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.
This project will study the chemical synthesis of the natural product, jujuboside A. The goal of this research will be to provide sufficient quantities of this compound to enable its study for cancer and infectious disease vaccine development.
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