Total synthesis of glycoprotein processing enzyme inhibitor (+)-mannostatin A. Synthesis and pharmacological evaluation of vinyl sulfone based anticancer agents
Abstract
The synthetic efforts towards Golgi processing mannosidase inhibitor (+) mannostatin A are described. A strategy featuring introduction of both the nitrogen and sulfur moieties in one step was adopted. This was accomplished by methansulfenyl triflate-promoted intramolecular cyclization of an allylic trichloroacetimidate. A previously unknown N-sulfenylimidate was identified as the reactive intermediate. The total synthesis was achieved in ten steps from the commercially available D-ribonolactone in excellent overall yield. Earlier model studies led to the discovery of two vinyl sulfone based synthetic transformations: (1) Intramolecular photocyclization of aryl vinyl sulfones and photochemical desulfonylation of N-sulfonyl oxazolidinones. (2) A base catalyzed intramolecular conjugated addition of allylic trichloroacetimidates to vinyl sulfones. A separate project dealt with the synthesis and pharmacological evaluation of vinyl sulfone based anticancer agents. Preliminary results in this area are summarized in the last chapter. Several tailored substrates exhibited excellent in vitro activity against HT-29 colon cancer cell line and measurable in vitro differential cytotoxicity against ras transformed rat kidney epithelial cell lines.
Degree
Ph.D.
Advisors
Fuchs, Purdue University.
Subject Area
Organic chemistry|Pharmacology
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