New Methodology for Indole Alkaloid Syntheses

描述(由申请人提供)：建议在吲哚合成方面进行两个独立的项目，一个针对磷酸酶抑制剂Dragmacidin家族的成员，另一个针对抗癌海绵原理罗布拉定。在每一种情况下，开发有效制备母环系统的新方法之后，计划全面合成天然产物Dragmacidin E和Perophoramidine，以及作为SAR研究的一部分，合理设计前一物种的结构类似物。选择性磷酸酶抑制已被提出作为一种治疗手段，用于从帕金森氏症到癌症等一系列疾病。这一领域尚未解决的一个关键问题是鉴定对磷酸酶PP1比类似的磷酸酶PP2A表现出显著选择性抑制的小分子。据报道，某些龙血黄素表现出这种选择性，本提案中概述的合成程序旨在为探索这种选择性的结构基础提供分子。以顺序Witkop环化和Dieckmann环化为特征的C(3)/C(4)环庚烷桥联吲哚的新方法是这些结构新颖化合物的合成策略的核心。这项研究将提供有用数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性能。这条合成路线从一种新的方法延伸到螺环氧吲哚衍生物，该方法利用吲哚底物的氧化环化。解决吲哚氧化环化化学中长期存在的挑战，如缺乏区域选择性键形成和产物(过度)氧化，属于本文提出的方法学的范围。使用一种新的Pummerer反应变体来控制吲哚核内的氧化水平和反应位置，形成了这种化学的基础。

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.