Thursday, February 17, 2022

A Silver Bullet for Terpene Synthesis

 Today, our manuscript on modular terpene synthesis enabled by mild electrochemical couplings came out in Science! This project was a tremendous journey with lots of ups and downs, successes and setbacks, and many utterings of the phrase “back to the drawing board.” Stephen and I worked side by side on this project for about 3 years. While Stephen was the synthetic mastermind behind the routes and synthetic target selection, I was responsible for developing the electrochemistry needed to pull off the syntheses. There are lots of inventive and creative sequences to a variety of small building blocks in the SI that I implore all interested to check out! His synthetic eye was unlike many people I have seen, and it was amazing to see how he came up with incredibly short routes for some of these building blocks. For this blog post, I wanted to share some of my perspective as the one principally responsible for developing the electrochemistry and how we ultimately arrived at the Ag-nanoparticle solution.

When I joined the project, the tactic that we had originally leveraged to make many of the polyene cyclization precursors was our lab’s decarboxylative alkenylation using redox active esters and vinyl zinc reagents that came out a few years ago. Owing to the reliance on lithium halogen exchange, arduous set up, large excess of reagents, and the need for protecting groups, we elected to branch off into the world of electrochemical reductive coupling to see if that change could alleviate those woes. Reductive coupling couples two electrophiles using a terminal reductant (electricity, or commonly Zn) and a transition metal catalyst. Since no reactive organolithium and organozincs would be generated, more sensitive functionality likely would be tolerated thus shortening synthetic sequences and eliminated the need for protecting groups. Setting up the reaction would also be less cumbersome. No lithium halogen exchanges, transmetallations, titrations, transfers, etc. 

 

After a few months of exploring, we were able to develop some first-generation electrochemical cross coupling conditions that allowed us to couple an expanded range of functional groups including unprotected alcohols. We then got a little ambitious and realized that if we could couple the acids directly on the vinyl iodide piece, then we could conceptually perform coupling after coupling to make linear terpenes and polyenes. However, when we set out to perform a coupling with a vinyl iodide bearing carboxylic acid, the reaction was very low yielding. We tried everything to get this reaction to perform reasonably well with acid bearing vinyl iodides. We explored ligands, electrochemical parameters, solvents, and many other variables all to no avail. We turned to screening electrolytes which is a less desperate way of saying “additive screen.” We tried all sorts of salts, but they only moved the needle a few percent or so. Then we finally found that the addition of AgNO3, initially intended to be an electrolyte, more than doubled the yield of the reaction with the acid bearing vinyl iodides! I ran this experiment just before I left for Thanksgiving and I got this salt from my friend, Samer’s bench where he recently screened electrolytes. In retrospect, I almost didn’t run this experiment had I left for Thanksgiving a day or two earlier and Samer had not just used this salt. This was a truly serendipitous discovery and probably the luckiest I have ever gotten since we were about to seriously reconsider our tactics to pull off the project and go back to the drawing board once again.


Of course, we immediately recognized that silver nitrate is a rather unusual additive for this type of chemistry… after all, silver is usually an oxidant and yet here it is helping in a reductive coupling reaction. It was at this point that we reached out to our collaborators within the CSOE (Center for Synthetic Organic Electrochemistry) to help us understand what role silver could be playing in our reaction. 

 

The first observations we made after adding silver to the reaction were 1) the reaction took longer to turn its characteristic red and had an induction period proportional in time to the amount of silver, 2) the electrode was coated in a gray film during the first 0.3 F/mol (read: equivalents of electrons) of the reaction and could be observed after the reaction, 3) the success of the reaction was dependent on having a halide present in that first induction period and 4) the electrode could be reused in a subsequent reaction without needing to add silver nitrate to that second reaction. All these observations led us to think that were first consuming and depositing silver onto the cathode and this newly “functionalized” electrode was responsible for the reactivity boosts we saw. 



We first teamed up with Dr. Paulo Perez and Professor Scott Anderson at the University of Utah to help us understand what we had done to our electrodes. After sending them many samples of functionalized electrodes (See SI for the workflow and design of these experiments) and sending many emails stating something along the lines of “I think these are the last set of electrodes we want to look at!”, they were able to reveal that in the cases of successful reactions, the electrode surface was littered with silver nanoparticles using S(T)EM imaging and EDX analysis. This was an exciting discovery, but we had absolutely no clue what these particles could be doing in our reaction. After digging around in the literature, it seems such electrodes have been used extensively in analytical sensor design. The deposition of Ag-nanoparticles on carbon electrodes has been used to develop selective sensors for various types of analytes from hydrogen peroxide to nitrobenzene. These sensors operate by either lowering the overpotential necessary for analyte reduction OR by increasing the current response for analyte reduction through nanoparticle-substrate interactions. What had not been reported were cases in electrode decorated with silver nanoparticles support catalytic cross coupling reactions. Go figure. 

