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The Realm of Organic Synthesis

August 15, 2009
11:53
Update
» ‎ The Realm of Organic Synthesis

Contrary to popular opinion, I’m alive, well and trying to get established in a new part of the country. Please sit tight.
July 19, 2009
14:22
A Brief History Lesson
» ‎ The Realm of Organic Synthesis

I recently Googled the name “John Roberts.” It turns out that the search ended up being a bit too broad. Apart from websites concerning the Chief Justice of the US Supreme Court, a New York-based comic and a collection of spas operating in Ohio, the name John Roberts has seemingly little to do with chemistry (at least in the public eye). Dig a bit deeper, and you’ll find information about a John D. Roberts of Caltech fame.

I draw attention to Roberts because of his recently published JOC perspective—a brief autobiography spanning the development of organic chemistry over the past 70 years (J. Org. Chem. 2009, 74, 4897-4917). Being a true lover of historical perspective, I found Roberts’ essay to be informative about how research was conducted years ago. Sure, we can read about secondhand accounts of “old school” organic chemistry in textbooks, but there’s really no substitute for vivid, subjective stories from primary sources.

What really jumped out at me (in the article) was the breadth of background Roberts gained before really delving into true organic chemistry. I think this is a trait we (as organic chemists) can relate to; our lives don’t just revolve around carbon-carbon bond formation or chemoselectivity. We supplement our training with spectroscopy, biochemistry, quantitative analysis, metals, quantum mechanics, history and/or business.

In other news, I’ve been busy finishing up last minute experiments before departing my research lab for a completely new part of the country and employment that doesn’t involve lab glasses or dressing like a graduate student (I’m deciding if I want to blog about that at a later point). I realized earlier today that by social standards I’m officially beyond ABD. All I have to do is walk.

My tasks as of late have involved synthesizing metal-hydride complexes, teaching undergraduate laboratories, advising undergraduate researchers and wrestling with a damn sulfonamide that doesn’t want to go into solution very well (though, I think as of this weekend, I’ve officially tamed the beast).

Headed back into the lab. Wish me luck.
July 01, 2009
16:21
Intellectual Property Forum
» ‎ The Realm of Organic Synthesis

Please spread the word:
If you have nothing to do in the late summer months, there's always Beijing. The second annual Internatioinal Pharmaceutical and Chemical Intellectual Property Forum will be taking place in Beijing, China (August 5-8, 2009).
ACS Chemistry and the Law members (Division website) can register for a significantly discounted price.
For more information, please visit the Forum website ( [www.chinaipforum.net] ).
June 30, 2009
12:26
Bees
» ‎ The Realm of Organic Synthesis

While replacing the specialty gas line in my hood, my brand new undergrad made an discovery in the cap. I’ve posted the photographic evidence below (a data collection courtesy of my new BlackBerry). My undergrad (let’s call him “Mr. Smith”) claimed that he didn’t want to be working in the lab and get stung (an outlier scenario, I know). We sent the cap back with our good friends from Airgas.
June 25, 2009
10:27
Utility in the Strecker Reaction
» ‎ The Realm of Organic Synthesis

Today, over breakfast, I decided to peruse the literature (courtesy of ChemFeeds).

One paper that really jumped out at me was Grygorenko’s synthesis of conformationally restricted amino acids (CRAAs; link to ASAP). I thought that this paper was interesting for various reasons. Although I won’t attempt to dissect the purpose (the authors claim that these molecules are “very important to drug design”; to each his or her own), I will raise a red flag at the graphical abstract (which I reproduced in ChemDraw). From an organic chemist’s perspective, ask yourself “what’s wrong with these molecules.” I’m surprised a referee didn’t pick up the mistake.
Chemical semantics aside, the authors contend that commonly employed chiral routes involve disconnection at the C-N bond in the 2-azabicyclo[3.1.1]heptane-1-carboxylic acid. Thus in these strategies, the bicyclic[3.1.1] framework derives from the corresponding n-halocyclobutane amino acid through a 6-exo-tet cyclization.
I was fascinated by the authors use of the Strecker reaction to prepare these compounds. Adolph Strecker purportedly reported the first instance of what is now called the “Strecker” reaction. The reaction involves the treatment of a carbonyl with an amine in the presence of a cyanide anion to create an a-amino acid via formation of an aminonitrile. Hydrolysis of the nitrile moiety results in the formation of the carboxylate.
From an electron pushing perspective, the Strecker reaction is a somewhat complex transformation involving lots of minor, simple details. In Grygorenko’s synthesis, benzylamine mediates the initial deprotonation of the cyanohydrin thus generating the cyanide anion and acetone. Keep in mind that the ammonium will likely be at equilibrium with HCN formation given their relative pKa values.
Acid-catalyzed iminium formation is performed by the benzyl amine. The resultant positive charge is quenched through nucleophilic attack of the cyanide anion, thus resulting in formation of the secondary benzyl amine. Finally, 6-exo-tet cyclization results in the formation of the bicyclic nitrile. Acid-catalyzed hydrolysis converts the nitrile into the corresponding carboxylate (not shown, dig out your sophomore organic textbook).
P.S. I apologise for the length of time between posts. Long story short, I successfully defended my Ph.D. research ~2 weeks ago and have been finalizing the assembly of my dissertation (a.k.a. making edits and formatting). I'm working on a post that covers the lessons learned from this journey...stay tuned ;-)
May 12, 2009
7:23
New Email System
» ‎ The Realm of Organic Synthesis

