Synthesis of Mycobacterial Phosphatidylinositol Mannosides

白諦(Patil Pratap Subhashrao)

指導教授 ： 洪上程 ； 廖文峯

國立清華大學/理學院/化學系/博士(2011年)

摘要

Phosphatidylinositol mannosides (PIMs) are ubiquitously distributed in both
pathogenic and non-pathogenic species of mycobacteria and play significant roles in cell
wall biogenesis and in many immunomodulatory events including phagocytosis of
organism. Different structures of PIMs impact the recognition and response of the host
cell and influence the intercellular fate of pathogen. Owing to the structural complexity,
the biosynthetic pathway of PIMs remains unclear. In order to understand a biosynthesis
and establish detailed structure-activity relationship, chemical synthesis of PIMs is
considered as one of the most practical way to obtain the pure and structurally verified
molecules at considerable scale. In addition, due to their role in various immunological
events, PIMs could act as potential immunotherapeutics. Thus, this dissertation describes
the preparation of PIMs and the resolution to the difficulties encountered during the
synthesis.
Chapter 1 gives an overview of tuberculosis, Mycobacterium tuberculosis, and the
structural components of mycobacterial cell wall in the beginning. Furthermore,
structural characterization of PIMs and their biological properties is illustrated to provide
a deeper understanding. Chapter 2 summarizes the synthetic works from the literatures
and reveals the synthetic urgency of these molecules.
Chapter 3 is dedicated to the synthesis of di- and triacylated phosphatidylinositol
mannosides. First part of this chapter explains our concerns with PIM studies, the specific
aims as well as the retro-synthetic plan. The following section demonstrates the
desymmetrization of myo-inositol using D-mannosyl donor as a chiral auxillary and its
application to the synthesis of di- and triacylated PIM2.
Chapter 4 outlines the synthesis of tetraacylated phosphatidylinositol
hexamannoside, beginning with the discussion about the aims and retrosynthesis. The
preparation of myo-inositol building blocks, including the regioselective 2-O-arylation of
myo-inositol-1,3,5-orthoformate is discussed in the following section. Next section of this
chapter explores the preparation of mannosyl building blocks. A regioselective one-pot
protection method was developed and applied for the preparation of 2-O and 6-O
differentiated mannoses. The desymmetrization of myo-inositol using 6-O differentiated
mannosyl donors and its exploitation for the synthesis of crucial pseudotrisaccharide
intermediate of PIM6 is also conversed. Our struggle for the construction of the
tetramannoside back bone and the synthesis of tuberculostearic acid is also narrated.
Chapter 5 concludes our synthetic work described in Chapters 3 and 4. Chapter 6
provides the experimental details of our synthetic work for this dissertation.

關鍵字

肌醇 ； 甘露糖

並列摘要

無資料

並列關鍵字

Mycobacteria ； Phosphatidylinositol mannoside ； myo-inositol ； tuberculosis ； one-pot protection ； tetraacylated PIM6

參考文獻

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(2) Bloom, B. R.; Murray, C. J. L. Science 1992, 257, 1055-1064.

(61) Owens, R. M.; Hsu, F. F.; VanderVen, B. C.; Purdy, G. E.; Hesteande, E.; Giannakas,

8th ed.; Saunders Elsevier: 2007, p 516-522.