The Total Synthesis of Phainanoids A-F

项目总结/摘要 天然产物和天然产物衍生物继续在发现和生产中发挥重要作用。 开发治疗人类疾病的药物。几乎在所有情况下， 天然产物作为药物的评价、修饰和应用是可及的。具体到这份提案， 考虑最近发现的“phainanoid”天然产物。这类新的结构复杂的 三萜类化合物已证明具有极强的免疫抑制活性，IC 50值为个位数 纳摩尔浓度（在任何药物化学启发的修改/改进之前）。所谓 特别地，类啡肽F对T和B细胞增殖的活性分别高7倍和221倍， 环孢菌素A是一种商业免疫抑制剂，特别是在世界卫生组织的基本药物清单上。 因此，很明显，Phainanoids可以代表有前途和有见地的调查路线， 开发一类新的免疫抑制药物;然而，目前进一步的研究受到阻碍 前面提到的可访问性问题。解决这个问题的一个可行的办法是一个简洁，有效的总数 这是一种理想地适用于药物化学的各种后期修饰的合成策略。 因此，本建议的具体目标是：1）制定一项战略， 类啡肽A-F和2）为类啡肽的后期修饰创造途径，以研究 构效关系本文提出的全合成策略寻求以化学方法获得类啡肽。 最小为18到21步的最长线性序列，并且它采用了几种现代合成方法， 最大限度地提高效率、可扩展性和步骤节省。其中包括最先进的脱羧烯化反应 策略、电化学氧化、光化学重排、催化和定向C-H官能化 化学，以及方法开发的建议机会（即分子内脱羧 烯化变体）。此外，合成被设计成使得在多环芳烃上的独特螺环基序 phananoid碳骨架战略上安装在序列中非常晚，因为这些被认为，在大 部分，是最负责观察到的生物活性。考虑到有初步证据表明 螺内酯片段对免疫抑制活性的显著影响，特别注意其 独立合成/安装。因此，成功地执行这种合成将为快速合成打开一扇大门。 以及类啡肽的容易多样化（例如采用当代的氟官能化策略），以及 随后将与免疫学实验室合作测试所有衍生物的活性。总之，这 将允许有效分析结构-活性关系，并希望提供有关如何改进 类啡肽作为潜在的免疫抑制药物候选物。

PROJECT SUMMARY/ABSTRACT Natural products and natural product derivatives continue to play a prominent role in the discovery and development of pharmaceuticals to treat human diseases. In nearly all instances, the critical barrier to the evaluation, modification, and application of natural products as drugs is accessibility. Specific to this proposal, consider the recently discovered "phainanoid" natural products. This new class of structurally-complex triterpenoids has demonstrated extremely potent immunosuppressive activity with IC50 values in single-digit nanomolar concentrations (prior to any medicinal chemistry-inspired modification/improvement). The so-called phainanoid F, in particular, is 7 and 221 times more active against the proliferation of T and B cells, respectively, than cyclosporine A – a commercial immunosuppressant notably on the WHO's List of Essential Medicines. Thus, it is evident that the phainanoids could represent promising and insightful lines of inquiry for the development of a new class of immunosuppressive drugs; however, further investigation is currently hindered by the aforementioned problem of accessibility. One viable solution to this problem is a concise, efficient total synthesis strategy that is ideally amenable to various late-stage modifications for medicinal chemistry. Accordingly, the specific aims of this proposal are 1) to develop a strategy for a practical total synthesis of phainanoids A-F and 2) to create avenues for late-stage modifications of the phainanoids in order to study structure-activity relationships. The total synthesis strategy proposed herein seeks to obtain the phainanoids in as little as 18- to 21-step longest linear sequences, and it employs several modern synthetic methods in order to maximize efficiency, scalability, and step savings. Among these are cutting-edge decarboxylative olefination tactics, electrochemical oxidations, photochemical rearrangements, catalysis, and directed C-H functionalization chemistry, as well as a proposed opportunity for method development (i.e. an intramolecular decarboxylative olefination variant). Furthermore, the synthesis is designed such that the unique spirocyclic motifs on the phainanoid carbon skeleton strategically are installed very late in the sequence, as these are believed, in large part, to be most responsible for the observed biological activity. Considering there is preliminary evidence for dramatic influence of the spirolactone segment on immunosuppressive activity, special attention is paid to its independent synthesis/installation. Thus, a successful execution of this synthesis will open up a door for rapid and easy diversification of the phainanoids (e.g. employing contemporary fluorofunctionalization tactics), and subsequently all derivatives will be tested for activity in collaboration with an immunology laboratory. In all, this will allow efficient analysis of structure-activity relationships and, hopefully, provide insight as to how to improve the phainanoids as potential immunosuppressive drug candidates.