My University just made a monumental change over the weekend in abandoning their email system for a partnership with Google’s Gmail. Instead of the miserly 10 MB of email space we were given from day one of grad school, we’re now allowed 7 GB, a significant increase over the previous technology (implemented in 2003). Unfortuanately, Mac Mail does not want to play nice with the new server, and I can’t download cached emails to my laptop. As such, I have to manually pull up a server, sign into the University’s student service-type program and then click a link just to pull up my email, all which could be avoided by using Mac Mail.

Well…let me back up. It’s not the Mac (or PC’s for that matter) that’s the problem. It is a fact that the University’s IT department hasn’t developed specific instructions on now to sync their student’s Gmail accounts with programs such as Mac Mail or Outlook. This normally wouldn’t be an issue if my email account were, “MrPerfect221@gmail.com,” for example. However, with the change in email came new email addresses that look something like, “MrPerfect221@descriptor.university.com.” So, as I configure my email account on my Mac, it’s not clear if you refer to the SMTP server (in one case) as “gmail.com” or “descriptor.university.com” or some combination of the two or a 4^th-20^th option that no one knows about (tends to happen more often than not).

Now, combine all of this silliness with my role as an organic chemist and, hopefully, you’ll see the issue unfold. All NMR spectra are immediately forwarded to our University email account. Having “tighter” access to my email now means that my precious data is stored somewhere on this vast planet of ours in a Gmail server instead of in the appendix of my dissertation (where it needs to be).

I’ve also been trading emails with my future employer about the giant packet of info that was sent a few days ago. It’s a pain to stop everything I’m doing every few hours, pull up a browser, sign in and make a few mouse clicks to access my mail, when I could be doing it using my email software. I guess I’m just disappointed that the process isn’t streamlined.

Does anyone have any suggestions?
May 07, 2009
10:30
Re-issuing Good Chemistry
» ‎ The Realm of Organic Synthesis

I recently bought a 2009 re-issued copy of Pearl Jam’s first album “Ten,” originally released back in 1991. Those who know me well are also aware of my interest in Pearl Jam; I enjoy collecting demos or live versions of their music. Anyhow, their officially released re-issue contains a remixed version of their 1991 album and (in my opinion) parts of it sound distinctly different than the original mix. For you music buffs out there in internet land, Brendan O’Brien—the original producer—dumped the supplemental reverb applied to the original tracks in this newer version. As a result, the guitars and drums sound much cleaner and less wet (I recommend listening to both versions of “Why Go” or “Oceans” for a good example of the remixing).

Thinking about the whole concept of “re-issue” got me thinking about organic chemistry (big surprise). How often do scientists report fantastically optimized results, table the idea, and then revisit it at a later date (to make vast improvements)? Or better yet, how much “new” chemistry has derived from “re-issuing” processed developed in the late 19^th or early 20^th century? My PI calls refers to this particular phenomenon as, “teaching an old dog new tricks.” In writing my dissertation (an ongoing process) I had the pleasure of reading Lipshutz’s recent review about cuprate chemistry (Synlett 2009, 509-524; DOI: 10.1055/s-0028-1087923). This personalized narrative discusses the Lipshutz group efforts and contributions to the field of copper(I) hydride chemistry.

