Title

Towards the Synthesis of Boronated Amino Acid Analogs: Precursors for Novel HIV-1 Protease Inhibitors

Presenter Information

Andrea Faulkner

Document Type

Oral Presentation

Location

SURC 137B

Start Date

17-5-2012

End Date

17-5-2012

Abstract

A class of HIV drugs called protease inhibitors have proven effective in slowing progression of the disease. This research aims to create two boronated amino acid analogs that will later be incorporated into potential HIV-1 protease inhibitors. These structures have been designed to decrease toxic exposure to patients and aim to increase bioavailability, allowing for more effective uptake and smaller required dosages. To synthesize the analogs, boronic acids were coupled with the protecting group (1R,2R)-dicyclohexyl-1,2-ethanediol (DICHED), which also served as a chiral director giving the product correct stereospecificity for biological activity. The product was homologated using butyllithium and dichloromethane to insert a new chiral chlorinated carbon between the R group and boron. In an SN2 reaction the chlorine was substituted for hexamethyldisilazane, which contains nitrogen and creates the analog amino group. The product was desilylated using methanol and immediately acylated with acetic anhydride and acetic acid. DICHED was removed and exchanged for two hydroxyl groups using phenyl boronic acid to yield the boronated amino acid analog. In the future, the boronated amino acid analogs will be coupled with tripeptides to create potential HIV-1 protease inhibitors.

Faculty Mentor(s)

Levente Fabry-Asztalos

Additional Mentoring Department

Chemistry

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May 17th, 2:10 PM May 17th, 2:30 PM

Towards the Synthesis of Boronated Amino Acid Analogs: Precursors for Novel HIV-1 Protease Inhibitors

SURC 137B

A class of HIV drugs called protease inhibitors have proven effective in slowing progression of the disease. This research aims to create two boronated amino acid analogs that will later be incorporated into potential HIV-1 protease inhibitors. These structures have been designed to decrease toxic exposure to patients and aim to increase bioavailability, allowing for more effective uptake and smaller required dosages. To synthesize the analogs, boronic acids were coupled with the protecting group (1R,2R)-dicyclohexyl-1,2-ethanediol (DICHED), which also served as a chiral director giving the product correct stereospecificity for biological activity. The product was homologated using butyllithium and dichloromethane to insert a new chiral chlorinated carbon between the R group and boron. In an SN2 reaction the chlorine was substituted for hexamethyldisilazane, which contains nitrogen and creates the analog amino group. The product was desilylated using methanol and immediately acylated with acetic anhydride and acetic acid. DICHED was removed and exchanged for two hydroxyl groups using phenyl boronic acid to yield the boronated amino acid analog. In the future, the boronated amino acid analogs will be coupled with tripeptides to create potential HIV-1 protease inhibitors.