tag:blogger.com,1999:blog-518460867604220682024-03-17T10:34:49.217-07:00Open FlaskBaranLabhttp://www.blogger.com/profile/01806245988209508968noreply@blogger.comBlogger116110tag:blogger.com,1999:blog-51846086760422068.post-24680097084915846492022-02-17T10:58:00.001-08:002022-02-17T10:58:11.575-08:00A Silver Bullet for Terpene Synthesis<p style="text-align: justify;"><span style="color: #f3f3f3; font-size: medium;"> <span face="Calibri, sans-serif" style="text-align: justify; text-indent: 0.5in;">Today, our manuscript on modular terpene synthesis enabled by mild electrochemical couplings came out in <a href="https://bit.ly/3gTWmWl" target="_blank">Science</a>! 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.</span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;">When I joined the project, the tactic that we had originally leveraged to make many of the polyene cyclization precursors was our lab’s <a href="https://www.nature.com/articles/nature22307" target="_blank">decarboxylative alkenylation</a> 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. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify;"><o:p><span style="color: #f3f3f3; font-size: medium;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;">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 AgNO<sub>3</sub>, 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.<o:p></o:p><a href="https://blogger.googleusercontent.com/img/a/AVvXsEjmbId6y30E_KiOgMsOOGlWgYmexeRxEapFesvmN7RQWP3ggwdn5ew5xMdgGtvcIojdY-cUoTDR-mKJMwXGUhTP3gvPc56GVKxZCknwtl9X1kPvb0Dze5wqMW6rHjbM0Qr-0q1ljnK0KEd1IUWGVh-cUIArNMpbmTtyekGugYf_8TmjHMik6yagI8ga=s1514" style="margin-left: 1em; margin-right: 1em; text-align: center; text-indent: 0.5in;"><img border="0" data-original-height="1138" data-original-width="1514" height="482" src="https://blogger.googleusercontent.com/img/a/AVvXsEjmbId6y30E_KiOgMsOOGlWgYmexeRxEapFesvmN7RQWP3ggwdn5ew5xMdgGtvcIojdY-cUoTDR-mKJMwXGUhTP3gvPc56GVKxZCknwtl9X1kPvb0Dze5wqMW6rHjbM0Qr-0q1ljnK0KEd1IUWGVh-cUIArNMpbmTtyekGugYf_8TmjHMik6yagI8ga=w640-h482" width="640" /></a></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;">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. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify;"><o:p><span style="color: #f3f3f3; font-size: medium;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;"><span style="text-align: start; text-indent: 0px;">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. </span><span face="-webkit-standard" style="text-align: start; text-indent: 0px;"></span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="text-align: start; text-indent: 0px;"><span style="color: #f3f3f3; font-size: medium;"><br /></span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEj1qKk-DiUcuP_We-ZMTBA3mAvlS5l1-WamAuJUiLDYWh0mL59foAQB3tZdtdBtD93OY4btErP21WGp2PxNJ7PomYcettDS9WTM8LNFgZUaErtEgBKw-KMm1367XTizBvd8V5jwv7h7wmeloks3wpPIIDECEkWiQa_UbS8TEnKdUQBH9RBISPpOZ6-9=s1800" style="margin-left: 1em; margin-right: 1em;"><span style="color: #f3f3f3; font-size: medium;"><img border="0" data-original-height="1800" data-original-width="1778" height="640" src="https://blogger.googleusercontent.com/img/a/AVvXsEj1qKk-DiUcuP_We-ZMTBA3mAvlS5l1-WamAuJUiLDYWh0mL59foAQB3tZdtdBtD93OY4btErP21WGp2PxNJ7PomYcettDS9WTM8LNFgZUaErtEgBKw-KMm1367XTizBvd8V5jwv7h7wmeloks3wpPIIDECEkWiQa_UbS8TEnKdUQBH9RBISPpOZ6-9=w632-h640" width="632" /></span></a></div><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;">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. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify;"><o:p><span style="color: #f3f3f3; font-size: medium;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify;"><o:p><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgb6NS1ZbhscSaEPla403901hOTtK7eMZh34tmG8cjPQjWCDmaSxMJJSCIdCbL38GjS41kMTIm1mI8BcmgdXFEu9Mg_m0tv6yDH_ilkqNtu-8L7bHOq5yFKfRi6kbTqmQCUc_WaUpQgcKMBsSJb9MpZBrrocggdu7hDVe0LSe9fcM0n4nWmgySaLtv_=s1822" style="font-family: -webkit-standard; margin-left: 1em; margin-right: 1em; text-align: center;"><span style="color: #f3f3f3; font-size: medium;"><img border="0" data-original-height="580" data-original-width="1822" height="204" src="https://blogger.googleusercontent.com/img/a/AVvXsEgb6NS1ZbhscSaEPla403901hOTtK7eMZh34tmG8cjPQjWCDmaSxMJJSCIdCbL38GjS41kMTIm1mI8BcmgdXFEu9Mg_m0tv6yDH_ilkqNtu-8L7bHOq5yFKfRi6kbTqmQCUc_WaUpQgcKMBsSJb9MpZBrrocggdu7hDVe0LSe9fcM0n4nWmgySaLtv_=w640-h204" width="640" /></span></a></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify;"><o:p><span style="color: #f3f3f3; font-size: medium;"><br /></span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;">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!<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgvFa2mXy3cvAD0vUCCrjL_gqN7yde0tkHQmKvTrdToKwGQISZkhwGis4cJgMm128n1S4npwkjvKnK27GlEcrvEMhgKUoFpc8lEMHZLia-ZCs2fM9fjuNrnjoxLYIOOeHODNk3Kq_ZDVCov1dOBb9kMoTQVbUo51Msn8wlNsnsWWNylDhSNA0JfkKRf=s1784" style="font-family: -webkit-standard; margin-left: 1em; margin-right: 1em; text-align: center; text-indent: 0px;"><span style="color: #f3f3f3; font-size: medium;"><img border="0" data-original-height="1784" data-original-width="1546" height="640" src="https://blogger.googleusercontent.com/img/a/AVvXsEgvFa2mXy3cvAD0vUCCrjL_gqN7yde0tkHQmKvTrdToKwGQISZkhwGis4cJgMm128n1S4npwkjvKnK27GlEcrvEMhgKUoFpc8lEMHZLia-ZCs2fM9fjuNrnjoxLYIOOeHODNk3Kq_ZDVCov1dOBb9kMoTQVbUo51Msn8wlNsnsWWNylDhSNA0JfkKRf=w554-h640" width="554" /></span></a></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;">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. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify;"><o:p><span style="color: #f3f3f3; font-size: medium;"> </span></o:p></p><div class="separator" style="clear: both; text-align: center;"><span style="color: #f3f3f3; font-size: medium; margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="886" data-original-width="918" height="386" src="https://blogger.googleusercontent.com/img/a/AVvXsEiZ6ode-q8IwkJHaN6pHMQGdOlxcZs9GG7z8QPF7oftqzkGWsAaba81xIGUOQeGdQr4abxnea_bGczWLO4IyFStsm_lIlkBJ51pSCEF14QQKzyWzJxtlwRQjh3s9PnI5tl3-tGJu_XpGT7s74s17u8LU5TWQLkHD8sOTojVZlpzxi2YOh3jrUrUzge6=w400-h386" width="400" /></span></div><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;">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 <u>very</u> 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: <a href="https://pineresearch.com/shop/kb/theory/hydrodynamic-electrochemistry/rotating-electrode-theory/">https://pineresearch.com/shop/kb/theory/hydrodynamic-electrochemistry/rotating-electrode-theory/</a>.</span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;">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!</span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEgPd8inSfCDUr2aoG7GsfGa88EN2XyRux36QLnX2brQUaF3qmZqHdN87S6OEwBvUvkp9jE-Fvr0721amhvOryuJMkT2o4cyGB15flhVil58ggapkdLCwIn8xq__cL90vzx63hNxBWuveMxCnoI1xpZ2osBbQSJQdP9exHQFAjdsQiQvg4IMOJ4m_DCz=s2168" style="font-family: -webkit-standard; margin-left: 1em; margin-right: 1em; text-align: center; text-indent: 0px;"><span style="color: #f3f3f3; font-size: medium;"><img border="0" data-original-height="1328" data-original-width="2168" height="392" src="https://blogger.googleusercontent.com/img/a/AVvXsEgPd8inSfCDUr2aoG7GsfGa88EN2XyRux36QLnX2brQUaF3qmZqHdN87S6OEwBvUvkp9jE-Fvr0721amhvOryuJMkT2o4cyGB15flhVil58ggapkdLCwIn8xq__cL90vzx63hNxBWuveMxCnoI1xpZ2osBbQSJQdP9exHQFAjdsQiQvg4IMOJ4m_DCz=w640-h392" width="640" /></span></a></div><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;">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! <o:p></o:p></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEiVxYyCKD_nLBrITqT4pPlzlPbbr0uII5yI_hsuUjFoPIVB2yA3d86PRmVPLn_Z3TBH6PT-eZkoMhupZLt_7oH1qsNvodoSR86p66MXKzi8sVARlJLJnALWLhYHDYEbh0vcum5HvHEKB-4ZeDQYzin7vRcvVYiJo4QGI-61O4FNtcMkBDM6UCka-1UO=s1612" style="font-family: -webkit-standard; margin-left: 1em; margin-right: 1em; text-align: center; text-indent: 0px;"><span style="color: #f3f3f3; font-size: medium;"><img border="0" data-original-height="1188" data-original-width="1612" height="472" src="https://blogger.googleusercontent.com/img/a/AVvXsEiVxYyCKD_nLBrITqT4pPlzlPbbr0uII5yI_hsuUjFoPIVB2yA3d86PRmVPLn_Z3TBH6PT-eZkoMhupZLt_7oH1qsNvodoSR86p66MXKzi8sVARlJLJnALWLhYHDYEbh0vcum5HvHEKB-4ZeDQYzin7vRcvVYiJo4QGI-61O4FNtcMkBDM6UCka-1UO=w640-h472" width="640" /></span></a></div><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;">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:</span></p><div class="separator" style="clear: both; text-align: center;"><span style="color: #f3f3f3; font-size: medium;"><iframe allowfullscreen="" class="BLOG_video_class" height="347" src="https://www.youtube.com/embed/6_5TtyDmiNc" width="417" youtube-src-id="6_5TtyDmiNc"></iframe></span></div><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><br /></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEieWvHmvF8rFBrCcnbqncHpvEnN2_ibqxHxgTD1OxmHkOoqWUYCPCQu5P-_4fteLx6yO6CXOAOV0uH8A5O7TIINDviXaQdyOe0sPm2F8uJj-e2XS7rX4_VohhZK9MMWH4MkQmyFt0wwR1hdlOqkQshHbjudw-vUYmHUK_XVOzkqfg2HmwmoloTWzkjp=s2270" style="font-family: -webkit-standard; margin-left: 1em; margin-right: 1em; text-align: center; text-indent: 0px;"><span style="color: #f3f3f3; font-size: medium;"><img border="0" data-original-height="1486" data-original-width="2270" height="418" src="https://blogger.googleusercontent.com/img/a/AVvXsEieWvHmvF8rFBrCcnbqncHpvEnN2_ibqxHxgTD1OxmHkOoqWUYCPCQu5P-_4fteLx6yO6CXOAOV0uH8A5O7TIINDviXaQdyOe0sPm2F8uJj-e2XS7rX4_VohhZK9MMWH4MkQmyFt0wwR1hdlOqkQshHbjudw-vUYmHUK_XVOzkqfg2HmwmoloTWzkjp=w640-h418" width="640" /></span></a></div><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;">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. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify;"><o:p><span style="color: #f3f3f3; font-size: medium;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify; text-indent: 0.5in;"><span style="color: #f3f3f3; font-size: medium;">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. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify;"><o:p><span style="color: #f3f3f3; font-size: medium;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify;"><span style="color: #f3f3f3; font-size: medium;">-Max, on behalf of Team Polyene. </span><br /><i><o:p></o:p></i></p>BaranLabhttp://www.blogger.com/profile/01806245988209508968noreply@blogger.com1tag:blogger.com,1999:blog-51846086760422068.post-11076528675939806822021-09-10T05:37:00.000-07:002021-09-10T05:37:44.663-07:00Reinventing Oligonucleotide Synthesis <p style="text-align: justify;"> <span style="font-family: Calibri, sans-serif;"><span style="font-size: medium;">Wow, where to begin,</span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: medium;"><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify;"><span style="font-size: medium;">Our latest endeavors on the P(V) front are now published in <a href="https://www.science.org/doi/10.1126/science.abi9727">Science</a>. 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.</span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify;"><span style="font-size: medium;"><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify;"><o:p><span style="font-size: medium;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify;"><span style="font-size: medium;">Bristol Myers Squibb: Yazhong Huang, Shenjie Qiu, Bin Zheng, Stephen Mercer, Richard Olson, Mike Schmidt, Ivar McDonald and Martin Eastgate<o:p></o:p></span></p><span style="font-family: Calibri, sans-serif;"><span style="font-size: medium;"><div style="text-align: justify;">TSRI: Wei Hao, Julien Vantourout, Natalia Padial, Javier Lopez, Rohan Narayan, Donna Blackmond and Phil Baran</div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg_bO2bZq7gdNbSXyXj7xhu2Yhyphenhyphen7Y5rA4D_9Nx8bpiD8Y3GA1dXLkH_amBRz-xIAZN6P4RD-shZcx9zqyUaUs6jDox-rWXfzYB6lv8Bx6qBt3SId9QR08g-GGxqfopsSWgDR3LHsGD_tfU/" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="934" data-original-width="1706" height="350" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg_bO2bZq7gdNbSXyXj7xhu2Yhyphenhyphen7Y5rA4D_9Nx8bpiD8Y3GA1dXLkH_amBRz-xIAZN6P4RD-shZcx9zqyUaUs6jDox-rWXfzYB6lv8Bx6qBt3SId9QR08g-GGxqfopsSWgDR3LHsGD_tfU/w640-h350/Screen+Shot+2021-09-09+at+8.20.47+PM.png" width="640" /></a></div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg4GYv3v-5SAFLjZS2TH7aqIDA8PzF4kV7tCINBqNJnHZ7e1dHFuenLdsbEnE66s9Fn1MwZK988vMiMYKQD0-wTYHa96BbWOb_PDYANjjomHfMTbwUw0U-HJcnDlEMc8BNO6JAyVrW_RZ4/" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="1106" data-original-width="1934" height="366" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg4GYv3v-5SAFLjZS2TH7aqIDA8PzF4kV7tCINBqNJnHZ7e1dHFuenLdsbEnE66s9Fn1MwZK988vMiMYKQD0-wTYHa96BbWOb_PDYANjjomHfMTbwUw0U-HJcnDlEMc8BNO6JAyVrW_RZ4/w640-h366/Screen+Shot+2021-09-09+at+8.20.57+PM.png" width="640" /></a></div></span></span><div style="text-align: justify;"><span style="font-size: medium;"><span style="font-family: Calibri, sans-serif;">After the team’s initial work developing the <a href="https://www.science.org/lookup/doi/10.1126/science.aau3369" target="_blank">PSI reagents</a> </span><span style="font-family: Calibri, sans-serif;">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.</span></span></div><div><span style="font-family: Calibri, sans-serif;"><span style="font-size: medium;"><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhdbtO1saunLnpo8Hhu0-FCwrL4ulUjMr2CIlEdLfx7ff59db0L4r2O5x0JOPPq29XISv40qu3y1pXnyJ4rx4OtjNkoPWgLnzWlKgtv1yfwgNE7JZ6iyRHS8pR8jrfQ1ewq0dhOn7guVv8/" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="846" data-original-width="1250" height="434" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhdbtO1saunLnpo8Hhu0-FCwrL4ulUjMr2CIlEdLfx7ff59db0L4r2O5x0JOPPq29XISv40qu3y1pXnyJ4rx4OtjNkoPWgLnzWlKgtv1yfwgNE7JZ6iyRHS8pR8jrfQ1ewq0dhOn7guVv8/w640-h434/Screen+Shot+2021-09-09+at+8.22.29+PM.png" width="640" /></a></div><div class="separator" style="clear: both; text-align: center;"><p class="MsoNormal" style="margin: 0in; text-align: justify;">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. <o:p></o:p></p><p class="MsoNormal" style="margin: 0in; text-align: justify;"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjd-EYPiMOcB7TbXgNCWyhYmjPVK_Rf7MzSsmxQY0mxvNhuHiNg_stF9kz5i6sqP2DCJCwALn4SYqqrEEVYYPGu7DflBzstzrPm8p3bcS3T0VnuFAK8HiGg2pjnW0IA3zlGqqwlj5f2lhA/" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="462" data-original-width="2190" height="136" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjd-EYPiMOcB7TbXgNCWyhYmjPVK_Rf7MzSsmxQY0mxvNhuHiNg_stF9kz5i6sqP2DCJCwALn4SYqqrEEVYYPGu7DflBzstzrPm8p3bcS3T0VnuFAK8HiGg2pjnW0IA3zlGqqwlj5f2lhA/w640-h136/Screen+Shot+2021-09-09+at+8.25.18+PM.png" width="640" /></a></div><br /><p></p><p class="MsoNormal" style="margin: 0in; text-align: start;">To address this, we evaluated new P(O) reagents on several criteria:<o:p></o:p></p><p class="MsoNormal" style="margin: 0in; text-align: start;">1. Could they be made (Synthesis)<o:p></o:p></p><p class="MsoNormal" style="margin: 0in; text-align: start;">2. Could they be reacted with a nucleoside to afford a monomer (Loading)<o:p></o:p></p><p class="MsoNormal" style="margin: 0in; text-align: start;">3. Could they be coupled via an organic base with a second nucleoside to afford a dinucleotide (Coupling)<o:p></o:p></p><p class="MsoNormal" style="margin: 0in; text-align: start;"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjMJLXpVBc22lTQ3V2A3wuQ27BPZfclkPtlWpdwoOcwmj0H0NqgLZI-t2b3QeDIWRJbh1aN_ZsgvvxHEa30SZdtCTDD2JTEV4AbRmLFfAKWQ0Lo62QjXSlkdAV0n1oJomG0RkfxGkmlPyE/" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="580" data-original-width="2188" height="170" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjMJLXpVBc22lTQ3V2A3wuQ27BPZfclkPtlWpdwoOcwmj0H0NqgLZI-t2b3QeDIWRJbh1aN_ZsgvvxHEa30SZdtCTDD2JTEV4AbRmLFfAKWQ0Lo62QjXSlkdAV0n1oJomG0RkfxGkmlPyE/w640-h170/Screen+Shot+2021-09-09+at+8.25.26+PM.png" width="640" /></a></div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjvI0BHzx0rwjV1LhJ6genCwLZY68bbMvpwmQuHmcV-aE81kHoD2tK-vu0OMsnSU2Qh4d9Rx02l7yJDjololu-df-plUkpwK-3xhfx9ttotB8PwkS-t2_cWCb6ZYB77o0BuNitQcorrST8/" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"><img alt="" data-original-height="808" data-original-width="1280" height="202" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjvI0BHzx0rwjV1LhJ6genCwLZY68bbMvpwmQuHmcV-aE81kHoD2tK-vu0OMsnSU2Qh4d9Rx02l7yJDjololu-df-plUkpwK-3xhfx9ttotB8PwkS-t2_cWCb6ZYB77o0BuNitQcorrST8/" width="320" /></a></div>We had two ways of making the reagents, either synthesizing 1,3-mercaptopropanols and reacting them with POCl<sub>3</sub> or by generating analogous compounds with 1,3-diols and PSCl<sub>3</sub> 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. <p></p><p class="MsoNormal" style="margin: 0in; text-align: start;">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 <span style="font-family: -webkit-standard;"></span><span style="text-align: justify;">reagents and observed that the Syn scaffold epimerized into an inactive form during the loading step.</span><span style="text-align: justify;"> </span></p><p class="MsoNormal" style="margin: 0in; text-align: start;"><span style="text-align: justify;"><br /></span></p><p class="MsoNormal" style="margin: 0in; text-align: start;"><span style="text-align: justify;"></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiH8mRQXWrpLiVZ0oXm97aHnZ_HFHCWJdB94mAT_iZBigKNsFOmey4VwYA4Wx1aguncgWalnMZ8skIuAp8R_wpudgHY-RSkP8pVg-aYuAUH4FF5r_CxoUstObYWi8pHecrhImDtwUww4ao/" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="1266" data-original-width="2040" height="398" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiH8mRQXWrpLiVZ0oXm97aHnZ_HFHCWJdB94mAT_iZBigKNsFOmey4VwYA4Wx1aguncgWalnMZ8skIuAp8R_wpudgHY-RSkP8pVg-aYuAUH4FF5r_CxoUstObYWi8pHecrhImDtwUww4ao/w640-h398/Screen+Shot+2021-09-09+at+8.25.38+PM.png" width="640" /></a></div><span style="text-align: justify;">Further investigation of the anti-backbone revealed that the (</span><i style="text-align: justify;">R,R</i><span style="text-align: justify;">) 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</span><span style="text-align: justify;"> </span><span style="text-align: justify;">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. </span><p></p><p class="MsoNormal" style="margin: 0in; text-align: start;"><span style="text-align: justify;"></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjKqv3BgebeZILTrUx9FY3nXhFgsdzKyumZCn7eXtaa5m-vhMUsn5CCHC9lJI1MsvJPIJ9P4XAAWdLlTReVj_hMsWRoBmFVRzwsadeYnAT90gddS5KZDhh2BlZbfVJptAYtN65QD4MMJu4/" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="1496" data-original-width="1972" height="486" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjKqv3BgebeZILTrUx9FY3nXhFgsdzKyumZCn7eXtaa5m-vhMUsn5CCHC9lJI1MsvJPIJ9P4XAAWdLlTReVj_hMsWRoBmFVRzwsadeYnAT90gddS5KZDhh2BlZbfVJptAYtN65QD4MMJu4/w640-h486/Screen+Shot+2021-09-09+at+8.25.45+PM.png" width="640" /></a></div><p></p><p class="MsoNormal" style="margin: 0in; text-align: justify;">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. </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg1qdavGc7-bZyemQGs-Uah1jZZEnGFPjJ309TJjTYViQ0Ld-n4WhBj2dHkoBG-kVdfIygh1aHUp9t7_qP5OCMZy6v8WFvoAbP5tpCArtsGbx3_PwiBeTT6IFbFFC_EJ8NjF6zR-v0quxA/" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="866" data-original-width="1938" height="286" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg1qdavGc7-bZyemQGs-Uah1jZZEnGFPjJ309TJjTYViQ0Ld-n4WhBj2dHkoBG-kVdfIygh1aHUp9t7_qP5OCMZy6v8WFvoAbP5tpCArtsGbx3_PwiBeTT6IFbFFC_EJ8NjF6zR-v0quxA/w640-h286/Screen+Shot+2021-09-09+at+8.25.51+PM.png" width="640" /></a></div><p></p><p class="MsoNormal" style="margin: 0in; text-align: justify;">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.</p><p class="MsoNormal" style="margin: 0in; text-align: start;"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjbOo5tHjLCVPtq9GN6fg7jtDgXYyrEnYAAhYXpAD2ANfPHr9Vj5IvWQsF4vAHgtOIBLOqUJ2abFSYsoAPV3vncy6t_Mx4U5qJfTs6rXuw9evY-g_n26kKRo5WBP7qK2OCUY2eD9gpqkZQ/" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="1170" data-original-width="2048" height="366" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjbOo5tHjLCVPtq9GN6fg7jtDgXYyrEnYAAhYXpAD2ANfPHr9Vj5IvWQsF4vAHgtOIBLOqUJ2abFSYsoAPV3vncy6t_Mx4U5qJfTs6rXuw9evY-g_n26kKRo5WBP7qK2OCUY2eD9gpqkZQ/w640-h366/Screen+Shot+2021-09-09+at+8.25.57+PM.png" width="640" /></a></div><p></p></div></span></span><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: medium;">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.