Expanding Structural Complexity in Condensed Phosphates: P(V) Reagents for Controlled Phosphoanhydride Bond Construction

Abstract

At the outset, Chapter 1 begins by examining the central importance of phosphorus in both nature and industry, situating the chemistry of polyphosphates within a broader historical and conceptual context. A brief overview of the history of polyphosphate research in the life sciences is given, as well as a discussion on the persistent ambiguities in condensed phosphate nomenclature. To frame the work in the following chapters, the idea of the "hydrocarbon analogy" is introduced: a conceptual strategy that draws parallels between the structure and reactivity of organic molecules and that of inorganic phosphate constructs, thus offering a new way of thinking about molecular complexity in this underexplored chemical space.

Building from this foundation, Chapter 2 details the discovery of a diphosphorylation reagent, identified to be a mixture of neutral zwitterionic adducts of P4O10 and pyridine. This reagent emerged serendipitously from our efforts to activate trimetaphosphate and has proved to be a powerful tool for synthesizing functionalized cyclic metaphosphates. Chapter 3 is the extrapolation of our strategy to activate otherwise inert metaphosphates by forming ring-strained bicyclic ultraphosphates. We discuss the reactivity of [P5O14]3–, the oligophosphate analog of the bicyclic hydrocarbon housane. Attempts to push this strategy further toward the synthesis of a hexaphosphorylation reagent were ultimately unsuccessful but provided valuable insight into the limitations of this ring-strain activation paradigm. The methods developed in earlier chapters set the stage for our collaboration with the Fielder group, described in Chapter 4. We designed new reagents to chemoselectively conjugate polyphosphates to densely functionalized peptides and proteins. These synthetic strategies pave the way for the study of recently discovered, but poorly characterized post-translational modifications featuring novel phosphorylation modes. Finally, Chapter 5 presents a series of unpublished studies that expand on the themes of the previous chapter. Together, these investigations contribute to a growing body of knowledge aimed at broadening the chemical space of condensed inorganic phosphates.