This article is of particular interest apart from discussing it at length in the ‘ol thesis. A few months back, I had a conversation with a colleague of mine who claimed that since Stryker’s contributions, “conjugate reduction chemistry has (basically) fallen to the wayside.” I recall laughing out loud at his remark. “What about Lipshutz or Riant or even Buchwald,” I asked. He claimed, with a sense of arrogance, that their work was “just a new twist on Stryker’s original work.” Based off of this logic, if someone successfully synthesized Taxol from table sugar in three steps, would it be considered a new twist on Nicolau or Holton’s contributions? Arrogance aside, this idea of “re-issuing” is a common phenomenon in research chemistry. It’s done frequently, often to the tune of 10-20 additional printed publications (apart from the seminal contribution). Perhaps, it’s these instances that call into question the process of “re-issuing” chemistry.

That said, re-issued chemistry can result in significantly new discoveries and improvements on original methods. Taking the conjugate reduction example, Stryker’s catalytic reactions, performed under a high pressure of H2, were plagued with over-reduced products. In switching the stoichiometric hydride source from hydrogen gas to PMHS, Lipshutz reported a vast improvement in reaction times and overall yields (Tetrahedron 2000, 56, 2779-2788; doi: 10.1016/S0040-4020(00)00132-0). This change has spawned a whole new area of carbon-carbon bond formation, particularly in the field of reductive alkylation reactions.

While I’m genuinely interested in the idea of inventing new and exciting reactions, the thought of tweaked processes resulting in “re-issued” chemistry is largely appealing (when done responsibly). A prominent neutron chemist once told me that real chemistry lies in unexplored places. “We want to be doing things that others aren’t,” he said. I agree. But on occasion, it’s necessary to explore the landscapes previously claimed by others for the betterment of the (scientific) community as a whole.
April 21, 2009
10:18
Qu'est-ce qui se passe?
» ‎ The Realm of Organic Synthesis

In a word, “writing.” I’ve gotten through the majority of my dissertation (a brief four chapters), and in a day or so I’m hoping to begin the ever long editing process. For the better part of a month, I’ve been toting a manilla file folder (graffitied in Dewey-decimal call numbers, Fibonacci spirals, chair confirmations and frontier orbitals) containing several papers relevant to my research topics. Suffice it to say that the only real literature reading I’ve done has been limited to references covered within the ol’ thesis. Though, I just learned this morning that thalium(I) ethoxide enhances the rate of Suzuki reactions relative to K2CO3 (Org. Lett. 2000, 2, 2691-2694). I assume it’s simply an issue over solubility; Occam’s razor at its finest.

In an isolated incident, I was a bit perturbed to learn I had limited access to the parking behind my department’s research building. Normally, parking on campus is not a huge problem, particularly at 9 am on a Saturday morning. However, on this fine April day, my beloved University was holding their annual spring football practice, and the powers that be would not let anyone park at the research building (~ 1 mile away from the stadium). I’ve since cooled down about the issue. The irony of the situation is my University’s propensity for bombarding national broadcasts with commercials highlighting the research efforts of our fair institution. The whole situation is contradictory in my mind. Clearly football is God, the rest is just noise.

P.S. In case you’re wondering about the Fibonacci art on my folder, I am a fan of Tool.
March 26, 2009
11:27
The Wrapup from ACS in SLC
» ‎ The Realm of Organic Synthesis

It’s a wrap. My bags are more or less packed, and I’m waiting on the airport shuttle. So, while it’s still fresh in my mind, I’ll give the last update from SLC.

The last two days were spent shuttling between organic and CHAL presentations. Hearing some lawyers (entrusted with protecting millions of research dollars) talk about rudimentary chemistry is an unbelievably painful experience. As a matter of necessity, I had to go to organic presentations to make sure I hadn’t lost my mind. In terms of the organic chemistry presentations, I didn’t see anything groundbreaking per se. Though, it was good to see that there’s some really interesting chemistry going on around the world. The ORG/MEDI poster session last night was particularly nice because it was a fairly reasonable mix of small molecule synthesis and methodology. I was most impressed with the work coming out of Matt Sigman’s lab at Utah. I admittedly never heard of him, though that’s probably understandable because U. of Utah is Peter Stang’s stomping ground. Anyhow, Sigman’s got a post doc working on copper-free Wacker oxidations, a methodology first discovered a few years ago (see: Org. Lett. 2006, 8, 4117-4120). Apart from using a DMA/water solvent system, the method looks pretty cool, and it could be interesting to see where Sigman takes the project in the future.
Additionally, I caught one of Sigman’s students give a talk on the development of an oxazoline catalyst used in hetero-Diels-Alder chemistry (ACIE 2007, 46, 4748-4750). Sigman (and his grad student, Jensen) altered the CF3 on the catalyst to a relatively less electron-withdrawing group then watched the change in rate and enantioselectivity. Sigman and Jensen ultimately concluded, “reaction rate and enantioselectivity can be directly correlated to catalyst acidity.” Pretty cool linear free energy relationship.

