The Total Synthesis of Phainanoids A-F

项目摘要/摘要 天然产品和天然产品衍生品继续在这一发现中发挥重要作用 开发治疗人类疾病的药物。在几乎所有情况下， 天然产物作为药物的评价、修饰和应用是可及性的。具体到这项提议， 想一想最近发现的“类胡萝卜素”天然产物。这类新的结构复杂 三萜类化合物表现出极强的免疫抑制活性，其IC50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)。所谓的 尤其是棕榈酸酯F，对T细胞和B细胞的增殖活性分别是7倍和221倍。 而不是环孢素A--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，指甲鱼可以代表有希望的和有洞察力的调查路线 开发一类新的免疫抑制药物；然而，进一步的研究目前受到阻碍 由于前面提到的可访问性问题。这个问题的一个可行的解决方案是一个简洁、有效的总体 理想的合成策略，适用于药物化学的各种后期修饰。 因此，这项提案的具体目标是1)制定一项战略，以便对 甲素A-F和2)为甲素的后期修饰创造途径，以便研究 结构-活性关系。本文提出的全合成策略寻求在 小到18到21步的最长线性序列，它依次使用了几种现代合成方法 以最大限度地提高效率、可扩展性并节省步骤。其中包括尖端的脱羧化烯化反应 策略、电化学氧化、光化学重排、催化和定向C-H官能化 化学，以及拟议的方法开发机会(即分子内脱羧剂 烯化变种)。此外，合成的设计使其上独特的螺旋环状基序 正如这些被认为的那样，果酸类碳骨架在序列中战略性地安装得很晚 部分，对观察到的生物活动负有最大责任。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，特别关注其 独立合成/安装。因此，这一综合的成功执行将为RAPID打开一扇门 和易于多样化(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对所有衍生品进行活性测试。总而言之，这 将允许有效地分析结构-活性关系，并有望提供关于如何改进的洞察力 作为潜在的免疫抑制药物候选者的类突触素。

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.