Site-Selective Catalysts for Organic Synthesis

有机合成的位点选择性催化剂

• 批准号: 7623540
• 负责人: Scott J Miller
• 金额: $ 29.84万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623540
• 关键词: Acceleration; Alkanesulfonates; Amaze; Antigens; Area; Binding Sites; Biological; Biological Factors; Biological Process; Catalysis; Catalytic Domain; Characteristics; Chemistry; Classification; Collaborations; Complex; Conjugate Vaccines; Coupling; Dependence; Development; Disease; Erythromycin; Excision; Eye; Face; Family; Generations; Goals; Inorganic Sulfates; Inositol; Inositol Phosphates; Laboratories; Masks; Metals; Methodological Studies; Methods; Modification; Organic Chemistry; Organic Synthesis; Pathway interactions; Peptides; Pharmacologic Substance; Phosphatidylinositols; Play; Process; Reaction; Research; Research Personnel; Risk; Role; Science; Screening procedure; Side; Site; Structure; Techniques; Time; Unspecified or Sulfate Ion Sulfates; Vancomycin; analog; apoptolidin; base; c new; catalyst; combinatorial; design; drug candidate; drug development; drug synthesis; hydroxyl group; interest; novel; polyol; prevent; programs; small molecule; success; thermophilic bacteria; tool; tool development; wasting

DESCRIPTION (provided by applicant): Polyfunctional molecules play an important role in the chemotherapeutic treatment of disease. The field of organic synthesis resides in the vanguard of pharmaceutical science, delivering both the small molecules for screening against biological targets, and ultimately the efficient processes for drug synthesis on an industrial scale. A large fraction of drug candidate syntheses depends on the selective functionalization of unique reactive sites within molecules that contain many such sites. Thus, the risk of undesired side reactions is extreme. To date, the dominant strategy to handle this situation is the use of "protective groups." Protective groups are inherently inefficient. They require a step for installation, an additional step for removal, and neither of these steps generally occurs in 100% yield, with no waste, nor loss of time. Furthermore, from a fundamental standpoint, protective groups bely a host of unsolved problems in organic synthesis. Protective groups mask one reactive site, while allowing chemistry to occur at another. The more direct challenge in synthetic organic chemistry would be to achieve the desired reactivity, in the face of competing reactivity, without the inefficient application of such a mask. The development of tools - i.e., catalysts - that would allow the selective functionalization of very similar sites within polyfunctional molecules would constitute a major step forward. While the goal is, in some circles, viewed as intractable, we have initiated a program that has documented a potentially new strategy. The implications for both de novo syntheses of complex molecules are significant. Moreover, the implications of the protective group-free modification of pharmaceutically proven, structurally complex natural products is also highly exciting. The amazing biological activity of natural products has guided generations of synthetic organic chemists. Yet, notoriously, many pharmaceutical companies are de-emphasizing natural products discovery and drug development efforts. A major reason is the structural complexity that prevents both efficient synthesis, and straightforward analog generation. By taking aim at the direct, efficient and protecting group-free manipulation of natural products, we endeavor to introduce new tools that may assist in their exploration in both academic and industrial laboratories, enabling efficient access to novel and otherwise inaccessible biologically active analogs.

描述（由申请人提供）：多官能分子在疾病的化疗治疗中发挥重要作用。有机合成领域位于制药科学的前沿，提供用于筛选生物靶标的小分子，并最终提供工业规模的药物合成的有效过程。候选药物的合成很大一部分取决于包含许多此类位点的分子内独特反应位点的选择性功能化。因此，发生不希望的副反应的风险是极大的。迄今为止，处理这种情况的主导策略是使用“保护团体”。保护基团本质上是低效的。它们需要一个安装步骤，一个额外的拆卸步骤，并且这些步骤通常都不会以 100% 的产率发生，不会浪费，也不会损失时间。此外，从基本角度来看，保护基团掩盖了有机合成中许多未解决的问题。保护基团掩盖一个反应位点，同时允许在另一个反应位点发生化学反应。合成有机化学中更直接的挑战是在面对竞争反应性的情况下实现所需的反应性，而不需要低效地应用这种掩模。工具（即催化剂）的开发将允许对多官能分子内非常相似的位点进行选择性官能化，这将是向前迈出的一大步。虽然这个目标在某些圈子里被认为是棘手的，但我们已经启动了一个计划，记录了一个潜在的新战略。对于复杂分子的从头合成来说意义重大。此外，对经过药物验证、结构复杂的天然产物进行无保护基修饰的意义也非常令人兴奋。天然产物惊人的生物活性指导了一代又一代的合成有机化学家。然而，众所周知，许多制药公司不再重视天然产物发现和药物开发工作。一个主要原因是结构复杂性阻碍了有效的合成和直接的模拟生成。通过对天然产物进行直接、高效和保护性的无基团操作，我们努力引入新的工具来协助学术和工业实验室的探索，从而有效地获得新颖的和其他无法获得的生物活性类似物。