Syntheses of Highly Substituted Pryocatechols

高取代原儿茶酚的合成

• 批准号: 7341446
• 负责人: Wayne Francis Schnatter
• 金额: $ 5.99万
• 依托单位: LONG ISLAND UNIVERSITY BROOKLYN CAMPUS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-21 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7341446
• 关键词: Acetates; Alkynes; Amination; Antibiotics; Biological Factors; Boronic Acids; Catecholamines; Catechols; Class; Classification; Complex; Condition; Coupling; Cyclization; Development; Development Plans; Ecteinascidin 743; Epinephrine; Funding; Goals; Mentors; Methodology; Methods; Modification; Numbers; Opiates; Palladium; Pilot Projects; Preparation; Process; Protocols documentation; Reaction; Reagent; Research; Route; Score; Solvents; Technology; Temperature; Therapeutic Agents; acylating agent; analog; antineoplastic antibiotics; antitumor agent; boronic acid; cycloaddition; novel therapeutics; preference; programs; saframycin A

DESCRIPTION (provided by applicant): Pyrocatechols (a.k.a. catechols) comprise an important class of pharmacologically active compounds. Epinephrine and other catecholamines as well as many opiates are derived from catechols, as are the powerful antitumor antibiotics saframycin and ecteinascidin-743. In this proposed pilot project, vinylketeneiron(0) complexes will be synthesized via readily available methodology from vinyllithium compounds and alkylating or acylating agents. The cycloaddition reactions of these vinylketeneiron(0) complexes with 1-haloalkynes will be used to synthesize a variety of halosubstituted catechols, specifically the chloro, bromo, and iodo compounds. The specific aim of the project is to unambiguously define the optimal reaction conditions for effecting the formal cycloaddition of vinylketenes with haloalkynes. The halocatechols, thus synthesized, will be subjected to palladium catalyzed coupling reactions to provide highly substituted catechol derivatives that would otherwise require lengthy multi-step syntheses. Preliminary studies to assess the applicability of the method toward the synthesis of the common core of the saframycin and ecteinascidin-743 will be carried out via a three-step protocol involving cycloaddition-allylation-asymmetric aminohydroxylation. Relevance: A simple expedient two-step method for the preparation of a large number of catechol derivatives will be made available. Access to novel therapeutic agents will be made available. Synthetic approaches to starting materials for the large scale preparation of the powerful antitumor agent ecteinascidin-743 and its analogues will be provided. Personal Development Plan: The PI will use the SC2 program to generate sufficient preliminary results to justify a more ambitious research program, which will be fundable through the SC1 mechanism, the ultimate goal being independence from SCORE funding and support through other programs (e.g., R15 and R01). The participation of the mentor will facilitate this process greatly by providing guidance in the selection and execution of the preparation of appropriate target molecules.

描述（由申请人提供）：邻苯二酚（又名儿茶酚）包含一类重要的药理活性化合物。肾上腺素和其他儿茶酚胺以及许多阿片类药物都源自儿茶酚，强效抗肿瘤抗生素 Saframycin 和 Ecteinascidin-743 也是如此。在这个拟议的试点项目中，乙烯基烯酮铁(0)络合物将通过现成的方法由乙烯基锂化合物和烷基化剂或酰化剂合成。这些乙烯基烯酮铁(0)络合物与1-卤代炔的环加成反应将用于合成各种卤代儿茶酚，特别是氯、溴和碘化合物。该项目的具体目标是明确定义实现乙烯基乙烯酮与卤代炔的正式环加成的最佳反应条件。由此合成的卤代儿茶酚将进行钯催化的偶联反应，以提供高度取代的儿茶酚衍生物，否则需要冗长的多步骤合成。将通过涉及环加成-烯丙基化-不对称氨基羟基化的三步方案进行初步研究，以评估该方法对 Saframycin 和 Ecteinascidin-743 共同核心合成的适用性。 相关性：将提供一种用于制备大量儿茶酚衍生物的简单方便的两步方法。将提供新型治疗药物。将提供用于大规模制备强效抗肿瘤剂ecteinascidin-743及其类似物的起始材料的合成方法。 个人发展计划：PI 将使用 SC2 计划产生足够的初步结果，以证明更雄心勃勃的研究计划的合理性，该计划将通过 SC1 机制提供资助，最终目标是独立于 SCORE 资助和通过其他计划（例如，R15）的支持和 R01）。导师的参与将通过在选择和执行适当目标分子的制备方面提供指导来极大地促进这一过程。