In summation, I think the meeting was a pretty good experience, subjectively. I got a ton of networking accomplished, developed several ideas I’m bringing with me back into the lab and may have found my PI a post doc for his lab (though, I’m still keeping an ear open).
March 24, 2009
9:23
Monday Update from ACS in SLC
» ‎ The Realm of Organic Synthesis

Generally Speaking. Aaron from Wired Blog made the comment that attendance looks low at ACS in Salt Lake City. I agree, and I wonder if it’s a function of the economy. On the humorous side of science, there was a vendor in front of the Salt Palace this morning selling “Obamium” t-shirts. I didn’t get one (we live in a McCain/Palin household). Also, I’ve noticed that there isn’t a lot of ground-breaking synthetic organic chemistry being presented.

LENR = Cold Fusion? Not quite a tabletop source of energy, but interesting nevertheless. Pamela Mosier-Boss, Steve Krivit, Antonella De Ninno and a few other experts took questions from a packed house about the interpretation of recent results surrounding advancements in low energy nuclear reactions (LENR). Those in attendance included Scott Chubb (of Infinite Energy fame), KSL-TV Channel 5 and the legendary Mitch Andre Garcia. I’m not even going to try and explain the crux of the talk (being a synthetic organic chemist, and all). However, the video of the press conference is available here, and I encourage you to check it out if you’re interested. Perhaps if you ask Mitch really nice, he’ll write a post on the ins and outs of the debate. While there are several critics of the research (for example, click here), the crux of the talk appeared to focus on recruiting young chemists to explore this “new” area of science.

Feel the Burn. The U.S. Geological Survey (USGS) announced their discovery of gas hydrates—“a frozen form of natural gas that bursts into flames at the touch of a match.” Tim Collett (project co-leader) claims that this work may bridge the gap between relatively dirty fossil fuels and clean energy because gas hydrates purportedly leave a small carbon footprint.

Just Scan it. I took a few moments to speak with Dr. Jeffrey Silk, president of Silk Scientific, about his digitizing software. I haven’t seen this sort of program before, so I’ll make the assumption that others haven’t either. The product (called “UN-SCAN-IT”) takes a chart, graph, HPLC trace, etc. and converts the image into data points, which can be dropped into a program such as Excel. With the “raw” datapoints, UN-SCAN-IT allows you to integrate, take derivatives, and perform curve fitting. If this sort of thing tickles your fancy, you can download a demo of the software here. For all of you bio-type peeps, Silk Scientific also sells a second program called “UN-SCAN-IT gel,” which acts as a densitometer for gel images. As for future generations of products for Silk Scientific, I suggested he make a program that will automatically solve ¹H-NMR spectra.
March 22, 2009
13:34
Sunday Update from ACS in SLC
» ‎ The Realm of Organic Synthesis

On my flight into Salt Lake City, I was greeted to nasty turbulence, an overcast sky but a comfortable mid-50 degree temperature, which eventually turned to rain (there’s a chance of snow tonight).

So, what happened today?

The Inorganic/Medicinal Version of Brown. M. Frederick Hawthorne is slated to win the highly coveted ACS Priestley medal for his contributions to boron chemistry in SLC this week (March 24, 2009). In addition to synthesizing polyhedral borane clusters such as B12H12^2-in the 1950’s, he is noted for his boron neutron capture therapy (BNCT)—a promising technique in the war on cancer (see: J. Am. Chem. Soc. 2007, 129, 6507-6512). I realize this isn’t really news per se since C&EN covered it last June, but some of you might have missed it.

