A Baran lab cycle of discovery: hydromethylation of unactivated olefins

If the Baran lab cycle of discovery was a baseball field, total synthesis is like the home plate where much of the action takes place. Just like a baseball player trying to score a run, a graduate student who joins the lab has to go through the first base of making a natural product, the second base of designing new strategies, the third base of finding new methodologies and back to home plate to complete the discovery cycle.

In my last project, I barely made it to the first base with the synthesis of some steroid skeletons. When I was about to continue “the cycle” with some ideas for a further development, Phil told me not to, and convinced me to start a seemingly non-related project, a method for an overall addition of a methane molecule to unactivated olefins.

How did we start?

  During the preparation for the manuscript of the last project, I went to Phil to get his opinion on how to describe the figure (below) more convincingly.

   Me: Since I did not make the methyl in the C,D-ring junction, how should I describe it?

   Phil: (Looks at the figure in 3 seconds)…why don’t you make it. 

   Me: uhh???(Thinking about his “irrelevant suggestion”!!! Com’on Phil!I just want to PUBLISH it).

  Phil: You can make an olefin in the D ring using Hans’ method, and add a methyl group to it…maybe useing our reductive iron coupling.

   Thinking about Phil’s suggestion more carefully, I actually liked it because it would fulfill my dream of making five different classes of steroids from the same intermediate, thus completing the idea of making a “steroid pyramid” using the idea of two-phase synthesis. So I decided to give it a try.  I quickly observed some C-C bond formation with N,N-diphenylhydrazones and O-benzyloximes while trying to wrap up the previous project.

Quentin made the first tosyl hydrazone in the lab based on studies reported by Kim and coworkers. However, after two weeks of investigation, we only got some undesired rearrangements but not C-C bond forming product. Based on the previous result with other hydrazones and oximes, I had a strong belief that the C-C bond between the olefin and tosyl hydrazones should also work. In addition, a quick search showed the feasibility of reductive C-N bond cleavage under basic conditions. Putting these things together, a two-step sequence could be envisioned. It took me a few days to prove that the C-C bond formation with a tosyl hydrazone was indeed feasible; however it took me more than a month to achieve the first C-C bond adduct with formaldehyde tosyl hydrazone, The rate-determining steps in this process were finding the conditions for in situ formation of the hydrazone and determination and suppression of the byproducts. Importantly, the C-N bond cleavage was also obtained just by heating the reaction mixture after C-C bond formation to 60 ^oC in methanol. Chao then joined the project, and in only a week he quickly modified conditions to a standard two-portion conditions to solve some reproducibility issues as well as improve the yield.

   During a discussion, Phil mentioned that we should call our methodology “a molecular editing method”. So two criteria for substrate scope were to have substrates with a “real name” and substrates with complexity. The good thing about the formal criterion is the diversity of the repertoire of commercially available compounds, as we basically just went through Sigma-Aldrich and TCI catalogs and ordered substrates with olefins. Commercially available terpenes such as carvone oxide, limonene oxide, dihydrocarvone, carene, rose oxide, dihydromyrcenol… all worked under our conditions but we could not separate the desired hydromethylated product from the hydrogenated byproduct; this problem is by far the biggest issue of the current work

While most of the work was completed at TSRI, in the other side of the country, Brad Maxwell at BMS tried to apply our method in radiochemistry. I told Brad that it would be my dream if he could make it because I don’t think I will have a future occasion to have radioactivity data in a publication that I co-author, and he did it amazingly with a complex terpene called rotenone using a very low concentration (ca. 1.5%) of [¹⁴C]formaldehyde. Here is what Brad taught us about the origin of ¹⁴C:

“Typically, ¹⁴C is not naturally in enriched form since it is not abundant enough to make the process feasible. Instead, ¹⁴C is produced by irradiating solid beryllium, aluminum nitride or saturated ammonium nitrate solution with neutrons for 1–3 years in a ¹⁴N (n,p)¹⁴C reaction within a nuclear reactor. Longer irradiation times produce higher specific activity of ¹⁴C. In the process, the ¹⁴N is converted to ¹⁴C. After the irradiation, the material is dissolved in H₂SO₄ and the effluent gases are oxidized by an appropriate catalyst.  The resulting  [¹⁴C]CO_2(g) is then passed through NaOH_(aq) and it is eventually precipitated as Ba[¹⁴C]CO₃ from which all ¹⁴C-labeled products are prepared. The only current producers of ¹⁴C are located in Russia.” 

   Looking back on what we had made in term of (radio)labeled compounds with the current method, Phil might be right when he said: “Since there is no other way to do this sort of methyl editing, even if it is a long reaction time and a complex reaction system, people still have to use it.”