</span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgyKdsAtMvr_N61DyYlVlbM6WhHhyphenhyphenX4dL7D4078Knu_Spywes2L2HYrI55KAhPfHMtXkSPcYaJ9iL3HtAROKnthgsGla5sDonKVmipGjs4UJAhVruTfwCp7J7bD0XR276ecKitONesbl8s/" style="margin-left: 1em; margin-right: 1em;"><span style="font-size: medium;"><img alt="" data-original-height="726" data-original-width="1286" height="362" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgyKdsAtMvr_N61DyYlVlbM6WhHhyphenhyphenX4dL7D4078Knu_Spywes2L2HYrI55KAhPfHMtXkSPcYaJ9iL3HtAROKnthgsGla5sDonKVmipGjs4UJAhVruTfwCp7J7bD0XR276ecKitONesbl8s/w640-h362/Screen+Shot+2021-09-09+at+8.26.04+PM.png" width="640" /></span></a></div><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: medium;">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 <a href="http://bit.ly/3nhDzbW">ACS Central Science</a>!<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><o:p><span style="font-size: medium;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in;"><span style="font-size: medium;">If you’re still reading, and want to follow the next steps of the P(V) story, keep an eye out on <a href="http://Elsiebio.com">Elsiebio.com</a> 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<o:p></o:p></span></p></div><div><span style="font-family: Calibri, sans-serif;"><span style="font-size: medium;"><br /></span></span></div><div><span style="font-family: Calibri, sans-serif; font-size: 12pt;"><br /></span></div>BaranLabhttp://www.blogger.com/profile/01806245988209508968noreply@blogger.com1tag:blogger.com,1999:blog-51846086760422068.post-3501870033645699142021-04-15T12:56:00.000-07:002021-04-15T12:56:33.526-07:00IKA GUEST POST ON CLASSIC ALTERNATING CURRENT MODE<p><span style="color: #f3f3f3;"></span></p><div class="separator" style="clear: both; text-align: center;"><b style="color: #f3f3f3; font-family: Calibri, sans-serif; font-size: 11pt;">ELECTRASYN 2.0 SOFTWARE UPDATE TO SUPPORT ALTERNATING POLARITY IN CONSTANT VOLTAGE REACTION MODE</b><b style="font-family: Calibri, sans-serif; font-size: 11pt;"><span style="color: #f3f3f3;"> </span></b></div><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in;"><span style="font-size: 10pt; line-height: 14.266666412353516px;"><span style="color: #f3f3f3;">Author information:<o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in;"><span style="font-size: 10pt; line-height: 14.266666412353516px;"><span style="color: #f3f3f3;">Chuanjun Jiao, IKA Works, Inc. 3550 General Atomics Court, MS G02/321, San Diego, CA 92121-1122, United States<o:p></o:p></span></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in;"><span style="font-size: 10pt; line-height: 14.266666412353516px;"><span style="color: #f3f3f3;">Email: charles.jiao@ika.net<o:p></o:p></span></span></p><p align="center" class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: center;"><o:p><span style="color: #f3f3f3;"> </span></o:p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"><span style="color: #f3f3f3;">Note: <b>This report is not related to the recently added new function “Rapid Alternating Polarity (rAP)”.</b> 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. </span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"><span style="color: #f3f3f3;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in;"><b><span style="color: #f3f3f3;">Background<o:p></o:p></span></b></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in;"><b><span style="color: #f3f3f3;"> </span></b></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in;"><span style="color: #f3f3f3;">Recently the Reid Group at University of Strathclyde reported a mechanistic study of electrochemical benzylic oxidation with the use of ElectraSyn 2.0 (</span><a href="https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/celc.202000648" target="_blank"><span style="color: #04ff00;"><i>ChemElectroChem</i> <b>2020</b>, 7, 2771</span></a><span style="color: #f3f3f3;">). 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. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjOrt66wNQ3BUYSWPs5tYJO0A-vJuDDcQgvLjMkRjtyLd-JUwWwUJzXSb7gdBd2VzvEF_nONpPhaOUrjmxUwSi_3gl4vq_6Al_AgUwf0ph3Zu-hLV56FnBsOE4zuhzgLvbuA-65iUSN0is/" style="margin-left: 1em; margin-right: 1em;"><span style="color: #f3f3f3;"><img alt="" data-original-height="982" data-original-width="1426" height="220" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjOrt66wNQ3BUYSWPs5tYJO0A-vJuDDcQgvLjMkRjtyLd-JUwWwUJzXSb7gdBd2VzvEF_nONpPhaOUrjmxUwSi_3gl4vq_6Al_AgUwf0ph3Zu-hLV56FnBsOE4zuhzgLvbuA-65iUSN0is/" width="320" /></span></a></div><div class="separator" style="clear: both; text-align: center;"><span style="color: #f3f3f3;"><br /></span></div><p></p><p class="MsoNormal" style="-webkit-text-stroke-width: 0px; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; font-style: normal; font-variant-caps: normal; font-weight: normal; letter-spacing: normal; line-height: 15.693333625793457px; margin: 0in; text-align: start; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><span style="color: #f3f3f3;">Here is the key points of their report:<o:p></o:p></span></p><div class="separator" style="clear: both; text-align: center;"><style class="WebKit-mso-list-quirks-style">
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</style><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in; text-align: start;"><o:p><span style="color: #f3f3f3;"> </span></o:p></p><p class="MsoListParagraphCxSpFirst" style="text-indent: -0.25in;"><!--[if !supportLists]--><span style="color: #f3f3f3;"><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->Unexpected outcome was obtained under the condition of constant potential reaction mode– reference electrode ON–alternating polarity ON.<o:p></o:p></span></p><p class="MsoListParagraphCxSpMiddle" style="text-indent: -0.25in;"><!--[if !supportLists]--><span style="color: #f3f3f3;"><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->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.<o:p></o:p></span></p><p class="MsoListParagraphCxSpMiddle" style="text-indent: -0.25in;"><!--[if !supportLists]--><span style="color: #f3f3f3;"><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->This asymmetric current distribution affected electrochemical reaction, resulting in unexpected product selectivity change.<o:p></o:p></span></p><p class="MsoListParagraphCxSpLast" style="margin-bottom: 0in; mso-add-space: auto; mso-list: l0 level1 lfo1; text-indent: -.25in;"><!--[if !supportLists]--><span style="color: #f3f3f3;"><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;">·<span style="font-family: "Times New Roman"; font-size: 7pt; font-stretch: normal; line-height: normal;"> </span></span><!--[endif]-->Therefore, ElectraSyn 2.0 might have an engineering concern. <o:p></o:p></span></p><p class="MsoListParagraphCxSpLast" style="margin-bottom: 0in; mso-add-space: auto; mso-list: l0 level1 lfo1; text-indent: -.25in;"><span style="color: #f3f3f3;"><br /></span></p><p class="MsoNormal" style="-webkit-text-stroke-width: 0px; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; font-style: normal; font-variant-caps: normal; font-weight: normal; letter-spacing: normal; line-height: 15.693333625793457px; margin: 0in; text-align: start; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><b><span style="color: #f3f3f3;">Summary of IKA investigation<o:p></o:p></span></b></p><p class="MsoNormal" style="-webkit-text-stroke-width: 0px; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; font-style: normal; font-variant-caps: normal; font-weight: normal; letter-spacing: normal; line-height: 15.693333625793457px; margin: 0in; text-align: start; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><b><o:p><span style="color: #f3f3f3;"> </span></o:p></b></p><p class="MsoNormal" style="-webkit-text-stroke-width: 0px; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; font-style: normal; font-variant-caps: normal; font-weight: normal; letter-spacing: normal; line-height: 15.693333625793457px; margin: 0in; text-align: start; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><span style="color: #f3f3f3;">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 <b>Detail of our investigation</b><span> in this document</span>. Here we would like to provide a summary of our investigation. <o:p></o:p></span></p><p class="MsoListParagraphCxSpFirst" style="margin-bottom: 0in; mso-add-space: auto; mso-list: l0 level1 lfo1; text-indent: -.25in;"><!--[if !supportLists]--><span style="color: #f3f3f3;"><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;"><span style="mso-list: Ignore;">·<span style="font: 7.0pt "Times New Roman";"> </span></span></span><!--[endif]-->We verified asymmetric current distribution in the same setting described in the report (constant voltage–reference electrode ON–alternating polarity ON).<o:p></o:p></span></p><p class="MsoListParagraphCxSpMiddle" style="margin-bottom: 0in; mso-add-space: auto; mso-list: l0 level1 lfo1; text-indent: -.25in;"><!--[if !supportLists]--><span style="color: #f3f3f3;"><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;"><span style="mso-list: Ignore;">·<span style="font: 7.0pt "Times New Roman";"> </span></span></span><!--[endif]-->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. <o:p></o:p></span></p><p class="MsoListParagraphCxSpMiddle" style="margin-bottom: 0in; mso-add-space: auto; mso-list: l0 level1 lfo1; text-indent: -.25in;"><!--[if !supportLists]--><span style="color: #f3f3f3;"><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;"><span style="mso-list: Ignore;">·<span style="font: 7.0pt "Times New Roman";"> </span></span></span><!--[endif]-->This is simply originated from how voltage is controlled in ElectraSyn 2.0. <o:p></o:p></span></p><p class="MsoListParagraphCxSpLast" style="margin-bottom: 0in; mso-add-space: auto; mso-list: l0 level1 lfo1; text-indent: -.25in;"><!--[if !supportLists]--><span style="color: #f3f3f3;"><span style="font-family: Symbol; mso-bidi-font-family: Symbol; mso-fareast-font-family: Symbol;"><span style="mso-list: Ignore;">·<span style="font: 7.0pt "Times New Roman";"> </span></span></span><!--[endif]-->Accordingly, ElectraSyn 2.0 does not have engineering concern.<o:p></o:p></span></p><p class="MsoNormal" style="-webkit-text-stroke-width: 0px; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; font-style: normal; font-variant-caps: normal; font-weight: normal; letter-spacing: normal; line-height: 15.693333625793457px; margin: 0in; text-align: start; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><b><o:p><span style="color: #f3f3f3;"> </span></o:p></b></p><p class="MsoNormal" style="-webkit-text-stroke-width: 0px; caret-color: rgb(0, 0, 0); font-family: Calibri, sans-serif; font-size: 11pt; font-style: normal; font-variant-caps: normal; font-weight: normal; letter-spacing: normal; line-height: 15.693333625793457px; margin: 0in; text-align: start; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><b><span style="color: #f3f3f3;">Software update<o:p></o:p></span></b></p><p class="MsoListParagraphCxSpLast" style="margin-bottom: 0in; mso-add-space: auto; mso-list: l0 level1 lfo1; text-indent: -.25in;"><style class="WebKit-mso-list-quirks-style">
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</style></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in; text-align: start;"><span style="color: #f3f3f3;">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). <o:p></o:p></span></p></div><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"><span style="color: #f3f3f3;"><br /><o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjN8tMzfiV0nRrYoQjry5dd5jfmAEQCX1bHBixGRbX6B4AZjuOVl3tLhxfYH_FVTYTqT0f49SxHOH7we9hMG5gAvoUp7nSNx5zSDvw__q0xmrO4ZHoe3hkzIvgfxuyKZkUcU862zYp_aEo/" style="margin-left: 1em; margin-right: 1em;"><span style="color: #f3f3f3;"><img alt="" data-original-height="680" data-original-width="1676" height="260" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjN8tMzfiV0nRrYoQjry5dd5jfmAEQCX1bHBixGRbX6B4AZjuOVl3tLhxfYH_FVTYTqT0f49SxHOH7we9hMG5gAvoUp7nSNx5zSDvw__q0xmrO4ZHoe3hkzIvgfxuyKZkUcU862zYp_aEo/w640-h260/Screen+Shot+2021-04-15+at+12.44.00+PM.png" width="640" /></span></a></div><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhAACzk8qv31ZcYeZP0Q4pmRKe9ydjwM5Tnhha7PihfnUOlqKeoPyUjfZv038vXOKIgXM74AyXcDu4i8BEvq7MhsdV1M9zPQypTEDTLZg3XF61cnyC_Bexl3QTwszEk_W31-T6-6HHxwEA/" style="margin-left: 1em; margin-right: 1em;"><span style="color: #f3f3f3;"><img alt="" data-original-height="618" data-original-width="754" height="328" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhAACzk8qv31ZcYeZP0Q4pmRKe9ydjwM5Tnhha7PihfnUOlqKeoPyUjfZv038vXOKIgXM74AyXcDu4i8BEvq7MhsdV1M9zPQypTEDTLZg3XF61cnyC_Bexl3QTwszEk_W31-T6-6HHxwEA/w400-h328/Screen+Shot+2021-04-15+at+12.45.23+PM.png" width="400" /></span></a></div><span style="color: #f3f3f3;"><br /></span><p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><b><span style="color: #f3f3f3;">When this setting change is needed<o:p></o:p></span></b></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><o:p><span style="color: #f3f3f3;"> </span></o:p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">A user needs to enable this function only when Constant Voltage reaction mode with Reference Electrode ON and Alternating Polarity ON <o:p></o:p></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><o:p><span style="color: #f3f3f3;"> </span></o:p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><b><span style="color: #f3f3f3;">Effect on past research <o:p></o:p></span></b></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><o:p><span style="color: #f3f3f3;"> </span></o:p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">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.<o:p></o:p></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in; text-align: justify;"><span style="color: #f3f3f3;"><br /><br /></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><b><span style="color: #f3f3f3;">Detail of our investigation <o:p></o:p></span></b></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><b><span style="color: #f3f3f3;"> </span></b></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">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. <o:p></o:p></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><o:p><span style="color: #f3f3f3;"> </span></o:p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">The recent report by the Reid group described a mechanistic study in synthetic organic electrochemical method development with the use of ElectraSyn 2.0 (<i>ChemElectroChem</i> <b>2020</b>, 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.<o:p></o:p></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><o:p><span style="color: #f3f3f3;"> </span></o:p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">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.<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"><span style="color: #f3f3f3;"><br /></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEivi71oDIeiYjNJVYZo9BxYXS5f4ZJ3BXfkGb5Lzw5EoNxH_kz-7hVrX98VoFSpf4AOLkrBk9Wiu9PWj9n5jRZdiZs1NjLmPsLM6I0HuzmX030CkjwPChWbVZlsaPKBHKmDyjX8G0PxZrY/" style="margin-left: 1em; margin-right: 1em;"><span style="color: #f3f3f3;"><img alt="" data-original-height="986" data-original-width="1806" height="350" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEivi71oDIeiYjNJVYZo9BxYXS5f4ZJ3BXfkGb5Lzw5EoNxH_kz-7hVrX98VoFSpf4AOLkrBk9Wiu9PWj9n5jRZdiZs1NjLmPsLM6I0HuzmX030CkjwPChWbVZlsaPKBHKmDyjX8G0PxZrY/w640-h350/Screen+Shot+2021-04-15+at+12.46.44+PM.png" width="640" /></span></a></div><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"><span style="color: #f3f3f3;"><br /></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">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.<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"><span style="color: #f3f3f3;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"><span style="color: #f3f3f3;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi5yzE9RZo5jmK6JYQYzEOeoUw7abxcO0yZBqSsyAA4xEvrr2W5k0hn06NTIwRGL5XrFIAPTF8FsmyZGxm-vB37YddVBDGLJdNShuJNJ77B-U2op6i6skdiPT3PoG2XuWTLOMicCFXA9Eg/" style="margin-left: 1em; margin-right: 1em;"><span style="color: #f3f3f3;"><img alt="" data-original-height="1300" data-original-width="1806" height="460" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi5yzE9RZo5jmK6JYQYzEOeoUw7abxcO0yZBqSsyAA4xEvrr2W5k0hn06NTIwRGL5XrFIAPTF8FsmyZGxm-vB37YddVBDGLJdNShuJNJ77B-U2op6i6skdiPT3PoG2XuWTLOMicCFXA9Eg/w640-h460/Screen+Shot+2021-04-15+at+12.47.28+PM.png" width="640" /></span></a></div><span style="color: #f3f3f3;"><br /></span><p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">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.<o:p></o:p></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><o:p><span style="color: #f3f3f3;"> </span></o:p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">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.<o:p></o:p></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><o:p><span style="color: #f3f3f3;"> </span></o:p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">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.<b> </b><u>It turned out that the varied cell potential was caused by the way ElectraSyn 2.0 controls voltage against the reference electrode.</u><o:p></o:p></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><o:p><span style="color: #f3f3f3;"> </span></o:p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><i><span style="color: #f3f3f3;">Method of voltage control<o:p></o:p></span></i></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><b><span style="color: #f3f3f3;"> </span></b></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in; text-align: justify;"><span style="color: #f3f3f3;"><span style="font-size: 11pt; line-height: 15.693333625793457px; text-align: start;">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. </span><span style="font-family: -webkit-standard; font-size: medium; text-align: start;"></span></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in; text-align: justify;"><span style="font-size: 11pt; line-height: 15.693333625793457px; text-align: start;"><span style="color: #f3f3f3;"><br /></span></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in; text-align: justify;"><span style="font-size: 11pt; line-height: 15.693333625793457px; text-align: start;"><span style="color: #f3f3f3;"></span></span></p><div class="separator" style="clear: both; text-align: center;"><span style="color: #f3f3f3;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg9XreVBAZIl-5IXAIwDy-o8oNfGShUCi1SoXds6Ekn_-hiLSoLgdFrfv6WqxYgQfyb7BLZWzyqfS9QHmQK54bAcyNAtQ8U0abpBGfHxvbCCyQbzeXwPyp0NKM-X9DbV_drtfcL58jobDA/" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="1592" data-original-width="1690" height="602" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg9XreVBAZIl-5IXAIwDy-o8oNfGShUCi1SoXds6Ekn_-hiLSoLgdFrfv6WqxYgQfyb7BLZWzyqfS9QHmQK54bAcyNAtQ8U0abpBGfHxvbCCyQbzeXwPyp0NKM-X9DbV_drtfcL58jobDA/w640-h602/Screen+Shot+2021-04-15+at+12.48.15+PM.png" width="640" /></a></span></div><span style="color: #f3f3f3;"><br /></span><p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">However, WE and CE do not necessarily indicate anode and cathode in electrolysis. <u>WE can be both anode and cathode</u>. 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.</span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgs48ewL0Niw6TA-1qAES1d4L2Ac8Pt_5IF9GdLckN-BGmdC5vdZbzHs3QTVdrm7qnhoGyk4OXn7dnw_OU-N5s-XefCB0uT2lWMkQmQVDuKI-ffuQSChrJlFc58NW6m7cV7Ev6OMTXb3wE/" style="margin-left: 1em; margin-right: 1em;"><span style="color: #f3f3f3;"><img alt="" data-original-height="914" data-original-width="1746" height="336" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgs48ewL0Niw6TA-1qAES1d4L2Ac8Pt_5IF9GdLckN-BGmdC5vdZbzHs3QTVdrm7qnhoGyk4OXn7dnw_OU-N5s-XefCB0uT2lWMkQmQVDuKI-ffuQSChrJlFc58NW6m7cV7Ev6OMTXb3wE/w640-h336/Screen+Shot+2021-04-15+at+12.48.58+PM.png" width="640" /></span></a></div><span style="color: #f3f3f3;"><br /><o:p></o:p></span><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"><span style="color: #f3f3f3;"><br /></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">On the other hand, if -1.2 V is applied, WE will play the role of cathode.</span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEic0n5L3MCtPFnrO2-xeSIZLfVP5sSAGbcypGT12l87A78P88VUXAcOOi7b49zEjIe1l8v-dgn2RaJ2CLh4N-7uN1jLJ8OkqZlZWdJifSto7vdMkVN_b6lcPCCcj5u4GEjaugj2_4OyxmA/" style="margin-left: 1em; margin-right: 1em;"><span style="color: #f3f3f3;"><img alt="" data-original-height="722" data-original-width="840" height="344" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEic0n5L3MCtPFnrO2-xeSIZLfVP5sSAGbcypGT12l87A78P88VUXAcOOi7b49zEjIe1l8v-dgn2RaJ2CLh4N-7uN1jLJ8OkqZlZWdJifSto7vdMkVN_b6lcPCCcj5u4GEjaugj2_4OyxmA/w400-h344/Screen+Shot+2021-04-15+at+12.49.24+PM.png" width="400" /></span></a></div><span style="color: #f3f3f3;"><br /><o:p></o:p></span><p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><i><span style="color: #f3f3f3;">Alternating polarity<o:p></o:p></span></i></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><o:p><span style="color: #f3f3f3;"> </span></o:p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">During alternating polarity, what is expected is <u>the cycle of applying +1.2 V between WE and RE, and then +1.2V between CE and RE.