Design and synthesis of glycoprotein processing inhibitors as anti-HIV agents: Regiospecific 4,6-functionalization of pyranosides
Abstract
Efforts directed towards the design and synthesis of analogs of DNJ 1.17, a known glycoprotein processing inhibitor, as potential anti-HIV candidates are described in this thesis. Two of the first generation DNJ analogs synthesized during the framework of this thesis research, 2.13 and 2.16, showed better activity against HIV-1 than N-BuDNJ 1.30, one of the lead compounds in the DNJ series which was withdrawn only after Phase II clinical trials in humans. Design of second generation DNJ analogs required the regiospecific differentiation of 4 and 6 position on the azasugar ring. Model study utilizing glucose derived pyranosides resulted in regiospecific differentiation of the 4 and 6 positions. Phthalide orthoester strategy was employed to bring forth this differentiation. The resultant C-4 benzoate was cleaved chemospecifically in the presence of NHAc, OAc, and SAc. Introduction of an appropriate sulfur residue at C-6 for further transformation to sulfonic acid was accomplished. The phthalide orthoester strategy was effectively employed in the case of DNJ derived substrate 2.16. The 4,6 differentiation was achieved with complete regiospecificity resulting in total reversal of chemoselectivity. An advanced intermediate 4.11 was synthesized in efficient manner from DNJ 1.17 for subsequent transformation to second generation substrates containing a C-6 sulfonic acid residue.
Degree
Ph.D.
Advisors
Fuchs, Purdue University.
Subject Area
Organic chemistry
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