Total Synthesis of the Adjuvant Saponin Jujuboside A

描述（由申请方提供）：分子免疫刺激佐剂的化学合成是疫苗开发中一个重要的、尚未开发的领域。当与亚单位抗原构建体共同施用时，皂苷天然产物已显示出有希望的佐剂活性。然而，将它们从自然来源中分离出来的方法往往是繁琐和浪费的。因此，合成获得这些实体用于临床前研究应该进一步促进癌症和传染病免疫治疗领域。皂苷A是一种皂苷天然产物，与已知的佐剂QS-21 A相比，它具有更高的佐剂活性和更低的溶血活性，是一种有希望的研究候选物。本项目将研究这种新型皂苷的全化学合成。目的：该项目的目标是建立一条合成路线，以提供纯样品的天然产物作为分子佐剂的临床前测试。具体目标：（1）通过应用催化亚砜促进的糖基化策略来合成麦冬皂苷A的五糖片段。(2)结构独特的山茱萸苷A苷元片段的合成。这将涉及开发阳离子-烯烃环化反应和C-H插入反应作为关键合成步骤。研究设计：本项目将利用有机合成技术，构建目标化合物--绞股蓝皂苷A。收敛合成策略将集中于有效制备五糖片段和糖苷配基片段。关于前者，一种新的催化亚砜促进糖苷键形成的方法将被应用。该方法得益于使用亚化学计量量的某些化学试剂和方便的反应条件。这两个因素应限制与五糖制备相关的所需成本和时间。糖苷配基的合成将采用仿生烯烃-阳离子环化反应进行。这种高度简化的转化将以立体控制的方式制备一种高级中间体，从而生成毛茛苷A。此外，C-H插入反应将完成石斛苷A的复杂碳环系统。

DESCRIPTION (provided by applicant): Chemical synthesis of molecular immunostimulating adjuvants is an important, underdeveloped area in vaccine development. Saponin natural products have shown promising adjuvant activity when co-administered with subunit antigen constructs. However, methods for their isolation from natural sources are often tedious and wasteful. Therefore, synthetic access to such entities for preclinical study should further the fields of cancer and infectious disease immunotherapy. Jujuboside A, a saponin natural product, is a promising candidate for study as it has been found to exhibit higher adjuvanticity and lower hemolytic activity as compared with the established adjuvant known as QS-21A. This project will study the total chemical synthesis of this novel saponin. Objectives: The goal of this project is to establish a synthetic route to jujuboside A providing pure samples of the natural product for preclinical testing as a molecular adjuvant. Specific Aims: (1) Synthesis of the pentasaccharide fragment of jujuboside A through application of a catalytic sulfoxide-promoted glycosylation strategy. (2) Synthesis of the structurally unique aglycone fragment of jujuboside A. This will involve development of a cation-olefin cyclization reaction and a C-H insertion reaction as the key synthetic steps. Study design: This project will utilize techniques of organic synthesis to construct the target of interest, jujuboside A. A convergent synthetic strategy will focus on efficient preparation of a pentasaccharide fragment and an aglycone fragment. Concerning the former, a novel catalytic sulfoxide-promoted methodology for glycosidic bond formations will be applied. This method benefits from the use of substoichiometric quantities of certain chemical reagents and convenient reaction conditions. Both these factors should limit the required cost and time associated with pentasaccharide preparation. The synthesis of the aglycone will be undertaken employing a biomimetic olefin-cation cyclization reaction. This highly simplifying transformation will prepare, in a stereocontrolled fashion, an advanced intermediate en route to jujuboside A. Additionally, a C-H insertion reaction will complete the intricate carbocyclic ring system of jujuboside A.