</u></span></p><div class="separator" style="clear: both; text-align: center;"><span style="color: #f3f3f3;"><u><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjXEl6VkMEc94qqe9Ee1AinzqaiACb9e1Dc-TLgcL58VBMrJ0X4MELiayMHzrP-EKHJ8JMcGM5UneLXJ3EruHINes1T8aKx2vkNYkYJDhAuNn1j2ulb1Pr9DuqXdA2TPbVcXW3-O3oxmuI/" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="1366" data-original-width="1610" height="339" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjXEl6VkMEc94qqe9Ee1AinzqaiACb9e1Dc-TLgcL58VBMrJ0X4MELiayMHzrP-EKHJ8JMcGM5UneLXJ3EruHINes1T8aKx2vkNYkYJDhAuNn1j2ulb1Pr9DuqXdA2TPbVcXW3-O3oxmuI/w400-h339/Screen+Shot+2021-04-15+at+12.49.52+PM.png" width="400" /></a></u></span></div><div class="separator" style="clear: both; text-align: center;"><span style="color: #f3f3f3;"><u><br /></u></span></div><p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">However, in the current ElectraSyn 2.0 software, <u>the voltage control remains between WE and RE during the entire period</u>. This means that applying -1.2V between WE and RE may induce completely different reaction, resulting in the observed asymmetric current behavior. <o:p></o:p></span></p><div class="separator" style="clear: both; text-align: center;"><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in; text-align: start;"><span style="color: #f3f3f3;">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.<o:p></o:p></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in; text-align: start;"><o:p><span style="color: #f3f3f3;"> </span></o:p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in; text-align: start;"><i><span style="color: #f3f3f3;">Software update<o:p></o:p></span></i></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in; text-align: start;"><b><span style="color: #f3f3f3;"> </span></b></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in; text-align: start;"><span style="color: #f3f3f3;">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).<o:p></o:p></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in; text-align: start;"><o:p><span style="color: #f3f3f3;"> </span></o:p></p><div class="separator" style="clear: both; text-align: center;"><span style="color: #f3f3f3;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg-rqCEgpwLJ2b-Z8MCEerLv8gPcX8SnfniCHAkv6AJSjBcFyW5tarTLP4s8Wxx03yLHl26c7rqH8Nectk8rzKtEj_mFz_PEJMgn8l1ufdOiWQzr18MosKvbeECyP5IwUGDMRelq3LYLuU/" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="1402" data-original-width="1786" height="502" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg-rqCEgpwLJ2b-Z8MCEerLv8gPcX8SnfniCHAkv6AJSjBcFyW5tarTLP4s8Wxx03yLHl26c7rqH8Nectk8rzKtEj_mFz_PEJMgn8l1ufdOiWQzr18MosKvbeECyP5IwUGDMRelq3LYLuU/w640-h502/Screen+Shot+2021-04-15+at+12.50.24+PM.png" width="640" /></a></span></div><span style="color: #f3f3f3;"><br /></span><p></p></div><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;"><u><br /></u><o:p></o:p></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">The new software version was validated by using following test. In the first test, the solution containing 0.114 M Bu<sub>4</sub>NClO<sub>4</sub> 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 <b>Figure 15</b>.). When the setting is changed as illustrated above, totally symmetric current was observed (orange circle).</span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhtonXzDwlWeY7KxSmbls6HN5g99Hai_b0YBZA7vv4Mee85XktFQhBDIlCGBmCQKejfiRgUApktr4P-keaKK3JsdkPq-0Iz3LZigyCkzRFT5eCL7VN3Q7rr5h0X93TTPyyzGoG9huwCOzE/" style="margin-left: 1em; margin-right: 1em;"><span style="color: #f3f3f3;"><img alt="" data-original-height="1182" data-original-width="1784" height="424" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhtonXzDwlWeY7KxSmbls6HN5g99Hai_b0YBZA7vv4Mee85XktFQhBDIlCGBmCQKejfiRgUApktr4P-keaKK3JsdkPq-0Iz3LZigyCkzRFT5eCL7VN3Q7rr5h0X93TTPyyzGoG9huwCOzE/w640-h424/Screen+Shot+2021-04-15+at+12.50.59+PM.png" width="640" /></span></a></div><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"><span style="color: #f3f3f3;"><br /><br /></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">This test was conducted with another solution, verifying symmetric current behavior in this case as well. <o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"><span style="color: #f3f3f3;"><br /></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgGgMErOTX3Kb9NlOMxQgfPwYeVMeDGPxqTTTZmN-FzblwbEeYSHO0sn8VjjfkKlwBXN9nzeeYbpFm8z9JgD3GHjzwByb2a6fN1kk8kLmWxGKKp08vBNc6zwOGv1Dq4kfv49m0n0u5xfGY/" style="margin-left: 1em; margin-right: 1em;"><span style="color: #f3f3f3;"><img alt="" data-original-height="1146" data-original-width="1740" height="422" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgGgMErOTX3Kb9NlOMxQgfPwYeVMeDGPxqTTTZmN-FzblwbEeYSHO0sn8VjjfkKlwBXN9nzeeYbpFm8z9JgD3GHjzwByb2a6fN1kk8kLmWxGKKp08vBNc6zwOGv1Dq4kfv49m0n0u5xfGY/w640-h422/Screen+Shot+2021-04-15+at+12.51.30+PM.png" width="640" /></span></a></div><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"><span style="color: #f3f3f3;"><br /></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">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.<o:p></o:p></span></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><o:p><span style="color: #f3f3f3;"> </span></o:p></p><p class="MsoNormal" style="line-height: 15.693333625793457px; margin-bottom: 0in;"><span style="color: #f3f3f3;">We thank Dr. Marc Reid, his colleagues, and all our users for supporting ElectraSyn 2.0 and providing valuable feedback.<o:p></o:p></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"><span style="color: #f3f3f3;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"><span style="color: #f3f3f3;"><br /></span></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; font-size: 11pt; line-height: 15.693333625793457px; margin: 0in; text-align: justify;"><br /></p>BaranLabhttp://www.blogger.com/profile/01806245988209508968noreply@blogger.com0tag:blogger.com,1999:blog-51846086760422068.post-71956722444500569952020-10-05T15:44:00.000-07:002020-10-05T15:44:03.334-07:00Adventures in P(V) Chemistry<p><span style="font-family: helvetica; font-size: large;"><span face="Calibri, sans-serif" style="text-align: justify;"><span style="color: #eeeeee;">Our two recent P(V)-based projects that were just published in </span><a href="https://pubs.acs.org/doi/10.1021/jacs.0c05595"><span style="color: #04ff00;">JACS</span></a><span style="color: #eeeeee;"> and </span><a href="https://pubs.acs.org/doi/abs/10.1021/acscentsci.0c00680"><span style="color: #04ff00;">ACS Central Science</span></a><span style="color: #eeeeee;"> were a lesson of teamwork and sometimes “serendipity” that we would like to describe in the following blogpost.</span></span><span face="Calibri, sans-serif" style="color: #eeeeee; text-align: justify;"> </span></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh8qU0-tKtI3Rh25j_8bYkxVIbQ8dunkh6S2nY19pePY229A-Q3rRpBsBDc0N50XNkjbssNmPivza9WKjbEKQ6IuM5X5cAfvbKsck9B0uRT1_n8VhhrdWK3o5V_c7K80cozboBEHWoIN08/s2562/Screen+Shot+2020-10-05+at+7.18.50+AM.png" style="margin-left: 1em; margin-right: 1em;"><span style="color: #eeeeee; font-family: helvetica; font-size: large;"><img border="0" data-original-height="458" data-original-width="2562" height="114" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh8qU0-tKtI3Rh25j_8bYkxVIbQ8dunkh6S2nY19pePY229A-Q3rRpBsBDc0N50XNkjbssNmPivza9WKjbEKQ6IuM5X5cAfvbKsck9B0uRT1_n8VhhrdWK3o5V_c7K80cozboBEHWoIN08/w640-h114/Screen+Shot+2020-10-05+at+7.18.50+AM.png" width="640" /></span></a></div><span style="color: #eeeeee; font-family: helvetica; font-size: large;"><span face="Calibri, sans-serif">Having worked on the P(V) reagent platform since its inception, I have spent a considerable amount of time sitting in front of the <b>only</b> NMR spectrometer at Scripps capable of detecting the <sup>31</sup>P 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 <br /></span><span face="Calibri, sans-serif" style="text-align: justify;"><br /><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhPcp5xx0wES577UUq1jidNYKZkOv6i72v2X40S0IKgLb-VXy0XQ5ykY-D6S2w-CxRE4-loW5nVO8V12-ZBMvds3MuMA7xDxI4GAKO7TJA_Zf0EroOR28QzsigpdVbeX7bBcG_SQTC5w1w/s2048/Screen+Shot+2020-10-05+at+7.19.03+AM.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1429" data-original-width="2048" height="446" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhPcp5xx0wES577UUq1jidNYKZkOv6i72v2X40S0IKgLb-VXy0XQ5ykY-D6S2w-CxRE4-loW5nVO8V12-ZBMvds3MuMA7xDxI4GAKO7TJA_Zf0EroOR28QzsigpdVbeX7bBcG_SQTC5w1w/w640-h446/Screen+Shot+2020-10-05+at+7.19.03+AM.png" width="640" /></a></div></span></span><p></p><p class="MsoNormal" style="margin: 0in; text-align: justify;"><span style="color: #eeeeee; font-family: helvetica; font-size: large;">lab to the Molecular Biology building where one of our NMR labs is. You begin by leaving the 4<sup>th</sup> 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 <sup>31</sup>P 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. </span></p><p><span style="color: #eeeeee; font-family: helvetica; font-size: large; text-align: justify;"></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhlwZgtfYhhYg61_A1KyWrRSh6_ukBjkQKJk0qzKk3z_RUsqxgwbgwX9Usgq8rjsxX5caM1EO4PpCmS5Evoiv1Hhh9Jb1Z9-xRu2VCq2SQ0K74qfRjc401a8VTcBeGZDaHVfP3nq-bc3JQ/s1794/Screen+Shot+2020-10-05+at+7.19.11+AM.png" style="margin-left: 1em; margin-right: 1em;"><span style="color: #eeeeee; font-family: helvetica; font-size: large;"><img border="0" data-original-height="920" data-original-width="1794" height="328" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhlwZgtfYhhYg61_A1KyWrRSh6_ukBjkQKJk0qzKk3z_RUsqxgwbgwX9Usgq8rjsxX5caM1EO4PpCmS5Evoiv1Hhh9Jb1Z9-xRu2VCq2SQ0K74qfRjc401a8VTcBeGZDaHVfP3nq-bc3JQ/w640-h328/Screen+Shot+2020-10-05+at+7.19.11+AM.png" width="640" /></span></a></div><p></p><p class="MsoNormal" style="margin: 0in; text-align: justify;"><span style="font-family: helvetica; font-size: large;"><span style="color: #eeeeee;">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 </span><a href="https://pubs.acs.org/doi/10.1021/acs.biochem.7b00536"><span style="color: #04ff00;">chart below</span></a><span style="color: #eeeeee;">.</span></span></p><p><span style="color: #eeeeee; font-family: helvetica; font-size: large; text-align: justify;"></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhP0AF2mjAZd7DwFeTQ8WavkWQwNfIwyrWpzoUUWcvTjWxgUUTkf05k96G0VgNR_iLkYuhJgjioN0DVa759XUl7aDNNUFeYES7ofy6zLMwtpH8FtT2vsTDH9k7zv3hoYmV1QzxvQSsYlxw/s2136/Screen+Shot+2020-10-05+at+7.19.18+AM.png" style="margin-left: 1em; margin-right: 1em;"><span style="color: #eeeeee; font-family: helvetica; font-size: large;"><img border="0" data-original-height="804" data-original-width="2136" height="240" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhP0AF2mjAZd7DwFeTQ8WavkWQwNfIwyrWpzoUUWcvTjWxgUUTkf05k96G0VgNR_iLkYuhJgjioN0DVa759XUl7aDNNUFeYES7ofy6zLMwtpH8FtT2vsTDH9k7zv3hoYmV1QzxvQSsYlxw/w640-h240/Screen+Shot+2020-10-05+at+7.19.18+AM.png" width="640" /></span></a></div><div class="separator" style="clear: both; text-align: justify;"><span style="font-family: helvetica; font-size: large;"><span style="text-align: start;"><span style="color: #eeeeee;">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, </span><a href="https://gbernardeslab.com"><span style="color: #04ff00;">Prof. Bernardes</span></a><span style="color: #eeeeee;"> 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 </span><sup style="color: #eeeeee;">31</sup><span style="color: #eeeeee;">P NMR (</span><sup style="color: #eeeeee;">1</sup><span style="color: #eeeeee;">H 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.</span></span><span face="-webkit-standard" style="color: #eeeeee; text-align: start;"></span></span></div><span style="color: #eeeeee; font-family: helvetica; font-size: large;"><br /></span><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgV59o-y9i9zbTq4hROvLBK8_ODGJ_vy9y24NyuhwTAO2ZxmzIG_nNTJ1iM-IP7y9j0EqCYOVSeZ8SrKUJC4W-kqKLzur01cgqt19XiQ_hCdICILeYH90BqS-onek_LogokwbFpeah63CY/s2048/Screen+Shot+2020-10-05+at+7.19.32+AM.png" style="margin-left: 1em; margin-right: 1em;"><span style="color: #eeeeee; font-family: helvetica; font-size: large;"><img border="0" data-original-height="1284" data-original-width="2048" height="402" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgV59o-y9i9zbTq4hROvLBK8_ODGJ_vy9y24NyuhwTAO2ZxmzIG_nNTJ1iM-IP7y9j0EqCYOVSeZ8SrKUJC4W-kqKLzur01cgqt19XiQ_hCdICILeYH90BqS-onek_LogokwbFpeah63CY/w640-h402/Screen+Shot+2020-10-05+at+7.19.32+AM.png" width="640" /></span></a></div><span style="color: #eeeeee; font-family: helvetica; font-size: large;"><br /></span><div class="separator" style="clear: both; text-align: center;"><span style="color: #eeeeee; font-family: helvetica; font-size: x-large; text-align: justify;"><br /></span></div><div class="separator" style="clear: both; text-align: left;"><span style="font-family: helvetica; font-size: x-large; text-align: justify;"><span style="color: #eeeeee;">Another great application of the P(V)-platform has been its association to RASS (developed by the </span><a href="https://dawsonlabscripps.wordpress.com"><span style="color: #04ff00;">Dawson lab</span></a><span style="color: #eeeeee;">) 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! </span></span></div><div class="separator" style="clear: both; text-align: center;"><p class="MsoNormal" style="margin: 0in; text-align: justify;"><o:p><span style="color: #eeeeee; font-family: helvetica; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in; text-align: justify;"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiVizwDuchat_oNvsk9WpFr23QhOuPZTZkR5h50dc225DegqjXPuf-J6hUKxxeqesp_IvAZFkaDtf0HufqptAARvWAhtNkNFnWmd88MaMj3IdOE8y149nvXQyhxYeuL0TI0jljKoe5kXX0/s2000/Screen+Shot+2020-10-05+at+9.34.12+AM.png" style="margin-left: 1em; margin-right: 1em;"><span style="color: #eeeeee; font-family: helvetica; font-size: large;"><img border="0" data-original-height="364" data-original-width="2000" height="116" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiVizwDuchat_oNvsk9WpFr23QhOuPZTZkR5h50dc225DegqjXPuf-J6hUKxxeqesp_IvAZFkaDtf0HufqptAARvWAhtNkNFnWmd88MaMj3IdOE8y149nvXQyhxYeuL0TI0jljKoe5kXX0/w640-h116/Screen+Shot+2020-10-05+at+9.34.12+AM.png" width="640" /></span></a></div><span style="color: #eeeeee; font-family: helvetica; font-size: large;"><br /></span><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiIJSdos4uvNA2jiaLh1Bf2A2wG_3fFAsyaKmGyvM2ve-mgfBrml1hBHL1jfXNrxZvftFiEa20GvmrSgyp69Vi5UcMbaQpTrJN9ax6XkabJrxVS2jEkfYVjv1Y0XvFfLTDPni2f9ixDUFY/s1980/Screen+Shot+2020-10-05+at+9.34.20+AM.png" style="margin-left: 1em; margin-right: 1em;"><span style="color: #eeeeee; font-family: helvetica; font-size: large;"><img border="0" data-original-height="362" data-original-width="1980" height="118" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiIJSdos4uvNA2jiaLh1Bf2A2wG_3fFAsyaKmGyvM2ve-mgfBrml1hBHL1jfXNrxZvftFiEa20GvmrSgyp69Vi5UcMbaQpTrJN9ax6XkabJrxVS2jEkfYVjv1Y0XvFfLTDPni2f9ixDUFY/w640-h118/Screen+Shot+2020-10-05+at+9.34.20+AM.png" width="640" /></span></a></div><p></p><p class="MsoNormal" style="margin: 0in; text-align: justify;"><span style="color: #eeeeee; font-family: helvetica; font-size: large;">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.<o:p></o:p></span></p><p class="MsoNormal" style="margin: 0in; text-align: start;"><o:p><span style="color: #eeeeee; font-family: helvetica; font-size: large;"> </span></o:p></p><p class="MsoNormal" style="margin: 0in; text-align: start;"><span style="color: #eeeeee; font-family: helvetica; font-size: large;">-Kyle and the P(V) team <o:p></o:p></span></p></div><p><span style="color: #eeeeee; font-family: helvetica; font-size: large; text-align: justify;"></span></p><div class="separator" style="clear: both; text-align: center;"><span style="color: #eeeeee; font-family: helvetica; font-size: large;"><br /></span></div><div class="separator" style="clear: both; text-align: center;"><span style="color: #eeeeee; font-family: helvetica; font-size: large;"><br /></span></div><br /><p></p><p class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify;"><o:p></o:p></p>BaranLabhttp://www.blogger.com/profile/01806245988209508968noreply@blogger.com1tag:blogger.com,1999:blog-51846086760422068.post-69125772116349048562020-07-20T07:44:00.002-07:002020-07-20T09:49:39.275-07:00Tagetitoxin: Total Synthesis with Friends<div class="MsoNormal" style="font-family: Calibri, sans-serif; margin: 0in; text-align: justify;">
<span style="color: #f3f3f3; font-size: large;"><span style="color: #f3f3f3;">Our recently completed synthesis of tagetitoxin was just </span><a href="https://bit.ly/32CQpqI" target="_blank"><span style="color: lime;">published in JACS</span></a><span style="color: #f3f3f3;">. I think it’s safe to say that this work is unlike anything we’ve done before in our lab. This is true not only from the standpoint of the chemical problems presented to us (see the paper, the SI, and some of the stories below), but also from a team standpoint, for everyone on this project is actually very good friends, both in and out of the lab. We therefore decided to use the space below for each friend on the team to write a little bit about their experience working with this beast of a natural product. </span><b style="color: #f3f3f3;">Warning: long blog post ahead!<o:p></o:p></b></span></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiBs9_Rr3FeuaCde7nOxG4-usTcuVPhkqptUeu3U8c-_McUAp0DX7TL6tDeU5dle0nX-_6w9UlTaOQVCKIqIwgc1yU4oVss3dQuJRM9GMFiPfvKhH7HUy1GSpLssDClvJz-yoKhMwNAAhg/s1600/Screen+Shot+2020-07-16+at+2.17.23+PM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><span style="color: #f3f3f3; font-size: large;"><img border="0" data-original-height="547" data-original-width="1600" height="109" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiBs9_Rr3FeuaCde7nOxG4-usTcuVPhkqptUeu3U8c-_McUAp0DX7TL6tDeU5dle0nX-_6w9UlTaOQVCKIqIwgc1yU4oVss3dQuJRM9GMFiPfvKhH7HUy1GSpLssDClvJz-yoKhMwNAAhg/s320/Screen+Shot+2020-07-16+at+2.17.23+PM.png" width="320" /></span></a></div>
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<span style="color: #f3f3f3; font-size: large;"><b>Hang Chu </b>(Oct. 2016 – May 2018)<o:p></o:p></span></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgABuRMGAqLk_S3dUcFmfPfQQy61pbPVDShX58XqUMPLTGzH7z46Cvm3tn4j3PWlOwrYbgTe2cYmdgpNAI7Y-n7gy3WQDKUlGjzHuFn2crDdL63ISU7m6B8S39swLoaL2VhR__YCumBFko/s1600/Screen+Shot+2020-07-16+at+2.17.31+PM.png" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><span style="color: #f3f3f3; font-size: large;"><img border="0" data-original-height="606" data-original-width="610" height="198" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgABuRMGAqLk_S3dUcFmfPfQQy61pbPVDShX58XqUMPLTGzH7z46Cvm3tn4j3PWlOwrYbgTe2cYmdgpNAI7Y-n7gy3WQDKUlGjzHuFn2crDdL63ISU7m6B8S39swLoaL2VhR__YCumBFko/s200/Screen+Shot+2020-07-16+at+2.17.31+PM.png" width="200" /></span></a></div>
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<span style="font-size: large;"><span style="color: #f3f3f3;">While searching for another molecule to pursue after the </span><a href="https://openflask.blogspot.com/2016/12/11-step-synthesis-of-thapsigargin.html" target="_blank"><span style="color: lime;">thapsigargins</span></a><span style="color: #f3f3f3;">, Phil sent me </span><a href="https://pubs.rsc.org/en/content/articlelanding/2016/ob/c5ob02076j#!divAbstract" target="_blank"><span style="color: lime;">Porter’s paper</span></a><span style="color: #f3f3f3;">, which disclosed the most recently revised structure of tagetitoxin (tgt) at the time. Having primarily worked on terpenes at that point in my Ph. D., tgt seemed like a suitable molecule. As I recall, I wanted to work with something that had a nitrogen or two. Tgt certainly satisfied that requirement. As a bonus, throw in some oxygens, sulfur and phosphorous. Sure, why not? <o:p></o:p></span></span></div>
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<span style="color: #f3f3f3; font-size: large;">One of the toughest challenges initially was coming up with a reasonable retrosynthetic analysis for tagetitoxin. While there were not that many logical ways to take apart the molecule, finding an efficient and creative strategy to build the densely functionalized cyclopentane posed a challenge. In the SI you’ll find the evolution of our strategy as problems arose, so I will not belabor an extensive explanation of our logic. Our initial retrosynthetic analysis is shown below. Long story short, we foresaw three distinct challenges at the start of the program: 1. Core construction, 2. Cyclopentane functionalization and 3. Cysteine incorporation. <o:p></o:p></span></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj_wGrHJ5FVh_SKA9PQQlm5G616_0H8aWh104PEAJiictSjs_07oxC89URMld76-hMGMnKNn0Kysp1LyqKsEo5j0a1I1WfmUYH1EukM7d6Aarb6TSYXSpBuYMWiztnE509EP1YOiUzfsIY/s1600/Screen+Shot+2020-07-16+at+2.18.08+PM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><span style="color: #f3f3f3; font-size: large;"><img border="0" data-original-height="750" data-original-width="1600" height="300" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj_wGrHJ5FVh_SKA9PQQlm5G616_0H8aWh104PEAJiictSjs_07oxC89URMld76-hMGMnKNn0Kysp1LyqKsEo5j0a1I1WfmUYH1EukM7d6Aarb6TSYXSpBuYMWiztnE509EP1YOiUzfsIY/s640/Screen+Shot+2020-07-16+at+2.18.08+PM.png" width="640" /></span></a></div>