 


To start exploring the effect these functionalized electrodes had on the cross-coupling reaction, I first had to find a way to miniaturize the system from our preparative electrodes to an analytic disk electrode that we could use in voltammetry studies. I needed to try to shoot for roughly the same coverage of silver nanoparticles on this smaller surface as we had in the preparative reaction. Doing a little math revealed a good experimental starting point. After a bit of tinkering, I was able to plate silver nanoparticles on the analytical disk electrode reliably just using a dilute solution of Ag and a supporting LiCl additive to ensure we were forming the same type of silver on this electrode as we were in the preparative reaction. Thankfully, anodic stripping experiments, replication of other Ag-NP (silver nanoparticle) based voltammograms, and S(T)EM as well as EDX analysis performed by Paulo helped confirm that we have functionalized our analytic electrode with silver nanoparticles. Time to run some CV’s!


This was probably the most tedious part of my entire PhD. There were tons of components to study in this reaction (catalyst, redox active ester, vinyl iodide, combinations of all of them with and without silver, etc.) which led to me spending weeks at the CV and barely touching synthetic chemistry. To add to this already monotonous undertaking, the analytical electrode (of which I only had one) needed to be freshly plated with the silver nanoparticles each time to ensure the most reliable voltammograms could be produced. We did not want to risk losing any of our silver during analysis. This meant that after every measurement, the electrode had to be oxidatively cleaned until there were no traces of silver, sonicated in EtOH, dried, and then checked again by CV to ensure that all the silver made it off. This long SOP meant that I could only really run 3-4 proper measurements a day and if you go through the SI, I will let you imagine how long it took to get that data. I wish I could say that this led to a watershed in understanding as to what the specific role of silver was but, as chemistry would have it, no dice. The CVs of certain reaction components had very subtle differences with and without silver and nothing that jumped out at us a clear indication of anything spectacular. It was at this point that we sought out our next collaboration. 

 

We teamed up with Professor Héctor Abruña and Cara Gannett at Cornell University to further probe this reaction using some more advanced voltammetry techniques. To make a very long story short, Cara was able to expertly dissect our reaction and its components and study them all using rotating disk electrode (RDE) voltammetry. In very simplified terms, RDE allows you to gain better insight into the kinetics of electrochemical steps of a reaction. I found this website super useful in explaining the technique: https://pineresearch.com/shop/kb/theory/hydrodynamic-electrochemistry/rotating-electrode-theory/.

After a few months, Cara was able to figure out several roles of the silver nanoparticle layer. In summary, the silver basically helps clean up the catalytic cycle for the cross-coupling reaction. It prevents catalyst degradation/deactivation (which is especially prevalent when using vinyl iodides bearing unprotected acids) and prevents background consumption of redox labile functionality such as the redox active ester. You can check out the paper and the SI for more!


After having made this truly serendipitous discovery and working for nearly 2 years to understand the finding, the project was brought back from the brink and was making a turn towards what we set out to accomplish: a robust platform for terpene synthesis. After demonstrating that the silver additive now allowed the reaction to tolerate free acids as well as many other functional groups, we shifted our attention to developing an in-situ protocol so that we could skip a step in redox active ester preparation. We quickly found some very simple conditions (acid, NHPI, DIC, THF, 1hr) and we were off to the races. Together, we made 13 molecules that highlight the tolerance of various functional groups and demonstrate the plug and play nature of this synthetic strategy. I won’t talk too much about the synthesis as they are discussed in detail in the paper and SI but I would like to shout out Asymchem for demonstrating that both the generation of silver nanoparticles and the electrochemical coupling could be performed on 100g scale in recirculating flow! Thank you Zhen and Lijie for your time and expertise! 


