CONTENTS 3.4.5. Phosphine-Catalyzed Addition to Phosphonic Alkynes 7997 3.4.6. Formation of Alkynyl Phosphonates by Lithiation and by Alkyne Sulfones Substitutions 7997 3.4.7. Summary 7998 4. Methods for the Hydrolysis of Mono and Dialkyl Phosphonates 8000 5. Conclusion 8003 Author Information 8004 Biographies 8004 Acknowledgment 8004 Glossary 8004 References 8005

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Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD and 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate. The 3-carboxyphenyl ring of 2e and 2f forms contacts comparable to those of the distal carboxylate in kainate.

A chiral phosphathiahelicene scaffold displaying a phosphole and a thiophene unit as the terminal rings of the helical sequence has been synthesized and characterized by spectroscopic methods and X-ray diffraction studies. The phosphine oxides (HelPhos-V oxides) have been obtained following a robust and scalable synthetic approach, based on a nickel-promoted alkynes cyclotrimerization reaction. Then, late-stage functionalization has been carried out via a bromination/palladium coupling reaction sequence. The HelPhos-V gold(I) complexes have been used as catalysts in the unprecedented enantioselective [2+2] cyclization of N-homoallenyl tryptamine derivatives, to afford indolenine-fused cyclobutanes in good isolated yields, with enantiomeric excesses up to 93%.