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<span style="color: #f3f3f3; font-size: large;"> <span style="font-family: "calibri" , sans-serif;">While there were many interesting snippets of problem solving in the first generation synthesis as disclosed in the SI, I’ll focus the two key reactions I had the pleasure to work on – 1) the oxidative furan rearrangement and 2) the thio-Claisen (see David’s section).</span><span style="font-family: "calibri" , sans-serif;"> </span></span></div>
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<span style="color: #f3f3f3; font-size: large;">To the best of our knowledge, there was no direct way in the literature to construct this type of amino hydroxy substituted cyclopentenone at the time (about 4 years ago..time flies). As the scheme illustrates, we had considered a couple of other ways to build this unusual cyclopentenone (double Claisen from a symmetrical aldehyde surrogate or an aziridine opening). These approaches were plagued with stereochemical issues and potentially harsh reaction conditions. We focused in on the β-hydroxy cyclopentenone portion of this building block and recalled that the Piancatelli rearrangement was an effective sequence to access these types of structure. Adding in the remaining functionalities took us back to a furanyl amino ester intermediate, which required the introduction of an equivalent of oxygen to get to the desired oxidation state. The problem-solving sequence to get this reaction to work initial was disclosed in the SI. Long story short, a non-basic reductant (dimethyl sulfide) was critical for this highly sensitive reaction to work. It has been a number of years since the discovery of this sequence so I’m a little cloudy on the details. I do recall isolating a wide range different retro-aldol initiated products along with a number of colorful decompositions. Also the use of the trifluoroethyl ester was essential to promote 1) good stability of the amino ester starting material and 2) the formation of the desired enone.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;"><b>David Kossler </b>(Mar. 2018 – Jan. 2019)<o:p></o:p></span></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhv8dnrEwTt5Gmrky77ExwmC0hvICJj7CPq2Rogt0yiYQ0ewljQHxHsfOx3zqs9AkT-Fy5LWKNhFzI9diqM80TL2qGNvhdjVl1UXdHr5oA1fAyyAb-ucCWjfzT3SMHX3lBtHjtNH2xPVRg/s1600/Screen+Shot+2020-07-16+at+2.18.52+PM.png" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><span style="color: #f3f3f3; font-size: large;"><img border="0" data-original-height="600" data-original-width="596" height="200" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhv8dnrEwTt5Gmrky77ExwmC0hvICJj7CPq2Rogt0yiYQ0ewljQHxHsfOx3zqs9AkT-Fy5LWKNhFzI9diqM80TL2qGNvhdjVl1UXdHr5oA1fAyyAb-ucCWjfzT3SMHX3lBtHjtNH2xPVRg/s200/Screen+Shot+2020-07-16+at+2.18.52+PM.png" width="198" /></span></a><span style="color: #f3f3f3; font-size: large;">Since the synthesis of tagetitoxin was just published, I have the opportunity to reflect on my time as part of the team. After a short stint in the lab, working on method development, I joined Hang at the beginning of 2018. As we were office mates, I already had a sneak view on what was going on. By that time, he had found a neat way to build up the cyclopentane core <i>via</i> an oxidative furan rearrangement. As the stereoselective installation of the sulfur was problematic, he envisioned a relay <i>via</i> the allylic alcohol. It was clear from the beginning that this project was technically challenging in terms of sensitivity of the substrates, requiring careful adjustments of reaction conditions and workup procedures. Small deviations could lead to disastrous outcomes, and this happened. After we fixed a couple of issues in the first steps, the precursor for the [<i>3</i>,<i>3</i>]-rearrangement could be obtained in high purity. To our favor, once running the thio-CDI step in acetonitrile, the minor diastereomer from the Luche reduction reacted first with TCDI, and then cyclized intramolecularly, which made it easy to remove by column.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;"> <span style="font-family: "calibri" , sans-serif; text-align: justify;">Subsequently the rearrangement became a robust and clean transformation. This period was one of the most enjoyable, with both of us as a team trying to get as far as possible with the project. The dihydroxylation proved to be tricky as well, as the osmate cleavage led either to decomposition or protecting group swap without unveiling of the free alcohols. So we decided to install the sidearm first and then conduct the osmylation afterwards. All the details are in the comprehensive SI. Hang wrote his thesis alongside the lab work and graduated in mid-2018, upon which I continued with the project. Eventually, the free diol could be accessed, and the crystal structure confirmed the correct stereochemical alignment of all substituents. Big shout out at this point to the X-ray facility at UCSD, who perfectly resolved all structures I brought over during my postdoc, which was really helpful.</span><span style="font-family: "calibri" , sans-serif; text-align: justify;"> </span></span></div>
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<span style="color: #f3f3f3; font-size: large;">A special moment was the first assembly of tagetitoxin’s skeleton. When analyzing the crude NMR, and in between all signal peaks, locating a set of multiplets that made sense for what we were trying to synthesize. Moreover, the comparison with the reported coupling constants for the natural product matched beautifully. With the <i>trans</i>-6,5 bicycle in hand, this was also the first proper evaluation point to see that the structure proposed by Aliev and co-workers was indeed the correct one. If the <i>J</i>s would have not correlated at this stage, it would have raised a big question mark that we were following the real structure of tagetitoxin.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;"> <span style="font-family: "calibri" , sans-serif; text-align: justify;">But in synthesis, for every problem you solve, you directly have the next step ahead of you, with the additional hurdle to bring material even further to the frontline. At this stage of the project limited material throughput became a real concern and hampered the advancement tremendously. I spent time on having a first look into the phosphorylation and the enantioselectivity challenge, but at some point the end of my Postdoc approached and I decided to go back from San Diego to Europe to finally enjoy some rain. Phil decided to hand the project over to Chi and Tom, who were about to finish the Herqulines. In order to not lose valuable knowledge and gained experimental details in this transfer, I assembled all available data and infos. Finally, in my last weeks we ran through the sequence together once. From then on, this well-oiled machine went on to make to target. Over the course of the last year I could still follow the updates and see the project evolving, one obstacle after another being removed. Looking on the finished sequence, it’s great to see how everything fell into place after extensive experimentation and many learnt lessons. I have nothing but huge respect for the final team in this relay run.</span></span></div>
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<span style="color: #f3f3f3; font-size: large;"><b>Tom Stratton </b>(Jan. 2019 – Jun. 2020)<o:p></o:p></span></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjXL2E9NgOYh8flcrOclfZ8OeIBqHPnED-n898ffh_ybQ9PRJ45CD4_1o1GyfVyCkLPi0305JmKpCGrA_K4FcXUGK46mkzdOVFMOhwWPxHOJlkjVKpV25pvl_lCpjbtetkQBt3bvaCorME/s1600/Screen+Shot+2020-07-16+at+2.19.20+PM.png" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><span style="color: #f3f3f3; font-size: large;"><img border="0" data-original-height="596" data-original-width="592" height="200" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjXL2E9NgOYh8flcrOclfZ8OeIBqHPnED-n898ffh_ybQ9PRJ45CD4_1o1GyfVyCkLPi0305JmKpCGrA_K4FcXUGK46mkzdOVFMOhwWPxHOJlkjVKpV25pvl_lCpjbtetkQBt3bvaCorME/s200/Screen+Shot+2020-07-16+at+2.19.20+PM.png" width="198" /></span></a></div>
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<span style="font-size: large;"><span style="color: #f3f3f3;">Fresh from our recent </span><a href="https://openflask.blogspot.com/2018/12/simply-strained-total-synthesis-of.html" target="_blank"><span style="color: lime;">herquline</span></a><span style="color: #f3f3f3;"> victory lap, Chi and I were confident we would quickly shut the door on this project. We were dead wrong and spun our wheels for the better part of 18 months trying to understand what makes these molecules tick. I personally spent much of this time optimizing the key bromocyclization step, a reaction that will haunt me for the rest of my days. Since that story is (mostly) told in the SI, I will instead use this space to talk about how much I’ve learned from my good friends.</span></span></div>
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<span style="color: #f3f3f3; font-size: large;">When I was a (highly) clueless first year grad student, Hang took notice. Right when things were starting to get truly ugly, Hang swooped in like a mama bird, brought me to his nest in BCC-439, and fed me tidbits of knowledge directly from his chemistry beak on a daily basis. He was a true mentor to me then and now, and a is also really strong dude.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;">I was assigned to be David Kossler’s (or Herr Doktor… show some respect) “temporary lab buddy” when he first arrived at Scripps from Europe. Lucky for us, the exact time component of “temporary” is ill-defined, as we still share cold beers together to this day, albeit from across the pond. The fact that we got to overlap (for one week) on this project was incredible as I got to see David’s remarkable precision, organization, attention to detail, and sense of team work first hand. We were lucky to have the wealth of knowledge gained by Hang and David at our disposable, mostly to the incredible work of my temporary buddy. Prost!<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;">Kelly joined the project for a relatively short time, but in doing so, solved a problem that was a “non-starter” in terms of wrapping this project up. That is, stoichiometric osmium was required to effect dihydroxylation, and Kelly figured out the solution in literally a couple of weeks. This is no surprise. When Kelly was interviewing at Scripps, we recruited her <i>hard</i>. Not only did she possess several years of experience as a process chemist, she displayed the poise, focus, and kindness that is required to be a successful student and excellent teammate. Thus when my new hoodmate Kelly was recruited onto this project, Chi and I were absolutely elated and she stepped up to the plate big time. <o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;">Dillon M. Flood has saved my ass more than once. Whether it be stuck on a 50<sup>o </sup>sketchy left traverse at Big Sky, or at the outer reef of Teresa’s when my leash snapped and the waves were the size of a small cathedral, Dillon has been there to bail me out. Thus, it should be of no surprise that he rose to the occasion and contributed so much to this project in its final stages. We had intended to use a CRO to run the RNA polymerase assay, and when I asked Dillon for recommendations, he said “dude we just got a new plate reader and I can do this for you next week.” Having already showed Chi and I the ins and outs of anion exchange chromatography, he decided to bring his impact on this project to the next level. Sure enough, one week later he was sending us beautiful data depicting that (+)-tagetitoxin is the sole enantiomer active against <i>E. coli </i>RNAP. What a guy! I’ll see you up north, my friend.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;">There are simply no words that can describe how I feel about my partner Chi, but I’ll do my best. I doubt there is a more patient, humble, brilliant scientist out there than my friend Chi. Thank you for everything you have given me. I hope I have been able to return even a fraction of it. <o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;">Finally, Phil is the best mentor I could have ever asked for. I truly feel like I won the PI lottery. Phil has a passion for exploring the unknown that is contagious and these ideas transformed the way I have thought about solving problems in chemistry forever. <o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;"><b>Kelly Eberle </b>(Sep. 2019 – Jan. 2020)<o:p></o:p></span></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjbTHvchXm7h-oi4eYv0DEKFhw3yrIgk-Km25vKqyOrXlxyaRJFvFE6fe1CI4kNAZwrc5SV80liIi5gmXzODkId8D2vRqK0t57R6GITZ4jfnMFikPGBNpUxfW50N8UJIn3JL_BtAZF8IR8/s1600/Screen+Shot+2020-07-16+at+2.19.26+PM.png" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><span style="color: #f3f3f3; font-size: large;"><img border="0" data-original-height="590" data-original-width="590" height="200" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjbTHvchXm7h-oi4eYv0DEKFhw3yrIgk-Km25vKqyOrXlxyaRJFvFE6fe1CI4kNAZwrc5SV80liIi5gmXzODkId8D2vRqK0t57R6GITZ4jfnMFikPGBNpUxfW50N8UJIn3JL_BtAZF8IR8/s200/Screen+Shot+2020-07-16+at+2.19.26+PM.png" width="200" /></span></a><span style="color: #f3f3f3; font-size: large;">I certainly feel lucky to have started in the lab at a time when there was still work to be done on Tagetitoxin. I knew that I wanted to do total synthesis, was interested in alkaloids, and that ideally I would work on an existing project to ‘get my feet wet’. When Phil suggested I join this team it seemed like a perfect opportunity. As a first year who had worked in pharma before coming to grad school, I thought I would know what I was doing. I can assure you that feeling went away very quickly. Thankfully I had joined a team of very intelligent chemists that were kind enough to mentor me and show me the ropes. Tom’s down-to-earth realness and Chi’s endless positivity helped get me through some of my darkest and most frustrating days as a first year. Working on this project also exposed me to several reactions I hadn’t run or even heard of before coming to grad school. Spending my first five months on this team taught me so much about technique, time-management, and chemistry in general; I’m very fortunate to have this foundation to build off of for the rest of my time in the lab.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;">Some key takeaways from working on TGT: Always be bringing material forward while you’re working at the front line. Compared to my past life of working in a process lab, scale up in academia is tough and the glassware is heavy. Ask your teammates questions (especially when things aren’t working) because there’s always more to learn.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;"><b>Chi He </b>(Jan. 2019 – Jun. 2020)<o:p></o:p></span></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjjuFs71zD7U4Nfc_Sx5MR-eCu20-ed6gRyewIZDRn4Ty6VYDpieqs6pvqpItlWQbrFNpUn0Z5XhxY5iWRKaPiU09FOmH3P3tWLhSmF9axp8JBpZ_DBAM9yocsz_yHGiIyUzcQhdkAX-tg/s1600/Screen+Shot+2020-07-16+at+2.19.32+PM.png" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><span style="color: #f3f3f3; font-size: large;"><img border="0" data-original-height="596" data-original-width="596" height="200" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjjuFs71zD7U4Nfc_Sx5MR-eCu20-ed6gRyewIZDRn4Ty6VYDpieqs6pvqpItlWQbrFNpUn0Z5XhxY5iWRKaPiU09FOmH3P3tWLhSmF9axp8JBpZ_DBAM9yocsz_yHGiIyUzcQhdkAX-tg/s200/Screen+Shot+2020-07-16+at+2.19.32+PM.png" width="200" /></span></a><span style="color: #f3f3f3; font-size: large;">After finishing the herquline project, Tom and I decided to keep working on total synthesis. At that moment, our friend Herr Doktor (David) was going back to Germany to start his professional career. Tom and I took over the tagetitoxin project from Herr Doktor, not only because of its intriguing structure, but also our friendship with Hang and David. <o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;">Hang and David had worked on this project for over 1 year. Moreover, David had confirmed the desired stereochemistry of bromocyclization product by X-ray in the last week before he left (see above). To be honest, this good news made me and Tom very excited to think we could put a bullet to this project soon. In two short weeks, however, we would come to understand just how many more problems awaited us. In general, we modified and optimized the whole route in the past 1.5 years (for more experimental details and logics, please see SI). Here, I would like to share my experiences and feelings from 2 late-stage procedures: phosphorylation and the final purification. </span></div>
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<span style="color: #f3f3f3; font-size: large;"> <i style="font-family: Calibri, sans-serif;">Des</i><span style="font-family: "calibri" , sans-serif;">-P tagetitoxin was easily generated by convenient workup after exhaustive hydydrolysis by Ba(OH)</span><sub style="font-family: Calibri, sans-serif;">2</sub><span style="font-family: "calibri" , sans-serif;">. We were excited to find the chemical shifts and</span><span style="font-family: "calibri" , sans-serif;"> </span><i style="font-family: Calibri, sans-serif;">J</i><span style="font-family: "calibri" , sans-serif;">-values in</span><span style="font-family: "calibri" , sans-serif;"> </span><sup style="font-family: Calibri, sans-serif;">1</sup><span style="font-family: "calibri" , sans-serif;">H NMR of</span><span style="font-family: "calibri" , sans-serif;"> </span><i style="font-family: Calibri, sans-serif;">des</i><span style="font-family: "calibri" , sans-serif;">-P tagetitoxin were significantly similar or identical to the original data in the isolation paper, which indicated the structure we were working on was promising (non-trivial given the structure of tagetitoxin had yet to be confirmed). It seemed we could put a bullet in this project</span><span style="font-family: "calibri" , sans-serif;"> </span><span style="font-family: "calibri" , sans-serif;"> </span><span style="font-family: "calibri" , sans-serif;">in just one more step! However, the final selective phosphorylation of C8 alcohol failed after several attempts with chemical conditions. The failure was probably due to the poor solubility of</span><span style="font-family: "calibri" , sans-serif;"> </span><i style="font-family: Calibri, sans-serif;">des</i><span style="font-family: "calibri" , sans-serif;">-P tagetitoxin in organic solvents. Although it might be possible to achieve the phosphorylation with the help of enzymes, we decided to pursue this final step using chemical methods.</span><span style="font-family: "calibri" , sans-serif;"> </span></span></div>
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<span style="font-size: large;"><span style="color: #f3f3f3;"> </span><span style="color: #f3f3f3; font-family: "calibri" , sans-serif;">To </span><span style="font-family: "calibri" , sans-serif;"><span style="color: #f3f3f3;">improve the solubility in organic solvents, we protected the free amino alcohol as the hemiaminal. After methanolysis, </span><b style="color: #f3f3f3;">18’</b><span style="color: #f3f3f3;"> was obtained as an ideal substrate for phosphorylation, with two masked methyl esters and hemiaminal to improve the solubility and stability. To our surprise, a lot of conventional phosphorylation conditions did not work on this substrate due to either poor chemoselectivity or low reactivity. Fortunately, our lab had already developed a practical method to achieve the chiral phosphorylation by a talented graduate student Kyle. With the help of Kyle, we successfully put on P(V) with highly reactive </span><a href="https://openflask.blogspot.com/2018/08/blog-post.html" target="_blank"><span style="color: lime;">(+)-Ψ reagent</span></a><span style="color: #f3f3f3;"> in excellent yield. The reaction condition is mild and highly reproducible. I want to highlight that the advantages of this method were not limited in phosphate installation, but also helpful in crystallization and chiral resolution. We confirmed the structure and absolute configuration through the X-ray of </span><b style="color: #f3f3f3;">19a</b><span style="color: #f3f3f3;"> and obtained both (+)-tagetitoxin <b></b>and (–)-tagetitoxin</span><b style="color: #f3f3f3;"> </b><span style="color: #f3f3f3;">in two more steps.</span></span></span></div>
