New Methodology for Indole Alkaloid Syntheses

吲哚生物碱合成新方法

• 批准号: 7344793
• 负责人: KEN S. FELDMAN
• 金额: $ 22.58万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-09 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7344793
• 关键词: Address; Area; Biological Factors; Cell Nucleus; Chemistry; Cyclization; Cycloheptanes; Development; Evaluation; Exhibits; Family; Indole Alkaloids; Indoles; Malignant Neoplasms; Methodology; Object Attachment; Parents; Parkinson Disease; Phosphoric Monoester Hydrolases; Porifera; Preparation; Procedures; Process; Property; Protein Phosphatase 2A Regulatory Subunit PR53; Reaction; Reporting; Research Design; Route; Site; Structure; System; Therapeutic Intervention; Variant; Veins; Work; analog; base; chemical synthesis; cycloheptane; design; improved; indole; member; novel; novel strategies; oxidation; oxindole; perophoramidine; phosphatase inhibitor; preference; programs; small molecule

The pursuit of two independent projects in indole synthesis, targeting members of the dragmacidin family of phosphatase inhibitors in one case and the anticancer sponge principle perophoramidine in the other, is proposed. In each case, development of novel methodology for the efficient preparation of the parent ring systems is followed by planned total syntheses of the natural products dragmacidin E and perophoramidine, as well as rationally designed structural analogues of the former species as part of an SAR study. Selective phosphatase inhibition has been proposed as a means of therapeutic intervention in a host of diseases, from Parkinson's to cancer. One key unsolved problem in this area is the identification of small molecules that display significant selectivity for inhibition of the phosphatase PP1 over the analogous phosphatase PP2A. Certain dragmacidins are reported to exhibit such preferences, and the program of synthesis outlined in this proposal is designed to provide molecules for probing the structural basis for this selectivity. A new approach to C(3)/C(4)-cycloheptane-bridged indoles that features sequential Witkop and Dieckmann cyclizations is at the core of the synthesis strategy for these structurally novel compounds. The perophoramidine work will provide useful amounts of this scarce sponge-derived natural product to aid in further evaluation of its anti-cancer properties. This synthesis route extends from a new approach to spirocyclic oxindole derivatives that utilizes an oxidative cyclization of an indolic substrate. Addressing long- standing challenges in indole oxidative cyclization chemistry, such as a lack of regioselective bond formation and product (over)oxidation, are within the purview of the methodology proposed herein. The use of a new variant of the Pummerer reaction to control both oxidation level and reaction site within the indole nucleus forms the basis of this chemistry.

追求吲哚合成中的两个独立项目，针对Dragmacidin家族的成员 在一种情况下，磷酸酶抑制剂，另一个情况下的抗癌海绵原理是磷酸酶抑制剂，另一种是 建议的。在每种情况下，开发新的方法来有效制备父环 系统之后是天然产物dragmacidin e和phophoramidine的计划的总合成， 以及以前物种的合理设计的结构类似物，作为SAR研究的一部分。选择性 已经提出了磷酸酶抑制作用，以作为一种治疗干预的手段 帕金森氏症。该领域的一个关键未解决问题是鉴定小分子 在类似的磷酸酶PP2A上抑制磷酸酶PP1的抑制作用显着。 据报道，某些dragmacidins表现出这种偏好，并且在此概述了合成程序 建议旨在提供分子来探测该选择性的结构基础。一个新 c（3）/c（4）的方法-Cycloheptane桥接的吲哚，具有顺序Witkop和Dieckmann 环化是这些结构新颖化合物的合成策略的核心。 phophoramidine的工作将提供有用的稀缺海绵来源的天然产品，以帮助 在进一步评估其抗癌特性时。该合成路线从新方法延伸到 利用吲哚基底物的氧化环化的螺旋环氧衍生物。解决长期 吲哚氧化环化化学中的挑战，例如缺乏区域选择性键形成 和产品（过度）氧化，在本文提出的方法的权限范围内。使用新的 Pummerer反应的变体以控制吲哚核内的氧化水平和反应位点 构成了这种化学的基础。