Overall, the tactics of this project came a long way from using alkylithiums and long arduous set ups. Now, with the silver-nanoparticle functionalized electrodes and the power of electrochemistry, we were able to run this chemistry in a true dump and stir fashion to make polyenes in a streamlined fashion. Just to highlight how much electrochemistry changed the project, the previous route developed towards the progesterone polyene required a large amount of pyrophoric reagents for the cross couplings, tedious procedures, protecting groups and intermediate functional group interconversions. Using electrochemistry and after developing the necessary tactics, we could make the same polyene in fewer steps, with no protecting groups, and in an operationally simple fashion. We recognize that this reaction sounds deceptively super hard to run. It has nickel, electrochemistry, and nanoparticles, it sounds like a nightmare. However, I assure you that it is so easy that even Phil and his “dilapidated hands” can do it:


If I haven’t made it totally clear yet, this project was a true team effort. No single person could have pulled this off single handedly. Paulo and Scott were instrumental in our electrode surface understanding and their expertise in microscopy was invaluable as they revealed the crucial formation of silver nanoparticles. Héctor and Cara brought us to understand the mechanistic underpinnings of the reaction and demystified the role of the nanoparticle functionalized electrode. Zhen and Lijie showcased the scalability of the platform in an awe-inspiring manner. Phil granted us grace, guidance, and patience as we have been telling him that were almost done for nearly 2 years… Finally, Stephen initiated this project a year before I joined and has been a great mentor to me. He taught me a lot about synthesis, and I am very grateful for his patience and generosity in letting a first year come into the project and try to stick electrodes in it. 

 

So anyway, that’s the story about how a lucky hit in an additive screen resulted in the story we are blessed to be able to tell today. 

 

-Max, on behalf of Team Polyene. 

Friday, September 10, 2021

Reinventing Oligonucleotide Synthesis

 Wow, where to begin,

Our latest endeavors on the P(V) front are now published in Science. Now, before talking about the research, I must begin by giving a shout out upfront the (rather large) team who is responsible for everything in the paper. It was an incredible collaboration and everyone had a crucial role to play.

 

Bristol Myers Squibb: Yazhong Huang, Shenjie Qiu, Bin Zheng, Stephen Mercer, Richard Olson, Mike Schmidt, Ivar McDonald and Martin Eastgate

TSRI: Wei Hao, Julien Vantourout, Natalia Padial, Javier Lopez, Rohan Narayan, Donna Blackmond  and Phil Baran
After the team’s initial work developing the PSI reagents for the stereocontrolled synthesis of phosphorothioate linkages, much work remained to build out the P(V) platform, both to include other types of desired P-linkages but also to develop a protocol for using the novel reagents on an automated oligo synthesizer. The development of these additional reagents PS2, PO and RacPS all proceeded in different ways.

The challenges overcome in the syntheses of the PS2 and RacPS reagents were a simpler story so I'll direct you to finding that info in the publication. On the other hand, there is the P(O) reagent. To the best of our knowledge there had never been a published P(V) reagent capable of forming a phosphodiester bond between two nucleosides with phosphoramidite-like kinetics (i.e. crazy quick). The initial hit for such a reagent came in July of 2018, followed by my famous last words: “shouldn’t take long to find the perfect P(O) reagent” Although the hit was exciting, it required KOtBu as a base and wasn’t compatable with DBU or organic bases that would be amendable to an automated oligo synthesizer. 


To address this, we evaluated new P(O) reagents on several criteria:

1. Could they be made (Synthesis)

2. Could they be reacted with a nucleoside to afford a monomer (Loading)

3. Could they be coupled via an organic base with a second nucleoside to afford a dinucleotide  (Coupling)

We had two ways of making the reagents, either synthesizing 1,3-mercaptopropanols and reacting them with POCl3 or by generating analogous compounds with 1,3-diols and PSCl3 followed by an interesting atom transposition using TBAI. We found a lot of things that could work (and plenty that couldn’t) but only one scaffold was able to accomplish all 3 of our goals. P(O)-5 the diphenyl scaffold.  After this discovery we investigated the aryl electronics and stereochemistry of the diphenyl backbone. Attempts to modulate the coupling efficiency through the aryl electronics proved negligible. 

The stereochemistry was a more interesting questions, because the first synthesis of this reagent used a racemic mixture of the mercaptopropanol, generating a racemic mixture of P(O) reagents which upon loading onto a chiral nucleoside revealed a mixture of the possible isomers that one could imagine. We began synthesizing single isomer versions of these reagents and observed that the Syn scaffold epimerized into an inactive form during the loading step. 


Further investigation of the anti-backbone revealed that the (R,R) substituted system gave the fastest coupling times. We next looked into the synthesis of this reagent, the stereochemistry could be programed in via a Noyori reduction and using PFP as a leaving group provided suitable physical properties to afford a solid reagent. Despite this success, the reagent still had two flaws, it wasn’t stable enough (could only survive about a week on the benchtop) and it was still a mixture of isomers, with one reacting much faster than the other. 