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<span style="color: #f3f3f3; font-size: large;"> <span style="font-family: "calibri" , sans-serif;">I still remember the first time I got tagetitoxin. I saw a huge rainbow outside of window in early morning of 2019 Thanksgiving. After taking a</span><span style="font-family: "calibri" , sans-serif;"> </span><sup style="font-family: Calibri, sans-serif;">1</sup><span style="font-family: "calibri" , sans-serif;">H-NMR of this crude mixture, I was excited to tell Yuzuru I might have made tagetitoxin! One day later, I emailed Phil and my teammates about this exciting news after confirming by</span><span style="font-family: "calibri" , sans-serif;"> </span><sup style="font-family: Calibri, sans-serif;">13</sup><span style="font-family: "calibri" , sans-serif;">C-NMR. That moment, I thought we could finally put an end to this project and enjoy the Christmas holidays. However, it was just a beginning of the most challenging problem I experienced during this project: the final purification.</span><span style="font-family: "calibri" , sans-serif;"> </span></span></div>
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<span style="color: #f3f3f3; font-size: large;">The natural product contains so many polar functional groups on a tiny skeleton, which makes it much more polar than peptides or even palau’amine. Attempts to purify with preparative HPLC were proved intractable as the highly-polar mixture eluted at very beginning. Luckily, our friend Dillon, another talented graduate student, gave me a hand at that moment. After trying several different purification methods, we found that anion exchange chromatography with DEAE resin was optimal. However, the only way to confirm the purity was by taking NMR of every fraction after lyopholization (LC/MS, for example, was not sufficient to determine purity). It was common that a single purification procedure could take several days, only to realize at the very end of the sequence that we had again failed. I forgot how many anion exchange columns I had tried, definitely >15. In most cases, the impurities came from the product and they were co-polar. Further, it was impossible to attempt re-purification from this mixture. The only solution was to carefully scale up a new batch of tagetitoxin and try a new purification. After several failures, we realized tagetitoxin is extremely sensitive to acid, as decomposition was observed at pH 4 for 30 min. After fully understanding this nuance, and combined with lots of effort and advice from Dillon, we finally collected clean NMR spectra of tagetitoxin! All told, the final purification took us almost half a year, finally enabling completion of this project. It was very challenging and at times frustrating for me to spend such a long time to deeply understand how fragile and tricky this molecule is. On the other hand, I am also very proud of our courage to overcome the array of challenges that were presented to us!<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;">Finally, the most impressive thing for me in this project is the great cooperation between friends. I would like to thank the support and help from Hang, David, Tom, Kelly, Dillon and Kyle. The project would not be done without any one of you!! <span style="font-family: "apple color emoji";">🍻</span><o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;"><b>Dillon Flood </b>(Jan. 2020 – Jun. 2020)<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;">Over the past few years, Tom and I have had countless conversations which generally revolved around south pacific storm cycles, where we were chasing swell that weekend, and who would pick up the Tecate before we left. Although never at the forefront, chemistry would bubble up through these interactions. The world of total synthesis inhabited by Tom and Chi felt foreign to me, so the usual griping about failed experiments, unrealistic deadlines, and long hours always seemed to need a bit of translation.</span></div>
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<span style="color: #f3f3f3; font-size: large;">I’m not sure what initially provoked Tom and Chi to ask for my help with an anion exchange purification but it very well could’ve been during a collegial discussion on right way to drink one’s preferred Mexican beer. However it happened, Tom and Chi were showed up on the first floor of the Beckmann, bright eyed and bushy tailed, taking copious notes, and very ready to purify their compound that I didn’t want to ask about how long it took them to make… Although this should’ve been a routine method, it never is. This led to Chi spending better parts of some days in the Dawson lab perfecting his anion exchange chromatography, while always expounding on the genius of LeBron James, just so I was sure. <o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-size: large;">At some point I made the mistake to ask Tom (while surfing at Blacks), what this compound even does? After a long story about phytotoxins, RNA polymerase, optical rotations, isolation chemists without compound, and a half-baked idea to spray plants (?!), all I could think at the time was that I needed another wave. But out of this conversation, and a little googling, came the idea of performing the <i>in vitro</i> assay on both enantiomers. At first, the pair was not so enthused when I mentioned the assay. But when I mentioned that I could run it for them, everyone was on board. And then again, Tom and Chi were back down on the first floor of Beckmann, compounds in hand, ready for me to tell them which enantiomer was active. At this point I had to ask them to leave, unless they wanted me to watch me mess this thing up. So after loading the plate to the Hamilton soundtrack, running the assay and reading the results, I was shocked the experiment had worked so well. One compound was active and the other was dead. But this was the beauty of working at Scripps, friends in totally different fields could halfheartedly bounce ideas off one another that may help resolve and unanswered question. <o:p></o:p></span></div>
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BaranLabhttp://www.blogger.com/profile/01806245988209508968noreply@blogger.com3tag:blogger.com,1999:blog-51846086760422068.post-26348543554699049962020-06-06T06:50:00.000-07:002020-06-06T06:51:29.033-07:00Realities of management style<span style="color: white;">(From Baran lab grad students, opinions entirely our own and may not reflect Phil or Scripps)</span><br />
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<span style="color: white;">I was very proud of Phil & Donna, and the Scripps community today, for their thoughtful counterpoint to the alarming recently-published essay about the field of organic synthesis. It makes me happy to see my mentors stand up for what's right.</span><br />
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<span style="color: white;">And so, I was a bit startled, and more than a bit upset, when my inbox started filling with notes making accusations that this thoughtful counter-essay amounted to nothing more than 'hypocrisy.'</span><br />
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<span style="color: white;">A verbatim text message I received: "How can a slave-driver like Phil Baran be hypocritical enough to condemn slave-driving in an essay, while simultaneously doing exactly that in his own lab?"</span><br />
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<span style="color: white;">This kills me, because it's so far from the truth. Openflask was created to give behind the scenes into our lab, so here it is: Our lab is a pretty nice, chill place to work. We're not slave driven. We work hard when we feel like it, and slack off when we feel like it.</span><br />
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<span style="color: white;">Don't believe me? Here are some emails from the boss (highlighting my own for emphasis):</span><br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgaXrWMy_uZXqiF1TvAVsA0uA_lBLPGi3jidw586yIxEhugLlNveTXnk0kK9_KGmBTxIAW8gNThO_o0FSN6rOD0h0e5yQAJ-HUq7Q4h-lUd46KFTEVWO7Yguy6k_XFrcIMAJKC4W56UAjg/s1600/Screen+Shot+2020-06-05+at+9.26.00+PM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><span style="color: white;"><img border="0" data-original-height="579" data-original-width="848" height="436" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgaXrWMy_uZXqiF1TvAVsA0uA_lBLPGi3jidw586yIxEhugLlNveTXnk0kK9_KGmBTxIAW8gNThO_o0FSN6rOD0h0e5yQAJ-HUq7Q4h-lUd46KFTEVWO7Yguy6k_XFrcIMAJKC4W56UAjg/s640/Screen+Shot+2020-06-05+at+9.26.00+PM.png" width="640" /></span></a></div>
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<span style="color: white;">Was the lab always like this? Probably not. Does it mean we're "going soft?" Almost certainly. Do we still seem to be cranking out papers, and having a happy, healthy time doing so? Yup. I'll take the softness.</span></div>
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<span style="color: white;">As it turns out, I know Phil will too:</span></div>
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<br />BaranLabhttp://www.blogger.com/profile/01806245988209508968noreply@blogger.com5tag:blogger.com,1999:blog-51846086760422068.post-756572213693483922020-06-05T17:00:00.000-07:002020-06-05T17:00:06.836-07:00Message to Organic Chemists<div class="MsoNormal" style="font-style: normal; font-weight: normal; letter-spacing: normal; margin: 0in 0in 0.0001pt; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">
<span style="color: #f3f3f3; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Dear Scripps Community,<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">It is self-evident that these are unprecedented times. Compounding the stress we are all feeling, the Organic Chemistry community received a startling blow with an Essay recently published (and then rapidly taken down) in <i>Angew. Chemie</i>, one of our premier journals. This topic we feel is appropriate for us to address.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><b>First</b>, the Essay offers <b><i>opinions</i></b> that are not even relevant to the field of synthesis – odd given its title: <i><span style="font-family: "ío˛¯‹85✸µ➪5➷i";">“Organic synthesis—Where now?” is thirty years old. A reflection on the current state of affairs,”</span></i><span style="font-family: "ío˛¯‹85✸µ➪5➷i";">. How such a treatise, published in a top scientific journal, would include what is essentially an ill-informed social commentary, without any citations or evidence to back up egregious claims, is puzzling to us. The author feels compelled to express sorrow over the lack of rigor in the primary chemistry literature (reproducibility, melting points, combustion analysis) yet feels none of this rigor should apply to the social commentary offered in the guise of a scientific essay. We are scientists, we publish facts and documented evidence. The unsubstantiated comments in this essay have no place in a scientific journal, even in an Essay format. We are troubled that a prestigious Journal like <i>Angew. Chemie</i> would somehow permit such an essay to pass the rigors of peer- and editorial-review. <o:p></o:p></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="color: #f3f3f3;"><b>Second</b>, the comments about diversity and inclusion (in green below) are at best ill-informed or ignorant, at worst malicious: </span><o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><i><span style="color: lime;">“In the last two decades many groups and/or individuals have been designated with “preferential status”. This in spite of the fact that the percentage of women and minorities in academia and pharmaceutical indutry (sic) has greatly increased.”</span></i><span style="color: black;"><o:p></o:p></span></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="color: #f3f3f3;">Recent essays about women in Med Chem, Process Chem, and academic careers (refs. 1-3) show clearly the discrepancies that still exist as women move up the ladder. One of us (D.B.) has experienced such hurdles personally. Extensive scientific studies in the social science literature also show such notions to be factually inaccurate (ref 4). This “despite the fact” comment clearly ignores these ongoing challenges.</span><o:p></o:p></span></div>
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<i><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="color: lime;">“It follows that, in a social equilibrium, preferrential (sic) treatment of one group leads to disadvantages for another.”</span><span style="color: red;"><o:p></o:p></span></span></i></div>
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<span style="color: #f3f3f3; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The author of this essay fails to grasp the irony of the above statement. In fact, he himself has been in a group receiving preferential treatment all throughout of his scientific career – it appears that he never thought to speak out about that, though. <o:p></o:p></span></div>
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<span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="color: #f3f3f3;"><b>Third</b>, and even more insidiously, we mention a point made by Jake Yeston of <i>Science</i> who said “There’s been some attention towards the lazy unsupported critique of diversity in Prof. Hudlicky’s essay, but less directed at this portion:”</span><o:p></o:p></span></div>
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<i><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="color: red;"> </span><span style="color: lime;">“The training and mentoring of new generations of professionals must be attended to by proper relationships of “masters and apprentices” without dilution of standards….there must be “an unconditional submission of the apprentice to his/her master.” This applies not only in the sciences but also in art, music, and martial arts.”</span><span style="color: red;"><o:p></o:p></span></span></i></div>
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<span style="color: #f3f3f3; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">The language here is disturbing for several reasons. The word “Master” has a subliminal message that goes beyond scientific mentoring relationships. The invocation of martial arts is also starkly out of place because chemistry is not simply discipline but also involves innovation, discovery, and imagination. But most of all, this quote appears to support an unhealthy work ethic that has in the past pervaded organic chemistry research but that is thankfully much less prevalent today, as younger faculty aim to achieve, and help their research groups achieve, a better work-life balance. It is this macho perception of synthetic chemistry that continues to be a barrier to inclusivity. Thus, “Master-apprentice” is not the way to think about relationships in a modern laboratory setting. We all learn from mentors, but it should be a holistic, interactive, nurturing relationship. In our own experience, by treating students as independent collaborators rather than apprentices, they grow to become brilliant scientists that think outside of the box and end up teaching us more than we could teach them. Instead of unconditionally submitting to a “master”, in the modern era of organic chemistry it is the norm to encourage our collaborators to challenge assertions, engage in debate, and work together as a team to achieve a common goal.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">We work in organic chemistry research because we are passionate about the science and the positive impact it can have on society. We need to ensure that we can direct this passion towards mentoring our students and postdocs to become the best scientists they can be. We value each and every student and postdoc, individually, for their own special strengths and their own humanity. Although some may think incidents like the publication of this Essay only serve to set us back when we need to move forward, it’s also important that the vestiges of such backwards thinking be brought to light and called out. It is no secret that organic chemistry, synthesis in particular, has a storied history of being a male-dominated, ruthless arena where the celebration of cult personalities and enriching one’s ego often took priority over enriching the science and mentoring students. Many chemists in previous generations did not subscribe to that approach and we contend that the current generation has all but eradicated it. <o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">At Scripps our groups are proud of the diverse representation which has always been an enabling strength in our research programs. It is a documented fact that vibrant, creative, and wildly imaginative science takes place when people from diverse backgrounds and cultures collaborate to solve important scientific problems. Doing this in an environment where students and postdocs feel supported as equal collaborators is part of the secret sauce that makes Scripps such a special place to do research. <o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">We are here to listen and provide support at any time, if anyone would like to reach out to us. Please stay safe, well, sane, and <i>passionate about chemistry</i> during these challenging times! <o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">Donna Blackmond and Phil Baran<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;">References<o:p></o:p></span></div>
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<!--[if !supportLists]--><span style="color: #f3f3f3; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin;"><span style="mso-list: Ignore;">1.<span style="font-stretch: normal; font-style: normal; font-variant-caps: normal; font-weight: normal; line-height: normal;"> </span></span></span><!--[endif]-->Huryn, D.; Bolognesi, M. L.; Young, W. B. Medicinal Chemistry: Where Are All the Women<i>? ACS Med. Chem. Lett</i>. <b>2017</b>, <i>8</i>, 900−902.<o:p></o:p></span></div>
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<!--[if !supportLists]--><span style="color: #f3f3f3; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin;"><span style="mso-list: Ignore;">2.<span style="font-stretch: normal; font-style: normal; font-variant-caps: normal; font-weight: normal; line-height: normal;"> </span></span></span><!--[endif]-->Ruck, R.T.; Faul, M.M. Gender Diversity in Process Chemistry, OPRD, <b>2019</b>, <i>23</i>, 109-113.<o:p></o:p></span></div>
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<!--[if !supportLists]--><span style="color: #f3f3f3; font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="mso-bidi-font-family: Calibri; mso-bidi-theme-font: minor-latin;"><span style="mso-list: Ignore;">3.<span style="font-stretch: normal; font-style: normal; font-variant-caps: normal; font-weight: normal; line-height: normal;"> </span></span></span><!--[endif]-->Sanford, M.S.; Chiu, P.; Kozlowski, M.C. Celebrating Women in Organic Chemistry. <i>Org. Lett. </i><b>2020</b>, <i>22</i>, 1227-1230.<o:p></o:p></span></div>
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</style><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif; font-size: large;"><span style="color: #f3f3f3;">4. Thanks to Prof. Tehshik Yoon for this compilation of resources: </span><a href="https://threadreaderapp.com/thread/1268968586065915905.html"><span style="color: lime;">https://threadreaderapp.com/thread/1268968586065915905.html</span></a></span>BaranLabhttp://www.blogger.com/profile/01806245988209508968noreply@blogger.com52tag:blogger.com,1999:blog-51846086760422068.post-91523755044626446502020-05-18T10:55:00.001-07:002020-05-18T10:55:38.187-07:00Guest Post: My Job Search Experience During the Great Recession<div class="MsoPlainText" style="margin: 0in 0in 0.0001pt; text-align: justify; text-indent: 13.5pt;">
<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">This post comes from outside the Baran Lab, from our collaborator Dr. Jesse Sabatini. He was recently asked to comment on his experience looking for jobs during the last big economic downturn. That publication did not use the entirety of his comments but we believe there is a lot of interesting wisdom here that will hopefully be useful to the community. Thanks Jesse for letting us post this on OpenFlask!</span></div>
