Synthesis and Application of a Hydrophobic Polyglutamate Bearing a Triphenylphosphine Group for the Orientation of Pharmaceutically Active Compounds and the Measurement of Residual Dipolar Couplings

For structure elucidation purposes, it is highly desirable to partially retain anisotropic observables in high-resolution NMR spectra, as they provide valuable information about the relative configuration, conformation, and dynamics of compounds in solution. Alignment media based on lyotropic liquid crystalline phases formed by α-helical polypeptides can be used to achieve weak solute alignment. We present a novel homopolyglutamate bearing a bulky and hydrophobic triphenylphosphine side chain, which proved to be an excellent alignment medium using chloroform as a co-solvent. We successfully applied the alignment medium for the measurement of residual dipolar couplings (RDCs) of artemisinin, an antimalarial drug, galantamine, which is used to treat Alzheimer's disease, and vincamine, a cerebral vasodilator and potential anti-cancer agent. Excellent agreement between experimental and back-calculated RDCs is obtained, and the enantio-differentiating property of the new medium is demonstrated using the model compound isopinocampheol. Our results show that this alignment medium is of high interest for elucidating compounds characterized by high complexity and relevance in the research field of small molecule pharmaceuticals.