Synthesis of Bioactive Small Molecule Building Blocks

 描述（由申请人提供）：创建下一代小分子治疗剂的一个重大障碍是缺乏用于获得某些立体化学致密结构的通用且有效的方法，所述立体化学致密结构含有对生物活性重要的功能性。该MIRA申请旨在合并两个生产性NIGMS资助的项目，广泛关注手性，功能化生物活性小分子构建模块的实验室制备。该计划的总体目标是开发新的合成化学平台，从而能够快速和选择性地构建与生物医学应用直接相关的新结构。我们将使用结构和功能复杂的生物活性天然产物的结构作为新的合成方法的发明的灵感，我们期望其效用超越直接应用于感兴趣的目标。与这种方法重叠的是将重点放在催化转化外消旋混合物对映体纯产品（动态动力学拆分，DKR）的反应的子集。因此，天然产物化学和新反应开发之间的共生循环是预计的结果。Jervine和deoxojervine是hedgehog信号通路的抑制剂，半合成变体正在肿瘤临床试验中进行评估。我们将使用甾体jerveratrum生物碱的结构作为灵感，开发新的对映体收敛反应，快速组装具有挑战性的稠合杂环部分的分子。实施我们的策略的关键是认识到目前的DKR方法仅限于相对少量的外消旋化机制。MIRA资助的一个重要部分旨在将DKR范式扩展到以前从未被认为是对映体收敛候选者的反应家族中，特别是在可以快速组装分子复杂性的反应中。我们的神经毒素河豚毒素的方法取决于一个新的双重氧化/环加成级联序列，快速组装的骨架，功能和立体化学的复杂性，将需要一个有效的合成的发展。同样，虽然该反应将使目标结构和同源物的容易构建成为可能，但预计更大的价值在于由于获得具有高水平的可独立寻址功能的刚性模板的新家族而打开的新化学空间。最后，我们将寻求发展涉及α-和β-二羰基结构的新反应化学。含有这些官能团的化合物的特殊功能产生了独特的和使化学，我们已经成功地和广泛地利用。许多新的流形将在MIRA赠款的支持下进行探索。总的来说，我们期望MIRA的研究活动将推进有机化学领域，并通过提供对迄今为止未知或只能通过低效和/或不切实际的方法访问的结构的便捷访问，在生物医学领域发挥作用。

 DESCRIPTION (provided by applicant): A significant obstacle to the creation of the next generation of small molecule therapeutics is the lack of general and efficient methods for accessing certain stereochemically dense structures that contain functionality important for bioactivity. This MIRA application seeks to merge two productive NIGMS-funded projects broadly concerned with the laboratory preparation of chiral, functionalized bioactive small molecule building blocks. The general goal of this program is to develop new synthetic chemistry platforms that will enable the rapid and selective construction of new structures of immediate relevance for biomedical applications. We will use the structures of architecturally and functionally complex bioactive natural products as an inspiration for the invention of new synthetic methods whose utility we expect to transcend the direct application to the target of interest. Overlaid with this approach will be a focus on a subset of reactions that catalytically convert racemic mixtures to enantiopure products (dynamic kinetic resolution, DKR). Thus, a symbiotic loop between natural product chemistry and new reaction development is a projected outcome. Jervine and deoxojervine are inhibitors of the hedgehog signaling pathway and semisynthetic variants are under evaluation in oncology clinical trials. We will use the structure of the steroidal jerveratrum alkaloids as an inspiration to develop new enantioconvergent reactions that rapidly assemble the challenging fused heterocyclic portion of the molecule. The key to implementation of our strategy is the recognition that current DKR methodology is limited to a relatively small number of racemization mechanisms. A significant part of the MIRA grant is designed to dramatically expand the DKR paradigm into families of reactions that have never before been considered as candidates for enantioconvergence, particularly in the context of reactions that can rapidly assemble molecular complexity. Our approach to the neurotoxin tetrodotoxin hinges on the development of a new twofold oxidation/cycloaddition cascade sequence that quickly assembles the skeletal, functional, and stereochemical complexity that will be required for an efficient synthesis. Again, while this reaction will enable facile construction of the target structure and congeners, the greater value is projected to lie in the new chemical space that opens as a consequence of having access to a new family of rigid templates with a high level of independently addressable functionality. Finally, we will seek to develop new reaction chemistry involving α- and β-dicarbonyl structures. The special features of compounds containing such functional groups engender unique and enabling chemistry that we have successfully and extensively exploited. Many new manifolds will be explored under the aegis of the MIRA grant. Collectively, we expect that the MIRA research activities will advance the field of organic chemistry and be of use in biomedical endeavors by providing facile access to structures that were heretofore unknown or accessible only by virtue of methods that were inefficient and/or impractical.