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

References

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: https://threadreaderapp.com/thread/1268968586065915905.html

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 jesse.j.sabatini.civ@mail.mil 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

Thursday, May 14, 2020

Taxol

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 JACS articlePLEASE READ the SI 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.

My first TOC draft. Phil said no.
In Dec 2015, a super postdoc Shige (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 sp3 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.

Around this rough time, we got a letter from another, more junior, "Baran", which made daddy smile and me pale.
We were happy to "complete" one of the two most difficult oxidations. However, the happiness in total synthesis always has a short half-life 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. 

Never saw the physical state of compounds until we started collecting SI, since we never had enough material to see it.
This deceptively benign-looking reaction took us 2 years (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. 

For the C–7 oxidation, with the C–5/6 epoxide installed, the oxidation relay 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, tert-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.

C–7 oxidation relay.
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. 

The photo evidence Phil chasing me around.
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).

We never really talked about the cyclase-phase 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.

#scaleupsucks
It was around this time that Chemveda 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.

The cyclase-phase end product prepared by Chemveda.
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).

(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.

However, that was the time we recalled a lesson "There's no such thing in total synthesis as 'almost done,' nor 'the last scale up.' "  The deceptively simple-looking C–4 acetylation (again, challenging steps always look easy on paper) worked in 3% 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. 

Vanilla with banana cream cake. Yes, I put anchovies on pizza. 

As a reward of 5 years of journey, we got to have a cake thanks to Sol publically shaming Phil. In the end, 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?

Post-defense Zoo party. Thanks everyone for coming!
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), Abraham (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.

– Yuzuru

Saturday, April 25, 2020

(–)-Maximiscin


Greetings fellow social isolationists. If you’re here, it may be because you spotted our recent synthesis of (–)-maximiscin in JACS, 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.

Are you not entertained?

Before getting into how we made maximiscin, 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. The molecule actually exists as a mixture of interconverting atropisomers, resulting from the hindered sp2-sp3 bond connecting the pyridone and cyclohexyl fragments (C3–7). Back in 2017, when this project began, the lab was very 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 bond of maximiscin. Not only would this enable a simplifying disconnection, but it would also allow us to push the limits of sp2-sp3 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 CO2


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 Molander group. With Ni(dpm)2, our heteroaryl zinc reagent and Zn powder (organozinc too hindered to homocouple and access Ni0) 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 sp2-sp3 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.


Realizing that our previous disconnection wasn’t going to work out, 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. We also liked that this would allow us to avoid a late stage pyridone N-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.

Revised retrosynthesis

One of the key steps of this synthesis is a nifty desymmetrizing C-H activation, which defines 4 stereocenters in a single step from a meso-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!

Desymmetrizing C-H activation

Sad day in the lab

With desymmetrized material in hand, we turned to a (wait for it…) decarboxylative homologation to build out the diacid fragment. Our initial tactic used conditions previously developed by the lab. 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 Kolbe electrochemical decarboxylation, motivated by its robust 100+ year history. Unfortunately for us, we could never get much more than 5% yield. 

Other motivating factors were also at play
What ended up saving my (Canadian) bacon were the humble Minisci conditions: Ag+ 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 old Fenton literature 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 in situ 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 dump and stir chemistry from the 70’s 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.


Decarboxylative homologation 
Crude NMR using one-pot Minisci conditions

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 in situ (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.



Initial attempts at pyridone synthesis

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, Sol finally got his cake too).  Thanks for reading!

Let them eat... molecules?
– Kyle M.


Edit: Some people have asked about the mechanism/stereomodel for the C–H activation step. 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 t-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. 2008130, 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. 2014136, 12771). The latter species is trapped by methanol in an SN2 fashion to give product.