Site-Selective Catalysts for Organic Synthesis

有机合成的位点选择性催化剂

• 批准号: 7483582
• 负责人: Scott J Miller
• 金额: $ 29.94万
• 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/7483582
• 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; Object Attachment; Organic Chemistry; Organic Synthesis; Pathway interactions; Peptides; Pharmaceutical Preparations; 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; concept; day; design; desire; 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（申请人提供）：多功能分子在疾病的化疗治疗中发挥着重要作用。有机合成领域处于制药科学的前沿，既提供用于筛选生物靶点的小分子，又最终提供工业规模的药物合成的有效过程。很大一部分候选药物的合成依赖于分子中含有许多这种位点的独特反应位点的选择性功能化。因此，不良反应的风险是极端的。迄今为止，处理这种情况的主要策略是使用“保护团体”。保护团体本质上是低效的。它们需要一个步骤进行安装，另一个步骤进行拆卸，这两个步骤通常都不能达到100%的产量，没有浪费，也没有时间损失。此外，从基本观点来看，保护基团掩盖了有机合成中许多未解决的问题。保护基团掩盖了一个反应位点，同时允许化学反应在另一个位点发生。在合成有机化学中，更直接的挑战将是在面对竞争性反应性的情况下，在不低效地应用这种掩膜的情况下实现所需的反应性。工具的发展——例如催化剂——可以使多功能分子中非常相似的位点选择性功能化，这将是向前迈出的重要一步。虽然这个目标在某些圈子里被认为是难以实现的，但我们已经启动了一个项目，记录了一个潜在的新战略。这两种复杂分子的从头合成都具有重要意义。此外，对经过药学验证的、结构复杂的天然产物进行无保护基团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，臭名昭著的是，许多制药公司不重视天然产品的发现和药物开发工作。一个主要原因是结构的复杂性阻碍了有效的合成和直接的模拟生成。通过瞄准直接、有效和保护无群体的天然产物操作，我们努力引入新的工具，可以帮助他们在学术和工业实验室的探索，使有效地获得新颖的和否则难以获得的生物活性类似物。