New Methodology for Indole Alkaloid Syntheses

描述（由申请人提供）：拟进行两个独立的吲哚合成项目，一个针对磷酸酶抑制剂家族成员dragmacidin，另一个针对抗癌海绵原理过磷脒。在每种情况下，开发有效制备亲本环体系的新方法之后，计划的天然产物dragmacidin E和perophoramidine的全合成，以及合理设计前物种的结构类似物，作为SAR研究的一部分。选择性磷酸酶抑制已被提出作为一种治疗干预手段在许多疾病，从帕金森氏症到癌症。该领域尚未解决的一个关键问题是确定小分子，这些小分子对磷酸酶PP1的抑制比类似的磷酸酶PP2A具有显著的选择性。据报道，某些dragmacidins表现出这种偏好，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。C(3)/C(4)-环庚烷桥接吲哚的新方法具有顺序的Witkop和Dieckmann环化，是这些结构新颖化合物合成策略的核心。对过磷脒的研究将为这种稀缺的海绵衍生天然产物提供有用的数量，以帮助进一步评估其抗癌特性。该合成路线从一种新的方法延伸到利用吲哚底物的氧化环化的螺环氧吲哚衍生物。解决吲哚氧化环化化学中长期存在的挑战，例如缺乏区域选择性键形成和产物（过度）氧化，都在本文提出的方法范围内。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.