New Methodology for Indole Alkaloid Syntheses

吲哚生物碱合成新方法

• 批准号: 6849382
• 负责人: KEN S. FELDMAN
• 金额: $ 26.62万
• 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/6849382
• 关键词: Porifera; alkaloids; analog; biological products; chemical structure function; chemical synthesis; combinatorial chemistry; cyclization; drug discovery /isolation; indoles; method development; nanotechnology; oxidation; phosphatase inhibitor; phosphoprotein phosphatase; piperazines; small molecule

DESCRIPTION (provided by applicant): 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 longstanding 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.

描述（由申请人提供）：提出了在吲哚合成中进行两个独立的项目，一个项目针对磷酸酶抑制剂dragmacidin家族的成员，另一个项目针对抗癌海绵原则perophoramidine。在每一种情况下，开发新的方法，有效地制备母环系统的天然产品dragmacidin E和perophoramidine，以及合理设计的结构类似物的SAR研究的一部分，有计划的总合成。选择性磷酸酶抑制已被提出作为一种手段的治疗干预在主机的疾病，从帕金森氏症到癌症。在这一领域中一个关键的未解决的问题是鉴定小分子，其显示出对磷酸酶PP 1的抑制超过类似的磷酸酶PP 2A的显著选择性。据报道，某些dragmacidin表现出这种偏好，本提案中概述的合成程序旨在提供用于探测这种选择性的结构基础的分子。C（3）/C（4）-环庚烷桥连吲哚的一种新方法，其特征在于连续的Witkop和Dieckmann环化是这些结构新颖的化合物的合成策略的核心。perophoramidine的工作将提供有用的数量，这种稀缺的海绵衍生的天然产品，以帮助进一步评估其抗癌性能。这种合成路线延伸到螺环羟吲哚衍生物，利用吲哚底物的氧化环化的新方法。解决吲哚氧化环化化学中的长期挑战，例如缺乏区域选择性键形成和产物（过）氧化，在本文提出的方法的范围内。使用Pummerer反应的新变体来控制吲哚核内的氧化水平和反应位点形成了这种化学的基础。