity accessible through asymmetric synthetic processes. These attributes have previously been exploited in the synthesis of libraries via the Petasis reaction.1 Recently, diversity-oriented synthesis (DOS)2 has increasingly emphasized skeletal diversity involving the structural manipulation of scaffolds and synthesis of molecules with distinct skeletal framework.3 The allyl-cation rearrangement of dihydropyran 1 (Figure 1A) mediated by Sc(OTf)3 to yield the bispyran 2 illustrates how a rearrangement process may provide access to compounds that possess different shape characteristics. Three dimensional analysis of the two compounds using shape similarity and electrostatics was accomplished using OpenEye Scientific Software (http://www.eyesopen.com, OMEGA and ROCS). The shape fingerprint matching process4 (Figure 1B) characterized the Shape Tanimoto Score as 0.43 and the Tanimoto Electrostatics Score5 as <0.20. The overlay of the two compounds illustrates how the shape of the two compounds is distinctly different, evidenced by the low similarity scores, and how scaffold rearrangements may be useful diversity-generating processes. However, sequences involving rearrangements or fragmentations are highly underdeveloped and should continue to receive attention. We seek to develop synthetic sequences for the creation of novel cyclic scaffolds for library development featuring novel stereoselective processes. Our approach involves methodologies such as skeletal rearrangements, photochemical-mediated electrocyclic processes, cycloaddition reactions, and ring annulations as routes towards accessing skeletal diversity. In particular, photochemical reactions are highly underdeveloped in diversity oriented synthesis and are very promising for the generation of complex ring systems. An important aspect of functional diversity in the construction of libraries, in which the quality of diversity is optimal for any given scaffold, is the ability to vary the relative position of diversity elements. Mindful of this design criterion, the topology of target molecules will also be varied by the preparation of structures and scaffolds through efficient and stereoselective rearrangement processes. This approach will optimally display functionality as positional diversity elements. Moreover, the reagents and building blocks employed in the synthesis of library members will be custom building materials available from other methodologies available to the CMLD-BU through the various research groups in order to access the greatest chemical diversity available from the Center's resources. In is anticipated that the combination of novel structural rearrangement processes and the use of novel reagents will result in the construction of library compounds rich in chemical functionality, shape diversity, and topologically unique frameworks. Ultimately, the synergistic efforts of the participating researchers of the CMLD-BU will enhance the level of molecular complexity accessible in library construction.

导论.集中的化学库的合成为发现提供了激励和灵感 新的化学反应。支架重排是一种有吸引力的 由于结构僵化， 支架可以拥有和立体化学多样性 通过不对称的合成过程。这些属性具有 以前通过Petasis在文库的合成中被利用 最近，多样性导向合成（DOS）2已经 越来越强调骨骼的多样性， 操纵支架和合成具有不同结构的分子 3二氢吡喃1的烯丙基阳离子重排 （图1A）由Sc（OTf）3介导产生双吡喃2， 重排过程如何提供获得化合物的途径， 具有不同的形状特征。三维分析 的两种化合物使用形状相似性和静电， 使用OpenEye Scientific软件完成 (http：www.eyesopen.com、OMEGA和ROCS）。形状 指纹匹配过程4（图1B）的特点是形状 Tanimoto评分为0.43，Tanimoto静电评分为5， <0.20。两种化合物的叠加说明了 这两种化合物是明显不同的，证明了低 相似性分数，以及支架重排如何可能是有用的 多样性生成过程。然而，序列涉及 重组或碎片化是高度不发达的， 应该继续受到关注。我们寻求开发合成 用于创建用于文库开发的新型环状支架的序列， 流程.我们的方法包括骨骼重排，光化学介导的 电环化过程，环加成反应和环化作为进入骨架的途径， 多样性特别地，光化学反应在多样性定向合成中是高度不发达的， 对于复杂的环系统的产生是非常有前途的。 功能多样性是图书馆建设中的一个重要方面，其中多样性的质量是 对于任何给定的支架最佳的是改变多样性元件的相对位置的能力。注意这一 设计标准，靶分子的拓扑结构也将通过结构的制备而变化， 通过有效的和立体选择性的重排过程的支架。这种方法将最佳地显示 功能性作为位置多样性元素。此外，用于本发明的试剂和结构单元可用于制备用于本发明的试剂和结构单元。 库成员的合成将是可从其他方法获得的定制构建材料， CMLD-BU通过各种研究小组，以获得最大的化学多样性 中心的资源。可以预期，新的结构重排过程的组合 并且新试剂的使用将导致构建富含化学官能团的库化合物， 形状多样性和拓扑上独特的框架。最终，参与者的协同努力 CMLD-BU的研究人员将提高文库构建中可获得的分子复杂性水平。