   Like a baseball player who undergoes the process of bating (hitting the ball/failing/trying to hit again), running to the next base, getting tagged out by the opponent and repeating the process again until scoring. Total synthesis requires a lot of trial and error, with a lot of time spent in going back and changing the strategy. In this project, the most important moment might be the lessons that we learnt during the previous synthesis (of steroid skeletons), gave us hints to the discovery of hydromethylation of olefins. Personally, I enjoyed my experience in the lab; however, one thing I still could not fully capture is how our “coach” makes his decisions. Most of the time just in the blink of an eye, and sometimes it just comes from nowhere…but it actually works (at least in my two projects).

Back to Heterocycles!

I guess this blog entry could be called "The Portable Chemist's Consultant Part 5” (see Part 4 here)

First off, we have new book updates (latest version 2.6.1), as listed in iTunes and on the book's website. 

In about ~2 years from the first launch of the book, its volume has roughly doubled in size. If you purchased the initial version of the book, all the updates were provided for free, and this will remain as such. This is in contrast to a traditional textbook, for which the consumer must pay every time a new edition is published. It is our belief that every good product out there should provide updates for free, much like Apple’s OS X Mavericks or Yosemite upgrades. Although our heterocyclic e-book may fall short of Apple’s contents and designs, our ultimate goal is to keep updating our work until we get there.

Speaking of a two-year anniversary, we also have another update to heterocyclic chemistry—that’s Phil’s Heterocyclic Chemistry Course 2015. The course is available on iTunes U, much like the class that was held in 2013 (but the videos are of better quality now and they don't have any cutting-off issues from last time). This course has been recently held every 2 years from April to June and we are currently headed into its final weeks, which includes the final exam. :)  Feel free to take a look at the midterm as well.

Happy Heterocycling!
Yoshi

Formal Olefin Hydroamination With Nitroarenes

Our latest work in the field of iron chemistry came out today in Science. First we would like to present a graph (shown below) on how this newly developed chemistry could simplify the synthesis of some biologically active intermediates: starting from the same starting material, this reaction only took one step and 1 hour to get the desired product, while the traditional route required 3 steps and 29 hours in order to get the same product. Taking all the estimated cost (materials and labor, for 1.5 g product) into account, this chemistry would start from 30¢ of iron catalyst, and save the total cost by ca. $1388 (1.2 oz of gold). In essence, this is the modern equivalent of the Alchemist’s dream of turning iron into gold.

Unlike our previous two papers in this area, which focused on the formation of C–C bonds, this time we developed a method for the construction of C–N bonds, more specifically, a reaction for the synthesis of highly hindered secondary aryl amines. Since all the scientific details are described in this research article, this blog post will serve to give our readers the background of this project.

First, how we discovered this reaction is a story on its own. During an ongoing project regarding new applications of iron-mediated bond formation, an unexpected product was isolated in 17% yield (scheme below). After full characterization, it was clear that it was a secondary aryl amine derived from a formal hydroamination process between the olefin and nitroarene. At that time, I didn’t fully realize the importance of this product and the transformation that had occurred, so I only reported this “unexpected” result to Phil after TWO weeks. But in 10 seconds, he replied: “Wait! Wait! This reaction is interesting!” In another 1 min, Phil was able to convince me (which he is naturally good at) of the high novelty of this discovery, and from then on, this new approach of hydroamination was developed.

Second, the mechanism of this reaction is indeed complicated. Even though we had performed a series of control reactions, we are still not quite sure what actually happens in the reaction. For this reason, we decided to move the mechanism proposal from the main text into the SI (detailed discussion on mechanism there). But in general, we propose that the nitrosoarene is the reactive intermediate, and the unique effectiveness of the iron catalyst plays a key role: it reduces the nitroarene to the nitrosoarene, and the olefin to the alkyl radical; then, these two reactive species combine with each other without over-reduction by the iron catalyst to give a fully reduced aniline or an olefin hydrogenation product. Notably, the cobalt and manganese catalysts completely failed in this reaction, since they were shown to be unable to reduce the nitroarene to the nitrosoarene (a convincing TLC plate is shown in the SI, Fig. S2). 

Third, in the paper, we presented over 100 examples to show the broad scope and generality of this reaction, which seems to be an unusually large number for a methodology paper. But in fact, this project only took 6 months from beginning to end due to some great teamwork. On the one hand, with the fantastic teammates (Eddie, Jin, Tian and Julian) at Scripps, we managed to build up the substrate scope, synthetic applications, as well as limitations very quickly and efficiently; on the other hand, through working with industry (BMS & Kemxtree), this chemistry was field-tested immediately by different research organizations. In late February of this year, our lab published our views regarding academia–industry symbiosis. Indeed, this project is another good example for the collaboration between academia and industry. As you could see in the main text and the SI, the examples provided by BMS (marked in blue in the SI) exemplified its utility in medicinal, process, and radiochemical settings, and the decagram-scale results provided by Kemxtree (also marked in blue in the SI) showed its feasibility in large-scale settings. 

