Nature Chose Phosphates and Chemists Should Too: How Emerging P(V) Methods Can Augment Existing Strategies

Abstract

Phosphate linkages govern life as we know it. Their unique properties provide the foundation for many natural systems from cell biology and biosynthesis to the backbone of nucleic acids. Phosphates are ideal natural moieties; existing as ionized species in a stable P(V)-oxidation state, they are endowed with high stability but exhibit enzymatically unlockable potential. Despite intense interest in phosphorus catalysis and condensation chemistry, organic chemistry has not fully embraced the potential of P(V) reagents. To be sure, within the world of chemical oligonucleotide synthesis, modern approaches utilize P(III) reagent systems to create phosphate linkages and their analogs. In this Outlook, we present recent studies from our laboratories suggesting that numerous exciting opportunities for P(V) chemistry exist at the nexus of organic synthesis and biochemistry. Applications to the synthesis of stereopure antisense oligonucleotides, cyclic dinucleotides, methylphosphonates, and phosphines are reviewed as well as chemoselective modification to peptides, proteins, and nucleic acids. Finally, an outlook into what may be possible in the future with P(V) chemistry is previewed, suggesting these examples represent just the tip of the iceberg.

Developing Structural First Principles for Alkylated Triphenylphosphonium-Based Ionic Liquids

“…Despite intense interest in P­(V) organophosphorus chemistry in the fields of biochemistry and organic synthesis, the potential of ionizable P­(V)-based compounds has not been fully embraced. The exquisite chemical stability and crystallinity of these phosphonium salts could make it a go-to strategy for those interested in synthesizing and studying molecules of life (oligonucleotides) and to those interested in basic organic transformations …”

“…The exquisite chemical stability and crystallinity of these phosphonium salts could make it a go-to strategy for those interested in synthesizing and studying molecules of life (oligonucleotides) and to those interested in basic organic transformations. 72…”

The phosphate ester group in secondary metabolites

“…To the best of our knowledge, there is no literature precedent that discusses the chemistry and biological profiles of secondary metabolites displaying the phosphate ester group. 2 c ,3 c ,4,5 Herein, we would like to describe a comprehensive account of the structural diversity and the biological and pharmacological profile of these metabolites, and illustrate the synthetic approaches applied for the incorporation of the phosphate ester functionality during total synthesis campaigns.…”

Structural insights into the catalytic and inhibitory mechanisms of the flavin transferase FmnB in Listeria monocytogenes

“…Ser257 and Thr256 form hydrogen bonds via water molecules to stabilize the deprotonated Ser257 (Figure S13B ). Because the p orbitals of oxygen and the d orbitals of phosphorus do not exactly match, 28 , 29 both phosphorus and oxygen, which can form only a double bond, have extra vacant orbitals that can hold more electrons, which allows the constant accumulation of electrons on oxygen to keep the substrate FAD in an active state. Meanwhile, Asp301 stabilizes the oxygen in the transition state through the coordination of magnesium ions, while Asn216 stabilizes Asp301 through a salt bridge with Asp301 (Figures 3D and S13C ).…”