Chemical Synthesis of Kendomycin and Garsubellin A

肯多霉素和加苏贝林 A 的化学合成

• 批准号: 7623852
• 负责人: Erik J. Sorensen
• 金额: $ 25.92万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-05 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623852
• 关键词: Achievement; Address; Agonist; Anabolism; Anti-Bacterial Agents; Applications Grants; Architecture; Biological; Biological Factors; Biomimetics; Calcitonin Receptor; Chemical Models; Chemical Structure; Chemicals; Chemistry; Complex; Core Assembly; Development; Disease; Endothelin Receptor Antagonist; Evolution; Exhibits; Future; Investigation; Lead; Maps; Methods; Molecular; Molecular Structure; Oxidation-Reduction; Process; Production; Property; Reaction; Research; Research Personnel; Skeleton; Structure; Therapeutic; analog; base; chemical synthesis; garsubellin A; hyperforin; innovation; insight; kendomycin; neurotransmitter biosynthesis; novel; programs; tool

DESCRIPTION (provided by applicant): This grant application addresses the chemical synthesis problems of two architecturally complex natural products, kendomycin and garsubellin A. The broad objectives of the research program are to develop innovative strategies for the efficient synthesis of molecular agents possessing therapeutic potential for the treatment of diseases and to develop powerful chemical methods of broad utility in the production of the compounds required in biomedical investigations. The specific aims of the present proposal are: 1) the achievement of an efficient total synthesis of kendomycin, a potent endothelin receptor antagonist and calcitonin receptor agonist that exhibits pronounced antibacterial, antitumor, and anti-osteoporotic activities, using a novel macroglycosylation approach; 2) the development of innovative strategies based on a mechanistically degenerative tandem approach that are appropriate for the expeditious synthesis of the core skeleton of kendomycin; 3) the establishment of a chemical model to gain insights into the biosynthesis of kendomycin through a total synthesis using a biomimetic cascade approach based on novel internal redox and macro-Michael addition processes; and 4) the achievement of a concise total synthesis of garsubellin A, a potent neurotrophic agent that induces the biosynthesis of neurotransmitters, using a multicomponent tandem approach that allows for rapid assembly of the core structure of hyperforin natural products. The proposed synthetic investigations take advavantage of multicomponent cascade approaches which most efficiently address the problem of constructing complex molecular structures. Thus, the chemistry we seek to develop through this grant application can be extended in many ways to bring significant advances in the chemical synthesis of bioactive compounds.

描述（由申请人提供）：这项拨款申请解决了两种结构复杂的天然产物——kendomycin和garsubellin a的化学合成问题。该研究项目的总体目标是开发创新策略，有效合成具有治疗疾病治疗潜力的分子制剂，并开发强大的化学方法，广泛应用于生物医学研究所需化合物的生产。本提案的具体目标是：1)利用一种新的大糖基化方法，实现有效的全合成肯多霉素，这是一种有效的内皮素受体拮抗剂和降钙素受体激动剂，具有明显的抗菌、抗肿瘤和抗骨质疏松活性；2)基于机制退化串联方法的创新策略的发展，适合于快速合成肯大霉素的核心骨架；3)建立了基于新型内部氧化还原和宏观michael加成过程的仿生级联全合成的生物合成模型；4)利用多组分串联方法，实现了garsubellin a的简明全合成，garsubellin a是一种诱导神经递质生物合成的强效神经营养剂，可以快速组装hyperperin天然产物的核心结构。提出的合成研究利用多组分级联方法，最有效地解决了构建复杂分子结构的问题。因此，我们通过这项拨款申请寻求发展的化学可以在许多方面得到扩展，从而在生物活性化合物的化学合成方面取得重大进展。

项目成果

Concise synthesis of the Erythrina alkaloid 3-demethoxyerythratidinone via combined rhodium catalysis.

• DOI: 10.1021/ol102535u
• 发表时间: 2010-12-17
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Joo, Jung Min;David, Ramoncito A.;Yuan, Yu;Lee, Chulbom
• 通讯作者: Lee, Chulbom

A highly enantio- and diastereoselective 1,3-dimethylallylation of aldehydes.

醛的高度对映选择性和非对映选择性 1,3-二甲基烯丙基化。

• DOI: 10.1016/j.tet.2006.07.070
• 发表时间: 2006
• 期刊: Tetrahedron
• 影响因子: 2.1
• 作者: Yuan,Yu;Lai,AmyJ;Kraml,ChristinaM;Lee,Chulbom
• 通讯作者: Lee,Chulbom

Enantioselective Total Synthesis of (+)-Garsubellin A.

• DOI: 10.1002/anie.202109193
• 发表时间: 2021-10-11
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Jang D;Choi M;Chen J;Lee C
• 通讯作者: Lee C

Total synthesis of kendomycin: a macro-C-glycosidation approach.

• DOI: 10.1021/ja0447154
• 发表时间: 2004-10
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Yu Yuan;H. Men;Chulbom Lee