Lastly, it is our lab’s publication tradition to show the limitations of the methodology being developed, in order to give the readers a better understanding of the reaction. Some of the limitations for the hydroamination are shown in Fig. 5 of main text, and here we provide more examples. The contents below may be helpful for those who decide to give this reaction a try for similar substrates.

Academia–industry collaboration in the route optimization of taxadienone

In early 2012, we reported the gram-scale synthesis of a non-natural taxane, taxadienone, as well as that of a natural taxane, taxadiene. Now, chemists at Albany Molecular Research Inc. (AMRI) report a route optimization of taxadienone in none other than the process chemistry journal, OPRD.

Before we describe how the story of this collaboration came about, we will take you through the route optimization process. The synthetic route itself is identical, as all the intermediates of our synthesis appear in their synthesis as well, but the reactions have been scaled up and the yields have been improved. 

Reaction scale-up: We made ~2 g of taxadienone whereas AMRI made ~10 g.

Reaction yields: Please see the figure below.

Although the contents of AMRI’s paper will not be reiterated, we will show their concluding paragraph here (almost verbatim from their manuscript):

“The reported route to taxadienone was successfully optimized and scaled-up to decagram quantity. Thermal hazards associated with the production of bromodiene were addressed by employing a continuous flow reactor. The crystallization of a cyclized diketone at the penultimate step proved to be a decisive factor for obtaining taxadienone of high quality.”

Now, as for the behind-the-scenes story. This story started out as an interesting “experiment” in academia-industry collaboration. Our laboratory is engaged in many collaborations with industrial groups, including LEO Pharma, Bristol-Myers Squibb, and Sigma-Aldrich, and in most cases, our industrial partner has a project goal toward which we provide expertise and in-house research findings (industry —> academia outsourcing). This Baran–AMRI collaboration has actually been a “reverse collaboration” in which our initial synthetic route was taken up by an industrial group for scale-up (academia —> industry outsourcing). Through many interactions, by email, by phone and in person, AMRI saved our group much time and effort by generating large amounts of enantioenriched taxadienone. With this extra time in hand, we were able to study the front-line chemistry for longer periods of time, resulting, for example, in the synthesis of taxuyunnanine D. AMRI’s work also validated our synthesis by having an independent group reproduce our results, even when some of the reactions can be tricky. This “field-testing” of chemistry further refined our initial work, when some reactions were difficult to scale up (even though our initial synthesis was performed on a decent scale already). 

Although this sort of “reverse” academia-industry collaboration is rare, we learned a lot from this experience! We understand that there is a time and place for this type of collaboration but we believe that in the near future, such collaborative work will be more commonplace. Finally, this is a wonderful advertisement for the impressive capabilities of the AMRI team and we recommend all our industrial friends that are looking to outsource challenging chemistry to give AMRI a try!

www.amriglobal.com

Written by Yoshihiro Ishihara

Uploaded by Nathan Wilde

Functionalized Olefin Cross-Coupling

Figure 1. Functionalized olefin cross-coupling at a glance.

The last paper of the year from the inner depths of our lab has made its way out earlier today. It’s the bigger brother of our reductive olefin coupling paper from January. In a nutshell, reductive olefin coupling allows chemists to break apart molecules into carbon-substituted donor and an acceptor olefins. By using an iron catalyst (available through Sigma-Aldrich if money is no object) and PhSiH₃, one can easily forge a C–C bond between those two components. However, all of the products we made in the last paper could already be accessed using other radical conjugate additions since they proceed through the same intermediates.

The new paper kicks things up a notch by throwing heteroatoms into the mix, expanding the scope beyond carbon substitution. Functionalized olefin cross-coupling allows the periphery to be decorated with various heteroatoms. And by various, I don’t mean just one or two types. I mean NINE different types. We even had a nifty graphic to show this, but it never made it to the final draft of the paper.

Figure 2. Heteroatoms utilized in this paper.

