Adventures in P(V) Chemistry

Our two recent P(V)-based projects that were just published in JACS and ACS Central Science were a lesson of teamwork and sometimes “serendipity” that we would like to describe in the following blogpost. 

Having worked on the P(V) reagent platform since its inception, I have spent a considerable amount of time sitting in front of the only NMR spectrometer at Scripps capable of detecting the ³¹P nucleus. Since these blog posts are supposed to be the behind the scenes version of papers we publish, I thought I would take this time to walk you through the fun journey from the Baran 

lab to the Molecular Biology building where one of our NMR labs is.  You begin by leaving the 4^th floor of the Beckman Center for The Chemical Sciences, traversing the intricate Hogwarts style staircases down to the lobby. After exiting the building and making a daring leap over the crosswalk between the two buildings, it’s time to go further into the depths of the MBB building. Okay, back to the science…as you can see in the figure below, the loading and coupling events between the P(V) reagents and alcohol nucleophiles proceeds with a rather boring and predictable outcome via ³¹P NMR. Over the course of ~3 years, hundreds of compounds have undergone this reaction sequence. Regardless of the compound in question, the only observable peaks are 100 ppm for the loading and 55 ppm for the coupling products. The reactions between nitrogen and sulfur nucleophiles were never observed. 

This led us to the realization that the P(V) reagents could potentially solve the challenge associated with Serine selective functionalization as highlighted in the chart below.

At that time, Julien joined the P(V) team and first performed a series of competitive experiments between Serine and other nucleophilic amino acid residues. The selectivity observed was excellent and after a quick optimization campaign we applied the reaction conditions to the functionalization of linear and cyclic peptides. The chemistry proved to be really robust and afforded really good yields even on complex structure such as Vancomycin. Then, Prof. Bernardes came to Scripps to give a lecture and after a meeting with Phil, he was really excited about applying the new method to the functionalization of proteins. One of his students, Srinivasa, successfully functionalized ubiquitin and repressors 434 demonstrating the broad applicability of our Serine selective P(V)-platform. Other than its broad scope, one thing we really like about this new method is the ease of running and analyzing the reaction. A simple ³¹P NMR (¹H coupled) will allow you to know if you functionalized the Serine residue over other nucleophilic amino acids by simply looking at the chemical shift and the multiplicity. The full details of the work are in the paper of which my favorite part is the computation work done by our amazing collaborators at BMS (Thanks again Antonio!!) which really explain this surprising level of chemoselectivity.

Another great application of the P(V)-platform has been its association to RASS (developed by the Dawson lab) to selectively functionalize DNA. It all started a few years ago when Dillon was working on DEL reactions. He would occasionally notice side reactions occurring at the terminal alcohol of the DNA head piece. This inspired him to dive deeper into developing selective reaction at that position. A year passed with many unsuccessful strategies and reactions explored… And just when hope seemed lost, he met PSI and learned about its exquisite reactivity. He decided to combine it to RASS and that’s how the SENDR platform for site selective DNA modification was brought to life (not without some hiccups). From there, the number of application idea flowing from the team grew with every day and many, many, many pilot experiments were pursued. Only a fraction of those made it into the paper, but as new ideas popped into our heads new collaborations were formed and exciting avenues explored! This project allowed us to dive into the powerful world DNA technology and has thus spurred exciting ongoing projects within our labs! These projects have allowed us to explore and participate regions of biomedical science that seemed completely foreign to us chemists before (we had never seen a DNA sequencer until a few days ago) and is enabling some remarkable science. We hope that this chemistry would enable the community to explore previously intractable and increasingly creative experimental designs! 

 

All in all, both of these papers were the result of many years of work across multiple labs (across the U.S and the Atlantic) and I am indebted greatly to the teams for not only the work but also the lessons and memories.

 

-Kyle and the P(V) team