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<b><u><span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">My Job Search Experience During the Great Recession<o:p></o:p></span></u></b></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Jesse J. Sabatini<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Let’s be honest with one another and acknowledge that it is a bad time economically out there for many people. As scientists, we need to understand that this is not a great time to be looking for a job right now. Although I am currently employed despite the wide-ranging economic shutdown due to the COVID-19 pandemic, I empathize with those that are currently looking for employment during this time. It was just a decade ago, during the Great Recession, when I was also navigating my own job search. I still have vivid memories of my job search, the emotional highs and lows, and the lessons learned as a result of this experience. Therefore, I wanted to share my experiences with you. I think that folks looking to be gainfully employed need to be aware that the job hunt is not always a smooth process. Even in good economic times, it can be a struggle. Certainly, during economic downturns, we know that it is. I want whomever reads this to know that my purpose in sharing my experience is not to make you feel good or bad, and it is not to scare or comfort you. It is just my view of how the real world works, from somebody that had to endure many heartbreaks before finding a job. After sharing my story with you, I will provide some pointers at the end of this post that I STRONGLY recommend those looking for employment will take to heart and seriously consider. You’ll notice that I focus on financial aspects quite a bit. Many grad students and postdocs, quite frankly, don’t have a handle on these important aspects. Yet they should, and they need to be very aware of this during their job search. <o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">My story begins during the late winter, spring and summer of 2007. At that time, I was nearing the end of my PhD graduate studies in natural products total synthesis at the University of Virginia. During this time, the economy was on solid footing and the unemployment rate was low. I had published my third manuscript of my graduate studies in February, during which time I was told to begin writing my dissertation. In March, I had committed to doing a postdoc at the University of Pittsburgh to continue my education. I had a passion and a love for teaching, and was told that if I aspired to go into academia, then a postdoc was a necessity. I do believe that this is sound advice, even today. In June 2007, I attended the National Organic Symposium (NOS), which was held at Duke University. I was riding a pretty high wave of success, and I believed that continued at the NOS. The highlight of the conference for me was actually not listening to the wonderful lineup of speakers, but was the evening that I presented a poster. There appeared to be a number of folks from the industry and academia that took an interest in my poster. I handed out many business cards and got many in return. By sheer luck, my poster was in a good strategic location, where people had to pass by it. I felt that many people were interested in hearing about my research. I remember the excitement that I felt. This was one of the biggest opportunities of my life, I thought at the time. I spoke so much that I was a bit hoarse when the night ended. Several employers from various pharmaceutical companies informed me that they would be looking to hire in the future, and that I should keep them in mind when I finished my postdoc. This was the news that I wanted to hear.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">I can remember going back into my hotel room that night, and I was ecstatic. At that time, I was just 25 years old...trying to figure out my life like most people in graduate school. Looking back on it, I realize now that there were likely many others who felt the same way that I did. Many of those employers that liked my research and that told me they were hiring had likely told dozens of others that same story. In the job search, you benefit most by worrying about yourself, and not what is happening around you.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">As soon as the conference ended, I made sure that I touched base with all of those prospective employers that gave me business cards, and that told me to keep in touch with them. I defended my dissertation the following month in July. Come August 2007, I was done at UVA, and moved on to my postdoc at Pitt. During this time, the economy was still doing well with respect to the stock market. I had heard negative news about the sub-prime mortgage crisis, and that the federal government was intervening to prevent the issue from spinning out of control. Despite this, the stock market continued to rise at the time. But the stock market is typically a lagging economic indicator. When one sees it fall dramatically, then bad times usually have already started. I was mindful of all of this, as I had enjoyed matters concerning economics, stocks, bonds and equities for a number of years. With the exception of my family (of which nothing is more important), much of my attention and focus was, and remained, on my chemistry. Yet I have always believed that folks should have a good knowledge about finances, saving for retirement, college savings accounts for their (future) kids, etc. It is never too early to learn about these aspects, because future generations, including our children and grandchildren, will also need to know about these matters if they are to be set up to succeed in the future.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">My postdoctoral research, I felt, went decently from the chemistry perspective. I continued working hard towards an additional total synthesis paper, and gave it everything that I had. Yet I did notice that as the winter of 2007 turned into the spring of 2008, the economy was heading downhill. This only accelerated during the summer months, and it had me concerned because I was ramping up my job search during this time. I knew that landing a job in times of economic prosperity were not easy. In 2005 and 2006, I saw several at UVA apply to countless positions during the good economic times before they landed something. Finding a job during tough economic times was going to be even more of a challenge. I made the decision in the summer of 2008 that I could not afford the luxury of restricting myself to a specific geographic location. Doing so was just going to make the job hunt even worse. I would apply to jobs across all 50 states. Furthermore, I also decided at this time to cast a wide net as to the type of job that I wanted. As a graduate student, I loved teaching and saw myself going into academia, with going into the pharmaceutical industry as a close second option. Now as a postdoc, I did not really have a preference. I would consider either option equally. My aspirations of becoming a professor were dashed during my postdoc tenure, however. Many of the positions that I was eyeing were no longer available, due to the worsening downturn. I did apply to a half-dozen academic positions. Two of these resulted in a phone interview, but I never made it past this stage. The honest reason as to why these phone interviews didn’t materialize further had nothing to do with the economic downturn. It had everything to do with the fact that there were better candidates out there that applied, and these candidates gave better interviews than me. In the job search, as disappointing as it may be, you must be honest with yourself. No matter how good you think you are, there is likely to be someone out there that is equally or more qualified for a position than you are. It's a hard lesson that I had learned years before on the wrestling mat. That lesson being that you can be as talented and as prepared to the best of your ability, and it may not be good enough to win. It's a lesson that reared its ugly head again and again during my job search. One thing is for sure, however. If you just give up, then losing out is an absolute certainty.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Through all of this, there was also a dark horse that emerged in the job search; the prospect of federal employment. Since my graduate studies, I heard about how government jobs offered less starting pay than the private sector, but offered excellent job security, benefits, and a stable retirement package. Due to the financial crisis, I had decided to look more into this field during my postdoc, which was a bit more non-traditional. Once again, the approaches of imposing no geographical restrictions and casting a wide net for employment became necessary in landing a job. <o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">During the summer of 2008, Pitt was hosting the National Medicinal Chemistry Symposium (NMCS), and I attended. Taking a page out of my experience at the NOS the previous year, I presented a poster there and made efforts to get some face time with people. Unfortunately, I kept hearing about how many companies (mostly small companies) were implementing hiring freezes. Needless to say, this was unfortunate news. Not only did a hiring freeze mean that there would be no hiring, but this can also be the first step toward layoffs at a company. Fortunately, larger pharmaceutical companies were still hiring at that time. Hiring or not, I remained in touch with every one of those that I had met at the NOS and the NMCS during the job search process. First, I figured that it would not hurt to keep in touch with these folks, for if a position opened up, perhaps they would still consider me for an interview. Second, I have never believed in being a "fair-weather friend." I genuinely cared about these folks, and wanted to hear about how they were doing. The fact that they could not help me get a job was not their fault. I wanted to continue building my network, because you never know when or how someone that you met several years ago can help you. I have always detested folks that simply use others to get what they want, and then proceed without any further care for the person that helped them. Understand that these people exist, and you may see them come out in droves during the job search process. My best advice is to ignore them and let them continue on with their self-destructing ways. Do not become one of these people. To be honest with you, I will never consider helping or hiring someone that acts this way. I don't care how skilled or gifted they are in a scientific discipline. If someone lacks the trait of common decency, I'll inform others, and will put their CV into a shredder.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">After the NMCS, which was a wonderful venue, but a personal disappointment, I attended the 2008 Summer ACS meeting in Philadelphia, which was held in August. I presented a poster at this venue on my postdoctoral work. I can remember how disappointed I was when I saw that my poster space was in one of the worst locations. Hidden from most of the foot traffic, it was temporarily a deflating feeling knowing that most wouldn’t bother going out of their way to see my work. I tried to make the best out of a situation where I was handed a lemon out of sheer bad luck. It happens sometimes. I had a prime location at the NOS, and there were others at this venue that had gotten the short end of the stick. The truth is that we cannot change the cards that we are dealt in situations like this. <o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">But we can change how we play the hand. So if nobody was going to come to me, I was going to go to them. It may be a futile effort, I remembered thinking at the time, but I was not going to be complacent. Complacency, or waiting for a job to come to you, is just a wasted opportunity. I, at that time, was not a very sociable person. But I needed to have the self-courage to overcome this, and get people over to see my poster so that I could show them my skill set. I had been rejected many times in the job search up to this point. So if someone wasn’t interested in seeing my poster, what did I care? I had nothing to lose. My efforts, to be honest, only had limited success. Most really didn’t care one way or the other about seeing my poster. But I could go to bed that night knowing that I was doing everything I possibly could to better myself. I am sure there are others that would have fared better than me in this situation. Admittedly, many out there are much better at selling and advertising their work than me. This is a skill that I strongly recommend you work to perfect. I have gotten a lot better over the years at this, but wish that I was better at it back then.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">I was fortunate enough to have several interviews at the ACS meeting with pharmaceutical companies that were still hiring. I felt good after these brief interviews concluded, which I was told could then lead to an on-site interview at the company. But as the unemployment numbers continued increasing and as the days passed without hearing anything, I became resigned to the fact that either these positions were no longer open, or the companies had decided to go in a different direction, thus hiring someone else. That latter option is certainly possible. Just because you feel that you crushed an interview does not mean that the people on the other side of the table felt the same way. You need to be prepared for the fact that you could give a very good interview, and still not get a position for any number of reasons. It does not mean you are a bad scientist. It just means that your background was not the right fit, or that someone else interviewed better than you did. Perhaps it is a combination of both.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">After the ACS meeting concluded, with academia out of the question for me, I turned my attention solely toward a job in the pharmaceutical industry and the federal government. I sent out a flurry of applications to both, but I did not hear anything back in most cases. Some of those that I had met at the NOS that I’d kept in touch regularly with had either told me that there were no positions available, or they had unfortunately been laid off themselves. One of the few replies that I did hear back from was Picatinny Arsenal, an Army installation located in Northern, NJ just 30 miles west of New York City. Their response to me via snail mail was simple; that they thanked me for my application, but that they had no positions available at this time for my skill set. More on this letter later.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">In September of 2008, with the stock market collapsing, there were some pharmaceutical companies that visited Pitt to conduct some interviews. Naturally, I signed up for these interviews, 4 in total. During these interviews, I was informed by two of the companies that they were proceeding with the interviews, but that they no longer had positions open. I remained respectful, professional, and gave the interview my best. These ended up serving as practice interviews for the other two that were to my knowledge at the time, my only legit shots at a job. I felt that I interviewed very well with these latter two companies. I had become an experienced interviewer through sheer repetition, and that is important sometimes in landing a position. Experience really is the best teacher, pardon the cliché. I was delighted that I'd finally had a hit, as two weeks after this interview, I was invited to an on-site interview from one of the companies. This on-site interview went so well, that I was told to expect an offer within the next couple of weeks. But unfortunately, with the job market continuing to decline and with unemployment rising, I was abruptly told that the position was closed and was no longer being advertised. The number of rejections and/or not hearing one way or the other was now in the 40's. That number seemed to tick up on a daily basis. That was a lot of rejection to take. I don't think that I was ever at a lower point in my job search than when the position that I was so excited to accept was taken away. In instances like this, it is important to have a strong support system. For me, it was my fiancé (now wife of 11 years) and some research associates of mine. My backup plan was to stay at Pitt another year for my postdoc. In August 2008, I had signed another 1 year extension, which I was very thankful to receive. I had another year to figure everything out, but was growing more and more concerned by the day as to what I was going to do.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Then in late September 2008, I received a phone call that changed the course of my life. It was from a former graduate student at UVA named Ronald Hann. At the time, Ron was an officer in the US Army, and had joined the Marshall lab in the summer of 2005. I had been there for about one year, and I was asked to mentor Ron, who had just returned from a tour of duty in Iraq. Ron and I worked closely together, and become very good friends. While I was in the midst of a job search that was not going so well in 2008, Ron had completed his PhD at UVA, and relocated to the United States Military Academy at West Point. He was calling to inform me of a position that existed at Picatinny Arsenal...the very place that had informed me a few weeks prior to his call that there were no positions available. When I told Ron about this occurrence, he told me that the key to getting a federal job was knowing somebody on the inside. I happen to believe that this advice is helpful to landing a job outside of the government as well. Ron advised me to send him my CV so that he could put it in the right hands. He explained to me that the job would not be in synthesis, but instead would be in the formulation of pyrotechnic materials. I was ecstatic, because as a kid, I remember playing with pyrotechnics all of the time. It was like I had the opportunity to be a kid again. Although I knew that I would miss synthesis, Ron explained to me that in the government, the key is to "get your foot in the door, and then you can move around." Well, that certainly turned out to be some excellent advice, as I found out years later.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">I passed my CV along to Ron, and on the final day of September, I received a call from a branch chief at Picatinny Arsenal's Pyrotechnics & Prototyping Division. We had a very pleasant conversation, and after they received other positive letters of support, I was invited to come out for an interview in the middle of October 2008. I prepared feverishly for that interview, as I believed that it may have been my last chance at getting a job. In addition, Ron had stuck his neck out for me. I did not want to disappoint him. The interview at Picatinny Arsenal went very well. It was on a Friday, and I was told that I would be made a formal offer the following Monday or Tuesday. I had heard this before, and so I kept my guard up. Yet Picatinny was true to its word. I did receive my offer that following Tuesday, which I signed immediately, because benefits, salary, retirement plans, etc. were all discussed during the interview. It took a couple of months to get all of the paperwork and forms filled out, but I had done it. I had found a job during the Great Recession, with a starting date of February 2, 2009!