Smith’s Dithiane Chemistry. I caught most of Amos Smith’s talk about his lab’s recent efforts in the realm of dithiane transformations (you should be thinking “umpolong”). He did a nice presentation on multicomponent anion relay chemistry (“ARC”; for example see: J. Am. Chem. Soc. 2006, 128, 12368-12369 and Angew. Chem. Int. Ed. 2008, 47, 7082-7086) while making a cute comment that the resultant “protected” alcohols are easily removed with Philadelphia tap water. For those not familiar, the Smith lab has been applying hybrid umpolong/Brook rearrangement chemistry to synthesize cool “proof-of-concept” natural product-like molecules. Smith mentioned that this type of work has caught Jeff Johnson’s attention (hence the umpolong connection) evidenced by a fairly recent publication about the synthesis of zaragozic acid C (J. Am. Chem. Soc. 2008, 130, 17281-17283). I had to leave the talk a bit early, but from my vantage point I noticed a lot of male chemists slowly starting to assemble for M. Christina White’s talk. I was truly sorry that I missed it. Oh, in case you were wondering, I did not notice her trademark ostentatious belt buckle.
CAS and Nanotechnology. In the few hours I’ve been at the ACS conference, I’ve noticed that there’s an awful lot of material (no pun intended) on nanotechnology. While nanotechnology touches areas of pharma, materials and even the molecular automotive industry, the issue of classification is making its way through the chemical community. Roger Schenck (of CAS) did a fine presentation on the issue from Chemical Abstracts Service’s vantage point. CAS currently catalogs 80 sections of chemistry (#1 is pharmacology), and, according to Schenck, CAS is not planning on adding #81 (which would be nanotechnology) anytime soon. It seems that the issue will be tabled for a bit longer while the field continues to grow/evolve. For you history buffs out there, Schenck contends that nanotechnology probably began with Kroto’s C60 discovery (Nature 1985, 318, 162-163). Interesting tidbit: Kroto even mentioned that he’d “prefer to let this issue of nomenclature be settled by the consensus.”
March 16, 2009
9:49
Oh Finkelstein
» ‎ The Realm of Organic Synthesis

In the midst attempting to alkylate a couple of our novel compounds, my PI recently suggested converting my alkyl bromide into an iodide via Finkelstein reaction. Having performed several of these reactions in the past, I’m no stranger to this transformation. A garden-variety Finkelstein reaction involves the treatment of an alkyl halide (or any other good leaving group for that matter) with sodium/potassium iodide in refluxing acetone (see: Tetrahedron 2004, 60, 10943-10948). The resultant byproduct salt is more or less insoluble in acetone thus your reaction mixture can be filtered over celite or florasil. Variations in this reaction include substituting methyl ethyl ketone (MEK) or toluene for the typical acetone since all three solvents typically do not dissolve salts (more specifically KBr, KCl, etc.). Employing MEK in place of acetone (for example) has an advantage of an increased boiling point, which can give your reactants a nice kick in the butt thus speeding up your reaction time.

Comparison of Common Finkelstein Solvent Temperatures

Acetone: 56 ^oC; MEK: 80 ^oC; PhMe: 111 ^oC

In a quick SciFinder search, I was shocked to learn that more off-the-wall variations of this reaction involve use of aqueous solvent systems. For example, this sort of transformation was demonstrated by Pauline Chiu and co-workers in the formal synthesis of pseudolauric acids (J. Org. Chem. 2003, 68, 4195-4205; also covered in Li’s Modern Organic Synthesis in the Laboratory). Instead of installing the typical iodide, Chiu’s team opted to substitute the chloride for the bromide using phase transfer conditions. While the reaction offers amazing yields, it’s not readily clear as to why this procedure was employed instead of classical conditions. Additionally, the alkyl halide is allylic, which raises questions over the mechanistic details (i.e. is it SN2 or more like an allylic substitution). Still the transformation’s pretty cool. Maybe not as cool as going to see Menudo as your first concert experience, but cool nevertheless. (Inside joke).
Subjectively speaking, I’ve found that progress of this sort of reaction can be monitored by crude ¹H-NMR analysis. More convenient methods such as TLC may not discern an alkyl chloride (for example) from an alkyl iodide.