Sitting around the lab one day, we thought to ourselves, why don’t start with the original PSI (a reagent we knew reacted at lighting speed) and swap the S for O? It seemed rather straightforward. In practice we were never able to do this successfully on the PSI reagent itself so we tried it on the PSI loaded monomers instead. Although we could succesfuly perform S-O transpositions on these monomers, there were always side reactions associated with the transformation, ultimately leading us to abandon this approach. 

Third times a charm as they always say, so revisiting the idea of performing the S-O transposition on the reagent itself, we knew we the reagent formed with PFTP (PSI) was too reactive after making the P(O) version of itself. So after generating PSI alternatives with different leaving groups, we found that we could successfully perform this transposition to generate a stable reagent, most notably the 4-bromothiphenol version.

There’s plenty more to the story. We evaluated the kinetics of the P(V) molecules, demonstrating that they are on par with phosphoramidite chemistry, we developed a novel universal linker capable of performing oligo synthesis under the unusual basic conditions found in the P(V) protocol and we even took a trip to Cambridge MA to visit our collaborators at BMS and see and learn first-hand how they were making oligonucleotides.

Also, if you’ve read this far it’s fair to assume you’re a fan of the P(V) approach to oligos so check out our perspective on P(V) chemistry that was also just published in ACS Central Science!

 

If you’re still reading, and want to follow the next steps of the P(V) story, keep an eye out on Elsiebio.com or drop one of us a line to check out how were using the P(V) technology (among other things) to develop the next generation of oligonucleotide therapeutics and “replace dogma with data”.  – Kyle and the P(V) Team



Thursday, April 15, 2021

IKA GUEST POST ON CLASSIC ALTERNATING CURRENT MODE

ELECTRASYN 2.0 SOFTWARE UPDATE TO SUPPORT ALTERNATING POLARITY IN CONSTANT VOLTAGE REACTION MODE 

Author information:

Chuanjun Jiao, IKA Works, Inc. 3550 General Atomics Court, MS G02/321, San Diego, CA 92121-1122, United States

Email: charles.jiao@ika.net

 

Note: This report is not related to the recently added new function “Rapid Alternating Polarity (rAP)”. The change described here is relevant only when the default “alternating polarity” function is used together with a reference electrode. Currently, only “alternating polarity” function is supported to be used with a reference electrode, and rAP function is not compatible with a reference electrode.  In addition, further software update is not necessary to a unit in which the rAP function is already installed, since the latest software supporting the rAP function already includes this change.  


Background

 

Recently the Reid Group at University of Strathclyde reported a mechanistic study of electrochemical benzylic oxidation with the use of ElectraSyn 2.0 (ChemElectroChem 2020, 7, 2771). During their study, the group observed unexpected product distribution change when alternating polarity was applied during a constant voltage experiment with ElectraSyn 2.0. The report describes their careful investigation of this phenomenon, and casts a practical consideration on users of IKA ElectraSyn 2.0.  


Here is the key points of their report:

 

·       Unexpected outcome was obtained under the condition of constant potential reaction mode­– reference electrode ON–alternating polarity ON.

·       During alternating polarity, the same magnitude of current would be expected in both positive and negative phase. However, the observed current magnitude was totally different between these two phases.

·       This asymmetric current distribution affected electrochemical reaction, resulting in unexpected product selectivity change.

·       Therefore, ElectraSyn 2.0 might have an engineering concern.   


Summary of IKA investigation

 

IKA conducted a series of experiments to clarify the nature of this phenomenon and to improve ElectraSyn 2.0. The detail of our internal investigation can be found in Detail of our investigation in this document. Here we would like to provide a summary of our investigation. 

·       We verified asymmetric current distribution in the same setting described in the report (constant voltage–reference electrode ON–alternating polarity ON).

·       This asymmetric current distribution was observed only when reference electrode is ON. In other words, this issue does not occur when reference electrode is OFF. 

·       This is simply originated from how voltage is controlled in ElectraSyn 2.0. 

·       Accordingly, ElectraSyn 2.0 does not have engineering concern.

 

Software update

Although we confirmed that ElecraSyn2.0 does not have any engineering flaw, we updated ElectraSyn 2.0 software to enable equal current distribution in the above experimental conditions (constant voltage–reference electrode ON–alternating polarity ON). 