<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">After all of the flash columns, hours of hard work, publications, job rejections and unsuccessful job interviews, it was my network that saved me when I needed it most. In my case, a connection that I made in the summer of 2005 came back to help me 2 and a half years later because this person (Ron) was familiar with how hard I worked, and appreciated the fact that I kept in touch with him. Ron will probably never admit it, but it was his phone call that opened the door for my interview. Otherwise, I would have been cast aside as another employee to inform in a generic letter that there were no openings. My network helped me open the door to a job, but I had to interview well to get the position. Fortunately, I knew how to do that from all of the previous unsuccessful interviews that I’d given before. I had learned from my interviewing mistakes and filled in many of the gaps. I have remained loyal to Ron ever since, as we continue to have a wonderful personal friendship and professional relationship, even though we have both since relocated to other positions within the government. <o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">As for me, I enjoyed my time researching pyrotechnics immensely. It gave me a deep understanding of how stupid I really was as a kid when I used to reverse engineer various fireworks and make my own devices. But it also allowed me to expand my network into a new field that I had not previously known. After 5 successful years in pyrotechnics, I had a desire to get back into synthesis, which I missed greatly. I found that opportunity, once again, through networking, when I was informed by someone that I knew within the government that a position was open at the Army Research Laboratory to lead the energetic materials synthesis team. I took that job without much hesitation. Synthesis is where I wanted to get back to, the cost of living in Maryland was significantly lower than in New Jersey, and my wife and I were interested in buying a house for ourselves and our two young daughters. We relocated to Maryland in 2014, and are very happy here. I will admit that it is nice to get paid to blow things up and light stuff on fire, but we are very safe about it (and yes, that is possible to do). I can talk about my experiences in energetics forever, but that’s another conversation for another day!<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">So my story had a happy ending. But it did take a while to get there, and there were many uncertainties and a range of emotions along the way. My pointers to those looking for jobs (both now and in the future, and in no order of importance):<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">1. Work hard, study hard, and complain as little as possible. The more people see these traits in you, the more apt they will be to help you out.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">2. Do not restrict yourself by geographic location, or by the kind of job you think you want to do. This is especially true during tough economic times. I wanted to go into academia, and that did not happen. I wanted to go into pharma, and that did not happen either. I did not think about federal employment until later in the job hunting process. I should have thought about it in the beginning, but never really knew that doing this kind of stuff and getting paid for it was a career option. With the baby boomer generation retiring by the masses, there will be plenty of federal jobs within many agencies that need to be filled in the next few years. Consider it as a source of employment, in addition to these other aforementioned job options.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">3. Network, network, network. It is never too early to begin this process, and even after you land a job, you should continue it throughout your career. You never know when somebody that you meet years prior can help you. Those who say that getting a job is all about how good of a researcher you either ignorant or are not telling the truth. Those who say that getting a job is all about who know are also ignorant or are not telling the truth. It is a hybrid, for sure. You need to be skilled in what you do, and you have to build a good network to maximize your chances of landing a job.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">4. Rejection happens to everybody, including those that many see as being incredibly successful. Rejection is a part of being a scientist and it is part of the job hunting process. Do not go to Twitter and begin shaming people or an organization because your job prospects did not turn out the way you wanted. This will alienate you from future employers (and justifiably so). Please take personal responsibility, ask yourself what you could have done better, and be honest with yourself. Sometimes, getting a job is outside of your control, but usually, someone else that applied did a better job than you did in the interview, or was more qualified to start with. Recognize these gaps, and use this to improve yourself in the future.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">5. Please, have an understanding of how the economy works. Understand how to negotiate a salary, how to save money, how to grow your savings, and have a knowledge of how much you should save. As Tennessee Williams once said, “you can be young without money, but you cannot be old without money.” Have a financial plan in place. When you get a job, start saving for your retirement in the form of a 401(k) right away, and make the necessary contributions possible so that you can maximize the company match.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">6. When thinking about what job you want to do, you need to evaluate your risk tolerance of making money vs. job security. It is different for each person. For me, job security was of paramount importance, and that's especially true during these times. I am fortunate that I have a job that carries with a high degree of job security, as well as a job that I enjoy very much. I was willing to take lower pay to start, with the understanding that there was a chance to see my salary rise significantly, provided that I churned out good research and did good science for the benefit of the country.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">7. If you plan on having children, is never too early to think about college savings funds for them, even before they are born. This should be evaluated when you negotiate your salary, and with respect to how long you'd like to remain with a company or organization.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">8. You want to make sure that you amass 6 months of living expenses in the form of savings, once you have a job out of grad school and/or your postdoc. You will thank yourself for a rainy day fund in the unfortunate event that you need it. <o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">9. Economic downturns happen. They can be shallow, moderate or severe. So-called experts will try and predict the markets, but nobody really knows how long an economic downturn will last. If you are investing, keep stocking money away. You need to take a long approach in order to maximize your retirement. Investing is a marathon, not a race. Downturns will reach a bottom and begin an upward trend again.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">10. Have fun with your job search. I encountered a lot of stress during my job search, but I still had fun. I still watched football, got into cooking, watching birds, and continued to exercise regularly when I was applying for jobs. You will need something else to think about besides the fact that rejection happened again. Understand something: Folks that work hard, are well-networked and that have published high-quality work will land a job. Remember that experience is a wonderful thing. As the late Professor Randy Pausch once said, “experience is defined as the thing you get when you did not get what you wanted.” You can pass these experiences on to others, like I am to you.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">11. Please be kind to others when you do make it, and remember that you likely needed help along the way from someone else that helped you get to where you are. When you get the job that you want, and are in a position to help others, please do it. I assure you that you will get more out of helping others than they get out of being helped. There are few things that charge me up more than seeing someone that I helped out grow in their careers. After all, I was in their shoes a little over a decade ago.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Please feel free to reach out to me at <a href="mailto:jesse.j.sabatini.civ@mail.mil">jesse.j.sabatini.civ@mail.mil</a> if I can provide any more pointers, help, advice, etc. Best of luck to you all, as you navigate your job search.<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Best wishes,<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Jesse J. Sabatini, Ph. D. <o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Team Leader-Energetic Materials Synthesis<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">US Army Research Laboratory<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Energetics Synthesis & Formulation Branch<o:p></o:p></span></div>
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<span style="color: #f3f3f3; font-family: Helvetica Neue, Arial, Helvetica, sans-serif; font-size: large;">Aberdeen Proving Ground, MD 21005<o:p></o:p></span></div>
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BaranLabhttp://www.blogger.com/profile/01806245988209508968noreply@blogger.com0tag:blogger.com,1999:blog-51846086760422068.post-82521771819894784542020-05-14T08:02:00.000-07:002020-05-14T08:02:21.500-07:00Taxol<div style="text-align: justify;">
Taxol! The fearsome jungle-gym-like structure of this molecule has attracted worldwide attention since the late 20th century. Our group was of course one of them, and has been working on this molecule for >10 years, which has culminated in this recent <a href="https://pubs.acs.org/doi/10.1021/jacs.0c03592" target="_blank">JACS article</a>. <b>PLEASE READ the SI</b> because it describes what actually happened and rationalizes why/how we arrived at the final route; looking only at scheme 1 could give a false impression that everything worked as designed from the outset. It was the longest project run in the lab and I happened to be the last person. Here I shall share some personal stories I experienced through this arduous oxidation-state-pyramid climbing.<br />
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">My first TOC draft. Phil said no.</span></td></tr>
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In Dec 2015, a super postdoc <a href="http://www.orgreact.sakura.ne.jp/members/en-umemiyaindex.html" target="_blank">Shige</a> (currently an assistant professor at Tohoku University) took over the Taxol project. (Phil said) there are "only" two more oxidations to complete the synthesis. However, these are very specialized and each are one of the most challenging <i>sp3</i> C–H bonds to be oxidized. Shige recruited me for the project in Jan 2016. For the record, back in June 2015, when I joined the lab, Phil offered three projects that I could work on and one of them was Taxol. I consulted with senior students in the lab and EVERYONE said "DON'T DO Taxol". In spite of this advice, I was naive enough to commit to the Taxol project. It must have sucked for Shige to work with "1st year me," who barely knew how to stain a TLC place. But he patiently taught me a lot of chemistry, experimental techniques and how to strategically carry out a total synthesis. We went through a lot of failures (see the 1st generation route in SI) but finally, it was found that C–2 β-OH was critical for C–1 oxidation, which led us to the 2nd generation route and established access to a handful of C–1 oxidation product.<br />
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">Around this rough time, we got a letter from another, more junior, "Baran", which made daddy smile and me pale.</span></td></tr>
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We were happy to "complete" one of the two most difficult oxidations. However, the <b>happiness in total synthesis always has a short half-life</b> and we immediately hit a wall called C–2 reduction. The challenge was two-fold: First, this ketone was a brick. The most difficult ketone reduction ever, it sometimes even survived super harsh conditions such as Birch and LiDBB. Second, it always gave us undesired C–2 β-OH in diastereomerically pure form. These were the worst sorts of optimizations because the results did not tell any directions to pursue, we were basically shooting in the dark. It was particularly painful since most substrates took about 20 steps to prepare, which all ended up failing. </div>
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">Never saw the physical state of compounds until we started collecting SI, since we never had enough material to see it.</span></td></tr>
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This deceptively benign-looking reaction took us <b>2 years</b> (the 2nd and 3rd generation routes) to figure out. Long story short, things finally got better when we found the C–4 α-OH β-Me motif, which gave us α-OH upon C–2 reduction on a model substrate. We integrated this moiety and carried out a new oxidase phase. Fortunately, both C–1 oxidation and C–2 reduction worked smoothly. </div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjX7JJ3KMWR_7w8WJcHu8WGQHC_JVKyninUUEWF9SxEKzqDevmV5yfszoD30SluzuQ7bF58ZJx1Fwj04H8t5R6rY99Fk48tq2cCaqJcRA78eQsCodP5ZthnDjGzOS2vXYmagmeJLxAa-iM/s1600/C%25E2%2580%25932+reduction.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="139" data-original-width="309" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjX7JJ3KMWR_7w8WJcHu8WGQHC_JVKyninUUEWF9SxEKzqDevmV5yfszoD30SluzuQ7bF58ZJx1Fwj04H8t5R6rY99Fk48tq2cCaqJcRA78eQsCodP5ZthnDjGzOS2vXYmagmeJLxAa-iM/s1600/C%25E2%2580%25932+reduction.jpg" /></a></div>
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For the C–7 oxidation, with the C–5/6 epoxide installed, <a href="https://science.sciencemag.org/content/339/6115/59" target="_blank">the oxidation relay</a> idea immediately emerged. C–6 iodoso elimination was more or less the first examined idea and worked beautifully well. The final key C–6/7 epoxide opening also went smoothly with Nugent-RajanBabu reagent in the presence of so many sensitive functional groups (carbonate, <i>tert</i>-OH, OTMS). This completed the two major objectives to achieve the total synthesis of Taxol. And indeed, this is actually our final route. The 5th generation route was already laid out 2 years ago from now.<br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiwOCjNuNC_mHM_LDE5srW61o1JtVUeIRUwU2fuShtrpeJXMz-sxZf2FFvgqEEQe3OGTNeLLxqDJpuos5NKuSjiStFsz-slIY60hjnZcdtezr0e5ptXjW_AKfPHhF958xxc8b6M5Da59yA/s1600/C%25E2%2580%25937+ox+relay.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="99" data-original-width="334" height="94" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiwOCjNuNC_mHM_LDE5srW61o1JtVUeIRUwU2fuShtrpeJXMz-sxZf2FFvgqEEQe3OGTNeLLxqDJpuos5NKuSjiStFsz-slIY60hjnZcdtezr0e5ptXjW_AKfPHhF958xxc8b6M5Da59yA/s320/C%25E2%2580%25937+ox+relay.jpg" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">C–7 oxidation relay.</span></td></tr>
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The day I was confirming the stereo- and regioselectivity of this reaction, Phil was obviously excited. He came to my office asking how the 2D NMR looked every 40 min, even after I told him my NMR wouldn't even start in 4 h. In sum, with all key structures installed, it took only <100 experiments (including scale up) to pave the route to this key intermediate. </div>
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">The photo evidence Phil chasing me around.</span></td></tr>
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After the completion of two key oxidations, our substrate and Holton's intermediate looked so similar that we stopped pursuing this route, assuming the downstream reactions should work without problems. Phil Baran is never satisfied when it comes to a synthesis and we started looking into more ambitious strategies (both the 4th generation route and also attempts that were so random that they are not even included in the SI or my thesis). They ended up not being incorporated into the final route but provided some fascinating insights (see SI).<br />
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We never really talked about the <a href="https://www.nature.com/articles/nchem.1196" target="_blank">cyclase-phase</a> in this blog post but we needed to go through the sequence so many times to provide a sufficient quantity of material to do any oxidase-phase chemistry. The cyclase-phase works amazingly well, but our lab is not designed for kg scale reactions and it was just physically tough. I had to run through the entire building and collect all the 5 L flasks from other labs.</div>
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">#scaleupsucks</span></td></tr>
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It was around this time that <a href="http://chemvedals.com/" target="_blank">Chemveda</a> offered us a collaboration opportunity, and prepared >100 g of the cyclase-phase end product. I have to say the cyclase-phase is not the most straightforward sequence, especially on scale. But they bravely undertook it, overcame issues associated with the scale up, and significantly improved the overall sequence. If there's anyone in Pharma looking for a great company to collaborate with, Chemveda is amazing.<br />
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjs79_NJOFtfd1MsCpcqk5JNykFt5zzF_Ktygd68WGUMkHDWn6SdeQJlzVz9PfpYQGv9GGyqDXboaXgCiCj6m55hnFROXEFpRwYN7WsK-FQQKZjyj1wNb-onePkDfrEKO7MWPQUkP7sYRo/s1600/taxadione.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="174" data-original-width="136" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjs79_NJOFtfd1MsCpcqk5JNykFt5zzF_Ktygd68WGUMkHDWn6SdeQJlzVz9PfpYQGv9GGyqDXboaXgCiCj6m55hnFROXEFpRwYN7WsK-FQQKZjyj1wNb-onePkDfrEKO7MWPQUkP7sYRo/s1600/taxadione.jpg" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">The cyclase-phase end product prepared by Chemveda.</span></td></tr>
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In the following year, we were joined by a talented postdoc Hugh, to finally complete the synthesis. As previously mentioned, our intermediate was almost identical to one of Holton's intermediates, so we optimistically assumed the only thing left was to make more material and push it to the finish line. Starting from the substrate shown below, we could indeed intercept Holton's intermediate (see the dirty NMR).</div>
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">(top) Holton's and our substrates. (left) Following the tradition, I celebrated the formal synthesis by drawing the structure, which turned out to be too soon. (right) What small-scale life looks like.</span></td></tr>
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However, that was the time we recalled a lesson <b>"There's no such thing in total synthesis as 'almost done,' nor 'the last scale up.' "</b> The deceptively simple-looking C–4 acetylation (again, challenging steps always look easy on paper) worked in <b>3%</b> yield. We spent as long as 3 months trying to install this small piece, but could not fix the step. We decided to take a detour which fortunately worked out alright. Although Holton's procedures worked on some of our substrates, their reactivities were often different, which required some modifications to reaction conditions. Overall, the end game ended eventually which completed the two-phase synthesis of Taxol. </div>
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;"><span style="font-size: x-small;">Vanilla with banana cream cake. Yes, I put</span> anchovies on pizza.<span style="text-align: justify;"> </span></span></td></tr>
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<span style="text-align: center;">As a reward of 5 years of journey, we got to have a cake thanks to </span><a href="http://openflask.blogspot.com/2020/01/tryptorubin-a.html" style="text-align: justify;" target="_blank">Sol publically shaming Phil</a><span style="text-align: justify;">. In the end, </span>we submitted from home because of the current situation. This also made me defend from home via Zoom (>100 people came!) but it went remarkably smooth! Maybe I am the only Baran alum who got Ph.D. from home?<br />
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">Post-defense Zoo party. Thanks everyone for coming!</span></td></tr>
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I should note that this synthesis was achieved by standing on the shoulder(s) of previous practitioners, of course, including those who worked on the two-phase taxane project before me: Yoshi (the first graduate student worked on taxane project), <a href="http://www.organ.su.se/am/" target="_blank">Abraham</a> (a brilliant postdoc now PI at Stockholm University), Nathan, Mine, Changxia and Yehua. I just joined the lab at the end and happened to be the one to finish this. I would like to thank again all those who dedicated their time to this project.<br />
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– Yuzuru</div>
BaranLabhttp://www.blogger.com/profile/01806245988209508968noreply@blogger.com3tag:blogger.com,1999:blog-51846086760422068.post-23993838060400993802020-04-25T08:21:00.000-07:002020-05-17T13:36:56.841-07:00(–)-Maximiscin<br />
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<span style="font-family: "helvetica" , sans-serif;">Greetings fellow social isolationists.
