New Methodology for Indole Alkaloid Syntheses

追求吲哚合成方面的两个独立项目，目标是#年的Dragmacidin家族成员 一种是磷酸酶抑制剂，另一种是抗癌海绵原理，即 建议。在每种情况下，开发用于有效制备母环的新方法 系统之后是天然产物Dragmacidin E和Perophoramine的计划全合成， 以及作为搜救研究的一部分，对前一物种进行合理设计的结构类似物。有选择性的 磷酸酶抑制已被建议作为一种治疗手段干预一系列疾病，从 帕金森氏症导致癌症。这一领域尚未解决的一个关键问题是识别小分子 对磷酸酶PP1的抑制比类似的磷酸酶PP2A表现出显著的选择性。 据报道，某些龙血黄素表现出这种偏好，在本报告中概述的合成程序 该提案旨在为探索这种选择性的结构基础提供分子。一种新的 C(3)/C(4)-环庚烷桥联吲哚的合成 环化反应是这些结构新颖化合物合成策略的核心。 博罗帕定的研究将提供有用数量的这种稀有的海绵衍生天然产品来帮助 以进一步评价其抗癌性能。这条合成路线从一种新的方法延伸到 螺环吲哚衍生物，其利用吲哚底物的氧化环化反应。地址长- 吲哚氧化环化化学面临的挑战，如缺乏区域选择性的键形成 和产物(过度)氧化，都在本文提出的方法的范围内。使用一个新的 Pummerer反应的变体，用于控制吲哚核内的氧化程度和反应位置 构成了这种化学的基础。

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.