Event Title

Synthesis of 2,2′,6,6′-Biphenyltetrol via Suzuki Coupling Utilizing Bulky Phosphine Ligands

Faculty Mentor

Dr. James M. Hanna, Jr., Dr. Robin K. Lammi

College

College of Arts and Sciences

Department

Chemistry, Physics and Geology

Location

West Center,Room 219

Start Date

22-4-2016 2:45 PM

End Date

22-4-2016 3:00 PM

Description

Amyloid-beta peptide (Abeta) self-assembles into neurotoxic, beta-structured aggregates, which are the primary component of the extracellular senile plaques characteristic of Alzheimer’s disease. A variety of small molecules have been shown to inhibit the aggregation process; typically, these contain aromatic groups and one or more hydrogen-bond donors to enable binding to Abeta. We have previously identified biphenyltetrols (BPTs) as a class of molecules exhibiting promising inhibitory efficacy. Of our symmetrical BPT series, 2,2′,6,6′-biphenyltetrol (2,6-BPT) was the final molecular structure to be synthesized. Previous efforts to prepare the sterically hindered 2,2′,6,6′-tetramethoxybiphenyl intermediate through a typical Suzuki coupling afforded no product. These results prompted a search for an alternative method, and a copper-catalyzed homocoupling of 2,6-dimethoxyphenylboronic acid was found to conveniently give the required 2,2′,6,6′-tetramethoxybiphenyl. However, obtaining reasonable yields of this intermediate required a stoichiometric amount of copper, which would likely complicate tests of inhibitory efficacy. We therefore have re-investigated the Suzuki coupling, this time employing a catalyst designed for coupling sterically hindered substrates. Through a coupling reaction using the catalyst comprised of bis(dibenzylideneacetone)palladium(0) (Pd(dba)2) and the bulky phosphine ligand (2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, the 2,6-intermediate was obtained in 27% yield after recrystallization. Demethylation of the intermediate afforded the desired 2,6-BPT in 20% yield after recrystallization. Future efforts will include evaluation of 2,6-BPT for its efficacy as an amyloid-beta aggregation inhibitor.

Grant Support?

Supported by a grant from the National Institutes of Health IDeA Networks for Biomedical Research Excellence (NIH INBRE)

This document is currently not available here.

Share

COinS
 
Apr 22nd, 2:45 PM Apr 22nd, 3:00 PM

Synthesis of 2,2′,6,6′-Biphenyltetrol via Suzuki Coupling Utilizing Bulky Phosphine Ligands

West Center,Room 219

Amyloid-beta peptide (Abeta) self-assembles into neurotoxic, beta-structured aggregates, which are the primary component of the extracellular senile plaques characteristic of Alzheimer’s disease. A variety of small molecules have been shown to inhibit the aggregation process; typically, these contain aromatic groups and one or more hydrogen-bond donors to enable binding to Abeta. We have previously identified biphenyltetrols (BPTs) as a class of molecules exhibiting promising inhibitory efficacy. Of our symmetrical BPT series, 2,2′,6,6′-biphenyltetrol (2,6-BPT) was the final molecular structure to be synthesized. Previous efforts to prepare the sterically hindered 2,2′,6,6′-tetramethoxybiphenyl intermediate through a typical Suzuki coupling afforded no product. These results prompted a search for an alternative method, and a copper-catalyzed homocoupling of 2,6-dimethoxyphenylboronic acid was found to conveniently give the required 2,2′,6,6′-tetramethoxybiphenyl. However, obtaining reasonable yields of this intermediate required a stoichiometric amount of copper, which would likely complicate tests of inhibitory efficacy. We therefore have re-investigated the Suzuki coupling, this time employing a catalyst designed for coupling sterically hindered substrates. Through a coupling reaction using the catalyst comprised of bis(dibenzylideneacetone)palladium(0) (Pd(dba)2) and the bulky phosphine ligand (2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, the 2,6-intermediate was obtained in 27% yield after recrystallization. Demethylation of the intermediate afforded the desired 2,6-BPT in 20% yield after recrystallization. Future efforts will include evaluation of 2,6-BPT for its efficacy as an amyloid-beta aggregation inhibitor.