If you’re here, it may be because you spotted our recent </span><span style="font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;"><a href="https://pubs.acs.org/doi/pdf/10.1021/jacs.0c03202" target="_blank">synthesis of (–)-maximiscin in JACS</a></span><span style="font-family: "helvetica" , sans-serif;">, thanks for stopping
by! If you’re looking for a harrowing tale of anguish, suffering and overcoming insurmountable odds, don’t worry the taxol blog post is coming soon. All jokes
aside, this molecule was no pushover and it took some creative solutions to bring it across the finish line. Hopefully I can convince you of this, while providing a brief distraction from whatever you might be bingeing on Netflix.</span></div>
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">Are you not entertained?</span></td></tr>
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<span style="font-family: "helvetica" , sans-serif; mso-bidi-font-family: "Times New Roman";">Before getting into how we made <a href="https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201306549" target="_blank"><span style="color: lime;">maximiscin</span></a>, it’s worth considering a little about
why we targeted it in the first place. In addition to having a cool name, it has
a relatively unique structure, originating from the union of three separate
biosynthetic pathways. </span><span style="font-family: "helvetica" , sans-serif; line-height: 107%;">The molecule actually
exists as a mixture of interconverting atropisomers, resulting from the hindered
sp<sup>2</sup>-sp<sup>3</sup> bond connecting the pyridone and cyclohexyl
fragments (C3–7).</span><span style="font-family: "helvetica" , sans-serif; mso-bidi-font-family: "Times New Roman";"> Back in 2017, when this project began, the lab was <i>very</i> into decarboxylative cross-coupling.
As a result, we wondered if (surprise, surprise) a decarboxylative cross
coupling could be applied to construct the hindered C3–7<sup> </sup>bond of
maximiscin. Not only would this enable a simplifying disconnection, but it
would also allow us to push the limits of sp<sup>2</sup>-sp<sup>3</sup> cross
coupling, which remains challenging for hindered systems. Additionally, an
alkyl carboxylic acid coupling partner would be more stable than its halide
counterpart, and would be “spring loaded” to undergo radical oxidative
addition, via extrusion of CO<sub>2</sub>. <o:p></o:p></span></div>
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<span style="font-family: "helvetica" , sans-serif; mso-bidi-font-family: "Times New Roman";">After devising a route to our
carboxylic acid coupling partner, we tried a lot of different conditions to
effect the cross-coupling. Nothing worked, until we used a set of ligand-free Ni
conditions initially reported by the <a href="https://pubs.acs.org/doi/10.1021/jacs.7b06288" target="_blank"><span style="color: lime;">Molander group</span></a>.
With <a href="https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201814524" target="_blank"><span style="color: lime;">Ni(dpm)<sub>2</sub></span></a><span style="color: #0070c0;">, </span>our heteroaryl
zinc reagent and Zn powder (organozinc too hindered to homocouple and access Ni<sup>0</sup>)
we were miraculously able to form the cross-coupled product in 9% yield. We
tried many different things to optimize this reaction, (see SI) but could
never dig ourselves out of that 9% hole, and eventually abandoned the cross-coupling
approach. Despite this disappointment, I still think it’s remarkable that we
were able to form the bond at all. The product is doubly alpha-substituted,
doubly ortho-substituted and exists as a mixture of atropisomers. It
represents, to my knowledge one of the most hindered sp<sup>2</sup>-sp<sup>3 </sup>bonds
built using cross coupling. Huge shout-out to Amin Minakar, an amazing visiting
student who slogged through the better part of this cross coupling saga with
me.</span><span style="font-family: "helvetica" , sans-serif;"> </span><span style="font-family: "helvetica" , sans-serif; mso-bidi-font-family: "Times New Roman";"><o:p></o:p></span></div>
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<span style="font-family: "helvetica" , sans-serif;">R</span><span style="font-family: "helvetica" , sans-serif;">ealizing
that our previous disconnection wasn’t going to work out,</span><span style="font-family: "helvetica" , sans-serif;"> </span><span style="font-family: "helvetica" , sans-serif;">we re-tooled our
retrosynthetic strategy. What we came up with was a rather non-intuitive
disconnection, opting to cut the central pyridone right down the middle. Perhaps
naively, we envisaged that the ring could be forged at a late stage from an
activated diacid, by “clicking in” an appropriately designed nucleophile. In
addition to making the synthesis completely convergent, we anticipated this might
ease construction of that constrained atropisomeric ring system by
pre-establishing the hindered C3-C7 bond.</span><span style="font-family: "helvetica" , sans-serif;">
</span><span style="font-family: "helvetica" , sans-serif; mso-bidi-font-family: "Times New Roman";">We also liked that this would allow us to avoid a late stage
pyridone <i>N</i>-oxidation, which I can
tell you from experience is a terrible reaction. For the sake of brevity, I’ll
touch on a few interesting steps we developed along the way.</span></div>
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">Revised retrosynthesis</span></td></tr>
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<span style="font-family: "helvetica" , sans-serif; mso-bidi-font-family: "Times New Roman";">One of the key steps of this synthesis
is a nifty desymmetrizing C-H activation, which defines <i>4 stereocenters</i> in a single step from a <i>meso</i>-carboxylic acid precursor.
It took us a while to find the right directing group/set of conditions,
but we were eventually able to form product in 58% yield with outstanding
selectivity. I’d like to thank Feng-yuan Wang, an incredibly talented vising
undergrad for all his help preparing the various functionalized directing
groups we screened for this reaction. Unfortunately, it wasn’t all smooth
sailing, and I learned an important lesson during this process: never trust an old sealed tube, especially on scale. The consequences of such a decision can
be seen here… extracting that oil bath was not fun. An important feature of
this chemistry was that we could actually remove the directing group after the
reaction (a frequent limitation of C-H activation methods), and could even recycle
it to make more C-H activation substrate!<o:p></o:p></span></div>
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">Desymmetrizing C-H activation</span></td></tr>
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">Sad day in the lab</span></td></tr>
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<span style="font-family: "helvetica" , sans-serif; mso-bidi-font-family: "Times New Roman";">With desymmetrized material in hand, we
turned to a (wait for it…) <i>decarboxylative</i>
homologation to build out the diacid fragment. Our initial tactic used <a href="https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201609662" target="_blank"><span style="color: lime;">conditions previously developed by the lab</span></a>. The
reaction worked beautifully, but our pesky substrate was perfectly setup to do
a 1,5-HAT, generating a more stable alpha-oxy radical. This led to a competing double
addition pathway via trapping of a second equivalent of phenyl vinyl sulfone. We
realized that if we could oxidize that intermediate alpha-oxy radical, it would
provide access to a later aldehyde intermediate directly; what we needed was a
reductant and oxidant in the same pot. We initially had success with photoredox
(PET) chemistry. Blue LEDs aren’t a common sight in the Baran lab, but the
reaction worked so we ran with it. A set of conditions were identified which were
reasonably efficient, but had issues with scalability and purification
(reactions were messy and aldehyde product silica unstable). Nonetheless, this
was an important proof of concept and we continued searching for a more
tractable solution. Specifically, we wanted to get away from the activated
ester and use the carboxylic acid directly. Oxidative decarboxylation seemed
like the obvious solution, and we began investigating the <a href="https://www.organic-chemistry.org/namedreactions/kolbe-electrolysis.shtm" target="_blank"><span style="color: lime;">Kolbe electrochemical decarboxylation</span></a>, motivated by
its robust 100+ year history. Unfortunately for us, we could never get much
more than 5% yield. </span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjf7Wnc6YDwAp3Sj_d1odN4LsNE5C30qBCSOmIPYrx1GQviM65eAeHTtjzOUuresaCDCDY-XaXP8uPVExYMC3J9Mjf4h1rk74-T7YZVIclQjipPwZvjkhHuE9gSfxAOdTKPFgcngQ6k3-o/s1600/picture+2.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="342" data-original-width="420" height="260" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjf7Wnc6YDwAp3Sj_d1odN4LsNE5C30qBCSOmIPYrx1GQviM65eAeHTtjzOUuresaCDCDY-XaXP8uPVExYMC3J9Mjf4h1rk74-T7YZVIclQjipPwZvjkhHuE9gSfxAOdTKPFgcngQ6k3-o/s320/picture+2.png" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">Other motivating factors were also at play</span></td></tr>
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<span style="font-family: "helvetica" , sans-serif;">What ended up saving my (Canadian) bacon were the humble
Minisci conditions: Ag</span><sup style="font-family: Helvetica, sans-serif;">+</sup><span style="font-family: "helvetica" , sans-serif;"> and persulfate. Although the initial yield
was modest (6%), we discovered a pretty cool Fe co-catalyst effect, which led
to a remarkable enhancement (71%). This finding was completely serendipitous,
we were evaluating other more common radical oxidants (e.g. Cu), and Fe was
sort of an afterthought – it almost didn’t get screened. We think it may be
acting as a selective radical oxidant; it’s known from the </span><span style="font-family: "helvetica" , sans-serif;"><a href="https://pubs.acs.org/doi/10.1021/ar50088a003" target="_blank"><span style="color: lime;">old Fenton literature</span> </a></span><span style="font-family: "helvetica" , sans-serif;">that Fe will selectively
oxidize alpha oxy radicals, but leave other alkyl radicals untouched. The final
conditions could be run one-pot, directly from the lactone after </span><i style="font-family: Helvetica, sans-serif;">in situ</i><span style="font-family: "helvetica" , sans-serif;"> hydrolysis, and proved highly efficient
on scale (91%). As an added bonus, the crude material was remarkably clean (see
crude NMR) and could be telescoped into the next step, which solved our aldehyde
purification issues. I think there are two important lessons here: (1) don’t
overlook the simple solution – we started out using some very trendy, very
powerful methodologies, but ultimately <a href="https://www.sciencedirect.com/science/article/pii/S0040402001977683" target="_blank"><span style="color: lime;">dump and stir chemistry from the 70’s</span></a>
worked the best; (2) don’t talk yourself out of an experiment – it’s not as
satisfying, but sometimes blind screening is what gets the job done.</span></div>
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">Decarboxylative homologation </span></td></tr>
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">Crude NMR using one-pot Minisci conditions</span><br />
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<span style="font-family: "helvetica" , sans-serif; mso-bidi-font-family: "Times New Roman";"><span style="font-size: small;">After a few more steps, it was finally
time to roll the dice on our late stage pyridone synthesis. Our first attempts
came up snake eyes – when we combined our diacid chloride electrophile with a
functionalized oxime-ether nucleophile (X=H), we ended up with some pretty sad
looking reaction mixtures. Our diacid electrophile pooped itself, as the
reaction color suggested, and we recovered the oxime-ether nearly
quantitatively. We had to tweak our initial conditions quite a bit, adding
AgOTf to activate our diacid electrophile, and using a silane to spice up the nucleophilicity
of our oxime-ether(X=TMS). The latter modification was an interesting
development, and led to the creation of an “aza-Sakurai”-type system. An added
benefit of this TMS activation effect was that it generated TMSOTf <i>in situ</i> (TMS derivatization observed by
LCMS). This led to capping of our pyridone C-4 OH in non-polar reaction solvents (e.g. PhMe) and
prevented product from reacting with activated diacid starting material.
Unfortunately, despite giving the best yield, acetonitrile proved too harsh for
the TMS group to survive, leading to some derivatization of product with
starting material. Fortunately, we found that a simple methanol quench could
liberate derivitized product and return the diacid as a mixture of mono- and
dimethyl-esters. Our final set of conditions delivered the protected natural product
in 41% yield. Luckily for us, the final deprotection went smoothly, to reveal maximiscin and complete our synthetic journey. Special thanks to the isolation chemists
Dr. Lin Du and Prof. Robert Cichewicz for sending us authentic material for
comparison.</span></span></div>
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<span style="font-size: small;">Initial attempts at pyridone synthesis</span></div>
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<span style="font-family: "helvetica" , sans-serif; mso-bidi-font-family: "Times New Roman";">It’s interesting to consider how this
synthesis evolved over time. We started with the goal of developing a hindered
cross coupling reaction, but this morphed into a completely different strategy,
and resulted in the development of some pretty cool chemistry. There were
certainly ups and downs on this project, but overall I had a blast making
maximiscin – I even got a cake for my efforts (don’t worry, <a href="http://openflask.blogspot.com/2020/01/tryptorubin-a.html" target="_blank"><span style="color: lime;">Sol finally got his cake too</span></a>). Thanks for reading!<o:p></o:p></span></div>
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<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: small;">Let them eat... molecules?</span></td></tr>
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– Kyle M.<br />
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<span style="font-family: Helvetica, sans-serif; line-height: 107%;">Edit: Some people have asked about the
mechanism/stereomodel for the C–H activation step. </span><span style="font-family: Arial, sans-serif; line-height: 107%;">Unfortunately we were never able to isolate a palladacycle to
validate our stereomodel. Based on the plastic model, there is obvious steric
clash between the <i>t</i>-Bu of the directing group and one of the
alpha-methyl substituents. We think this leads the palladium to C–H activate
one methyl group selectively via CMD mechanism (J. Am. Chem. Soc. <b>2008</b>, <i>130</i>,
10848) to give the favored Pd(II) cycle. This is oxidized by NaIO4 to Pd(IV)
which can undergo reversible X-ligand dissociation to form a cationic complex
(J. Am. Chem. Soc. <b>2014</b>, <i>136</i>, 12771). The latter
species is trapped by methanol in an SN2 fashion to give product.</span><o:p></o:p></div>
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