As you can see from Figure 2, you can have the donor olefin substituted with pretty much any element you would want to use as a synthetic organic chemist. Traditionally, heteroatoms throw a wrench in the generation of nucleophilic radicals, as they result in starting materials that are either labor intensive to synthesize, are chemically unfeasible entities, or lead to functional group incompatibilities or other chemoselectivity difficulties. Functionalized olefin cross-coupling easily circumvents all of these problems, allowing one to use the hundreds of thousands of heteroatom-substituted olefins that are already readily accessible as latent radical donors. The neatest part of the work conceptually is that you can basically treat all of these heteroatom-substituted donor olefins the same regardless of the exact identity of the heteroatom involved. This is unlike traditional heteroatom substituted olefins where the identity of the heteroatom typically dictates the reactivity of the molecule (e.g., the traditional reactivity of enol ethers in no way parallels the reactivity of vinyl iodides).

The bulk of this work is embodied in Figure 3 in the actual paper. It has some generic caption like “Adducts synthesized by functionalized olefin cross-coupling,” but we’ve always internally referred to it as the “carpet bomb,” which was a term coined by PSB himself. What started out as 10 entries began to multiply like rabbits. At one point I was joking with Phil saying, “before you know it Phil, we’re going to have 100 substrates!” and he got this kid-in-the-candy-store look in his eyes. I then realized I pretty much shot myself in the foot at that point, but luckily we capped out at around 60 substrates.

As a consequence of the size of our carpet bomb, we naturally found some cases where our reaction didn’t give the best yields. We actually decided to include some of those in the paper, but we were afraid that the reviewers would reject it if we stuffed it full of too many low yielding results. Since the best part of a paper is finding out what didn’t go so smoothly, I’ve decided to compile a table of around half of our low yielding results, along with a few examples that didn’t make the paper for one reason or another. The contents could be useful for those who just need to make their product and don’t necessarily care about the yield.

Table 1. Functionalized olefin cross-coupling B-sides.

A fair amount of the products in Table 1 were synthesized during some feasibility studies that I ran in February and were never later optimized (see compounds 1, 3, 8, 12, and 13). Truth be told if we got extremely low yields on the initial hit, we usually opted to abandon the donor immediately to find one that gave a higher yield. Dichloride 4 was an interesting adduct since the corresponding donor contained a pretty sensitive allyl chloride functionality. Despite the conditions for our reaction being pretty mild, they still competitively reduced the allyl chloride to generate an adduct analogous to 4, but bearing an additional methyl group instead of the chloromethyl group. Additionally it’s worth pointing out that yields with phenyl vinyl sulfides bearing extra substitution around the olefin (9–11) were pretty low even though the analogous alkyl vinyl sulfides were competent donors (see 51 and 52 in the actual paper). 

After we submitted the paper, we realized that we didn’t have nearly enough substrates with nitrogenous heterocycles for a PSB paper, so that’s the reason for the inclusion of pyridine 2 and the super med chemmy 5 in Table 1. We were also able to show post-submission that a vinyl phosphonate (6) and a vinyl phosphonium salt (7) could be used could be used as donors to generate classes of adducts, albeit in moderate yields, that can be used for subsequent Horner-Wadsworth-Emmons and Witting olefinations.

Figure 3. Running the reaction in unconventional solvents.

On a less serious note, after group meeting one day, Phil told me to go to BevMo and pretend I was shopping for solvents for our reaction. The thought was that since we typically run the reaction in ethanol, it’d be pretty cool to see if we could also use various spirits as a solvents. Successful couplings would show that our reaction could tolerate a sea of random flavor and aroma compounds. Sounded like a good task for a Saturday and it was an even better Saturday when we found out that it worked! After our first round of success with vodka, tequila, gin, and whiskey, we found that Stone IPA, a chardonnay, and a merlot also worked as solvents. The purple/reddish spot at the top of the TLCs in Figure 3 is the desired coupled product.

For my previous project’s blog post, I made a video of myself setting up a reductive olefin coupling. However, having a seasoned reductive olefin coupler setting up the reaction just doesn't do justice to how easy it really is. What’s now pretty routine for me might not be easy for someone who’s never touched Fe(acac)₃ and PhSiH₃ before. I’ve spent a decent amount of time thinking about people who could possibly make a guest appearance in the video this time. A couple of months ago, I told my mom how she could probably set up the reaction in her kitchen. But from a safety standpoint, it’s probably not the best idea for her to be cooking up methyl vinyl ketone outside of a hood. Then I thought about the lab admin. She’s not a chemist at all—sounds perfect! But she did set up that zinc sulfinate (now branded as Baran Diversinates, name courtesy of Sigma-Aldrich) trifluromethylation of caffeine so she did do some chemistry recently. I needed someone significantly rustier than her. Someone who hasn’t set up any sort of reaction in years…

I eventually found the perfect person to set up a functionalized olefin cross-coupling reaction. It’s so easy, even a PI can do it.