Synthesis of 2,2′,6,6′-Biphenyltetrol via Suzuki Coupling Utilizing Bulky Phosphine Ligands
College
College of Arts and Sciences
Department
Chemistry, Physics, Geology, & the Environment
Faculty Mentor
Dr. James M. Hanna, Jr., Dr. Robin K. Lammi
Abstract
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)
Start Date
22-4-2016 2:45 PM
End Date
22-4-2016 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.
