Monday, October 5, 2020

Adventures in P(V) Chemistry

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

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

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

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

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

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


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


-Kyle and the P(V) team 

Monday, July 20, 2020

Tagetitoxin: Total Synthesis with Friends

Our recently completed synthesis of tagetitoxin was just published in JACS. 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. Warning: long blog post ahead!

Hang Chu (Oct. 2016 – May 2018)
While searching for another molecule to pursue after the thapsigargins, Phil sent me Porter’s paper, 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? 

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. 

 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). 
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.

David Kossler (Mar. 2018 – Jan. 2019)
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 via an oxidative furan rearrangement. As the stereoselective installation of the sulfur was problematic, he envisioned a relay via 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 [3,3]-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.

 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. 

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 trans-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 Js would have not correlated at this stage, it would have raised a big question mark that we were following the real structure of tagetitoxin.
 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.

Tom Stratton (Jan. 2019 – Jun. 2020)
Fresh from our recent herquline 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.

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.
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!
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 hard. 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. 
Dillon M. Flood has saved my ass more than once. Whether it be stuck on a 50sketchy 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 E. coli RNAP. What a guy! I’ll see you up north, my friend.
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. 
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. 

Kelly Eberle (Sep. 2019 – Jan. 2020)
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.
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.

Chi He (Jan. 2019 – Jun. 2020)
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. 

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. 
 Des-P tagetitoxin was easily generated by convenient workup after exhaustive hydydrolysis by Ba(OH)2. We were excited to find the chemical shifts and J-values in 1H NMR of des-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  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 des-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. 
 To improve the solubility in organic solvents, we protected the free amino alcohol as the hemiaminal. After methanolysis, 18’ 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 (+)-Ψ reagent 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 19a and obtained both (+)-tagetitoxin and (–)-tagetitoxin in two more steps.
 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 1H-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 13C-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. 

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!

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!! 🍻

Dillon Flood (Jan. 2020 – Jun. 2020)
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.

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. 
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 in vitro 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. 

Saturday, June 6, 2020

Realities of management style

(From Baran lab grad students, opinions entirely our own and may not reflect Phil or Scripps)

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.

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.'

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?"

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.

Don't believe me? Here are some emails from the boss (highlighting my own for emphasis):

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.

As it turns out, I know Phil will too:

Friday, June 5, 2020

Message to Organic Chemists

Dear Scripps Community,

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 Angew. Chemie, one of our premier journals.  This topic we feel is appropriate for us to address.

First, the Essay offers opinions that are not even relevant to the field of synthesis – odd given its title: “Organic synthesis—Where now?” is thirty years old. A reflection on the current state of affairs,”. 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 Angew. Chemie would somehow permit such an essay to pass the rigors of peer- and editorial-review. 

Second, the comments about diversity and inclusion (in green below) are at best ill-informed or ignorant, at worst malicious: 

“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.”

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.

“It follows that, in a social equilibrium, preferrential (sic) treatment of one group leads to disadvantages for another.”

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. 

Third, and even more insidiously, we mention a point made by Jake Yeston of Science 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:”

 “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.”

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.

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. 

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. 

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 passionate about chemistry during these challenging times! 

Donna Blackmond and Phil Baran


1.     Huryn, D.; Bolognesi, M. L.; Young, W. B. Medicinal Chemistry: Where Are All the Women? ACS Med. Chem. Lett20178, 900−902.
2.     Ruck, R.T.; Faul, M.M. Gender Diversity in Process Chemistry,  OPRD, 201923, 109-113.
3.     Sanford, M.S.; Chiu, P.; Kozlowski, M.C. Celebrating Women in Organic Chemistry. Org. Lett. 202022, 1227-1230.
4.  Thanks to Prof. Tehshik Yoon for this compilation of resources:

Monday, May 18, 2020

Guest Post: My Job Search Experience During the Great Recession

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!


My Job Search Experience During the Great Recession
Jesse J. Sabatini

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. 
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.
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.
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.
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.
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. 
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.
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. 
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.
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.
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.
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.
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.
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!
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. 
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!
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):
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.
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.
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.
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.
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.
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.
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.
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. 
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.
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.
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.
Please feel free to reach out to me at if I can provide any more pointers, help, advice, etc. Best of luck to you all, as you navigate your job search.
Best wishes,
Jesse J. Sabatini, Ph. D. 
Team Leader-Energetic Materials Synthesis
US Army Research Laboratory
Energetics Synthesis & Formulation Branch
Aberdeen Proving Ground, MD 21005