Development of Spirodiepoxide-Based Methods of Chemical Synthesis

描述（由申请人提供）：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在各个层面上的评价成为可能：细胞靶点鉴定、生物学机制阐明、药物靶点验证、先导物鉴定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实质性的障碍。提高对反应性的理解，开发有效而简洁的方法，以及改进合成策略，是加速了解疾病和推进分子医学进程的必要条件。本研究将开发创新的方法来缓解这些瓶颈基于螺二环氧化物（SDEs），双环氧化产物的烯。结合灵活和收敛的烯合成方法，基于sde的转化将能够直接进入天然产物和复杂药物中大量存在的广泛分子基序。本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，并完善合成策略，将这些方法应用于化学和医学相关靶点的合成。本提案的具体目的是开发碳亲核试剂打开SDEs的方法，并应用于合成9-(S)-二氢红素内酯A，这是一类重要抗生素的前体。其次，完善立体选择性SDE形成和分子内杂原子亲核试剂SDE开口的方法，重点是吡喃和呋喃的合成，并将用于合成抗肿瘤药物psyberin和pectenotoxin 4。最后，我们将开发包括邻域多元醇在内的高氧基序的合成方法。

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.