Development of Spirodiepoxide-Based Methods of Chemical Synthesis

描述(申请人提供)：在可预见的未来，有机化合物将继续作为药物制剂在分子医学中占据主导地位，除了极少数例外，这些物质必须通过化学合成。合成使生物活性有机分子能够在各个层面上进行评估：细胞靶标识别、生物学机制阐明、药物靶标验证、先导识别以及临床候选药物的优化和生产。化学合成的局限性常常给生物活性分子的研究带来很大的障碍。为了加快了解疾病和推进分子医学的进程，需要提高对反应性的理解，开发有效和简洁的方法，并改进合成策略。这项研究将开发基于螺二环氧化物(SDE)的创新方法来缓解这些瓶颈，螺二环氧化物是联烯的双环氧化产物。与灵活和收敛的丙烯合成方法相结合，基于SDE的转化将使人们能够直接进入广泛的分子基序，这些分子基序富含天然产物和复杂药物。这项研究的长期目标是建立对SDE反应性的深入了解，开发基于SDE的方法，并改进应用这些方法合成化学和药物相关目标的合成策略。本建议的具体目的是开发SDE的碳亲核开环方法，并应用于合成9-(S)-二氢赤藓内酯A，这是一类重要的抗生素的前体。第二，改进立体选择性SDE的形成方法和分子内杂原子亲核开环的方法，重点是合成吡喃和呋喃，并将其用于合成抗肿瘤药物psymberin和果胶毒素4。最后，我们将开发合成包括邻位多元醇在内的高氧基元的方法。

DESCRIPTION (provided by applicant): Organic compounds will continue to dominate molecular medicine as drug agents for the foreseeable future, and with few exceptions, these substances must be chemically synthesized. Synthesis enables the evaluation of bioactive organic molecules at all levels: cellular target identification, elucidation of biological mechanism, drug target validation, lead identification, and optimization and production of clinical candidates. The limitations of chemical synthesis often present a substantial obstacle to the study of bioactive molecules. Improved understanding of reactivity, development of effective and concise methods, and refinement of synthetic strategies are required to accelerate the process of understanding disease and advancing molecular medicine. This research will develop innovative methods to relieve these bottlenecks based on spirodiepoxides (SDEs), the double epoxidation products of allenes. Combined with flexible and convergent methods of allene synthesis, SDE-based transformations will enable direct entry into a wide range of molecular motifs that abound in natural products and complex pharmaceutical. The long-term goals of this research are to establish a in-depth understanding of SDE reactivity, to develop methods based on SDEs, and to refine synthetic strategies in the application of these methods to the synthesis of chemically and medicinally relevant targets. The specific aims of this proposal are to develop methods for carbon nucleophile opening of SDEs and apply to the synthesis of 9-(S)-dihydroerythronolide A, a precursor to an important class of antibiotics. Second, to refine methods for stereoselective SDE formation and intramolecular heteroatom nucleophile SDE-openings focused on the synthesis of pyrans and furans and will be utilized in the synthesis of psymberin and pectenotoxin 4, which are antitumor agents. Lastly, we will develop methods for the synthesis of highly oxygenated motifs including vicinal polyols.