When this setting change is needed

 

A user needs to enable this function only when Constant Voltage reaction mode with Reference Electrode ON and Alternating Polarity ON  

 

Effect on past research 

 

The issue only occurs when Constant Voltage reaction mode with Reference Electrode ON and Alternating Polarity ON. In other conditions, current and voltage control is accurate and experimental data is reliable.



Detail of our investigation 

 

IKA ElectraSyn 2.0 provides many functions that satisfy different requirements for electrosynthesis. Among those functions, Constant Voltage is a reaction mode where the reaction is executed at a fixed voltage. This reaction mode is generally more selective than Constant Current mode, though the reaction time tends to be longer. Alternating Polarity is an option that periodically switches anode and cathode. This option is useful when electrode fouling is observed. Switching polarity helps to alleviate accumulation of deposit. Both Constant Voltage and Alternating Polarity are routinely used for electrosynthesis. 

 

The recent report by the Reid group described a mechanistic study in synthetic organic electrochemical method development with the use of ElectraSyn 2.0 (ChemElectroChem 2020, 7, 2771). In this report, unexpected product selectivity change was observed in electrochemical benzylic C–H oxidation of toluene derivatives by employing Constant Voltage alongside Alternating Polarity function equipped in ElectraSyn 2.0.

 

During those experiments, it was observed that the magnitude of the current during the second half of alternating period was greater than during the first half; giving an asymmetric current over time response. This is not desired because alternating polarity is simply an electrode cleaning technique and should not alter the magnitude of current.



Further in-depth investigation of cell potential with alternating polarity revealed that the voltage during the negative phase was not controlled. The set voltage was 1.5V, which means the reaction voltage should alternate between 1.5V and -1.5V. However, the observed voltage was clearly not in this case.




In additional tests, a rapid degradation of NHPI was observed in Alternating Polarity experiments due to this unexpectedly high current input. Such degradation leads to the unexpected product selectivity.

 

Accordingly, the group published their findings to highlight an equipment engineering concern that is likely to influence and inform optimization strategies for a wide range of synthetic organic electrochemical methods under development.

 

To ensure product quality and to further improve EletraSyn2.0, IKA has conducted a thorough inspection of the instrument as well as detailed investigation of this issue. It turned out that the varied cell potential was caused by the way ElectraSyn 2.0 controls voltage against the reference electrode.

 

Method of voltage control

 

In the default setting of ElectraSyn 2.0, potential difference between Working Electrode (WE) and Reference Electrode (RE) is controlled when Reference Electrode is ON. Such setting remains unchanged during the experiments. In the ElectraSyn 2.0 apparatus, the working electrode (WE) is installed to the left side of the reaction cell and the counter electrode (CE) is installed to the right side. 



However, WE and CE do not necessarily indicate anode and cathode in electrolysis. WE can be both anode and cathode. For example, if 1.2 V is applied, WE will play the role of anode and the voltage should be set as +1.2 V between WE and RE.



On the other hand, if -1.2 V is applied, WE will play the role of cathode.


Alternating polarity

 

During alternating polarity, what is expected is the cycle of applying +1.2 V between WE and RE, and then +1.2V between CE and RE.


However, in the current ElectraSyn 2.0 software, the voltage control remains between WE and RE during the entire period. This means that applying -1.2V between WE and RE may induce completely different reaction, resulting in the observed asymmetric current behavior. 

In other words, if ElectraSyn 2.0 could switch WE and CE during alternating polarity, the problem of asymmetric current will be solved. This function was installed in an updated software.

 

Software update

 

After our investigation in software development, the aforementioned voltage control method was implemented. Users are provided with the option of enabling/ disabling the alternate polarity, with the latest software version (0.0.026 / 0.0.027).

 



The new software version was validated by using following test. In the first test, the solution containing 0.114 M Bu4NClO4 with acetone/MeCN = 1/1 ratio was used. As pointed out by the Reid group, constant potential mode with reference electrode-ON and alternating polarity-ON gave asymmetric current (blue circle in Figure 15.). When the setting is changed as illustrated above, totally symmetric current was observed (orange circle).



This test was conducted with another solution, verifying symmetric current behavior in this case as well. 



Accordingly, we have concluded that, alongside the existing function, an updated software version (0.0.026 / 0.0.027) will enable ElectraSyn 2.0 to perform a constant voltage reaction with reference electrode under alternating polarity conditions.

 

We thank Dr. Marc Reid, his colleagues, and all our users for supporting ElectraSyn 2.0 and providing valuable feedback.




Monday, October 5, 2020

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 4th 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