New Methodology for Indole Alkaloid Syntheses

吲哚生物碱合成新方法

基本信息

批准号：
7582248
负责人：
KEN S. FELDMAN
金额：
$ 22.57万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-09 至 2012-01-31
项目状态：
已结题

项目摘要

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.

针对吲哚合成中德拉马西丁家族成员的两个独立项目的追求一种情况是磷酸酶抑制剂，另一种情况是抗癌海绵原理perophoramidine，建议的。在每种情况下，开发有效制备母环的新方法系统随后计划全合成天然产物德拉马西丁 E 和哌罗佛脒，以及作为 SAR 研究的一部分合理设计的前物种的结构类似物。选择性磷酸酶抑制已被提议作为许多疾病的治疗干预手段，从帕金森病到癌症。这一领域尚未解决的一个关键问题是识别小分子，与类似的磷酸酶 PP2A 相比，对磷酸酶 PP1 的抑制具有显着的选择性。据报道，某些德拉马西丁表现出这种偏好，并且本文概述了合成程序该提案旨在提供用于探索这种选择性的结构基础的分子。一个新的具有连续 Witkop 和 Dieckmann 特征的 C(3)/C(4)-环庚烷桥吲哚方法环化是这些结构新颖的化合物的合成策略的核心。 Perophoramidine 的工作将提供有用量的这种稀有的海绵衍生天然产品，以帮助进一步评估其抗癌特性。该合成路线从新方法延伸到利用吲哚底物的氧化环化的螺环羟吲哚衍生物。解决长吲哚氧化环化化学面临的长期挑战，例如缺乏区域选择性键形成和产物（过度）氧化均在本文提出的方法的范围内。使用新的普默勒反应的变体，用于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。