P.S. I’ll be attending the ACS meeting in Salt Lake City next week with Mitch over at Chemistry Blog. In addition to contributing to his site, I’ll be keeping a running daily post to satisfy your synthetic curiosities. Keep checking back here for updates.
March 03, 2009
16:39
Brominate like a Wizard...a Lesson in Gen Chem
» ‎ The Realm of Organic Synthesis

Organobromides are a necessary part of synthetic organic chemistry. Think of all of the functionalization and carbon-carbon bond forming a chemist can accomplish through the installation of a bromine atom into their molecule of choice. Admittedly, there are alternatives to bromides such as iodides, sulfonyl esters, acetates and carbonates (for example see: Adv. Syn. & Cat. 2000, 343, 34-36). However, in most cases you cannot beat the ease and simplicity of bromine installation. By comparison, the installation of other comparable synthetic handles often requires more than one step and/or several reagents to accomplish.

Despite the utility, there is an obvious concern over the safety of using magical element #35. It’s nasty stuff, and bromine burns can take quite some time to heal (see: Jap. J. Tox. 2005, 18, 141-147). On top of that, physiologically speaking, there are a silent few who cannot tolerate organobromides (see: Risk Management for Hazardous Chemicals by Jeffrey W. Vincoli). For what it’s worth, I learned that I was a member of this club (mind you, the hard way) my second year of graduate school, but I cannot do my job without them. Then again, I’m deathly allergic to cats and dogs, but I can’t think of life without Miss Piggy or Isabelle (respectively).

The installation of a bromine atom is a task that successful organic chemists must master. Despite the inherent danger of working with pure, elemental bromine, there are alternate ways of installing a Br atom without using the characteristically, brown/red chemical. The obvious solution to an organic chemist is to use NBS or pyridinium bromide perbromide. There’s another way that’s even cooler, is pure alchemy and covered in most general chemistry classes (high school or college). I discovered this beauty during my third year of graduate school and never gave it much thought until I started writing my dissertation. For my purposes, the procedure in question (an old Chem. Ber. paper from the 1950’s), called for dissolution of the starting material in strong, aqueous acid, followed by the slow addition of KBr then KBrO3. After 2 hours of reacting, the solution was then neutralized, which precipitated a solid that was filtered off. Analysis of the resultant solid confirmed the addition of a bromine atom.
The whole equilibrium is very interesting. As confirmed by my dear, Midwestern inorganic Jedi friend, if you add acid to a solution of KBr and KBrO3, the equilibrium shifts toward bromine formation. If, however, you add base (i.e. NaOH), the equilibrium shifts back to the left and you get sodium hypobromite—a powerful oxidant (of course, on the scale of Clorox bleach). While this chemistry has been applied as far back as the early 1900’s (J. Am. Chem. Soc. 1903, 25, 2169-2171), more recent examples have been lightly peppered through the literature (J. Org. Chem. 1981, 46, 2169-2171).

Bonus Material

Everything you’ve ever wanted to know about Br2 can be found here (Courtesy of Great Lakes Chemical Corporation).

Derek Lowe has a great story about how not to brominate like a wizard.
February 12, 2009
10:44
Quick Update
» ‎ The Realm of Organic Synthesis

Busy. Really busy. Should be working on my dissertation, but I’m dropping you a line to say I’m incredibly busy. I could talk about the chicken housing market, which in some strange way relates to synthetic chemistry (think imidazolium-based N-heterocyclic carbenes). But, I don’t want to bore you.

I read yesterday that Janine Cossy, Christophe Meyer (N.B. the links are in Français) and company are making good progress on phoslactomycin B. Yes, their synthesis features her trademark Ru-catalyized, enantioselective, Meerwein-Ponndorf-Verley-type reduction of an acetylenic ketone (Org. Lett., 2009, 11, 935-938). In all sincerity, I hope she’s at the ACS conference in March because I’d like to meet her.

In the blogosphere, Mitch is working on an online name reactions book. Kyle is stepping up to make a practical organic laboratory techniques resource (apart from irritating US Senators). And I have agreed to help develop ChemSpider to make it more reagent-friendly for of my fellow organic chemists. Check out all three projects if you get a chance.

Yes. All three of us were in talks (as it were) to work on a group project.

Yes. It fell through.

Yes. I’m hoping to contribute to their projects. Cross-pollination is a wonderful thing. Don’t believe me? Daschunds (the epitome of perfection) are a product of cross-pollination. Check mate.
February 03, 2009
11:16
Throwing Down the Gauntlet for my Fellow Geeks
» ‎ The Realm of Organic Synthesis

I love Wikipedia. I think deep down we all do. There’s something truly amazing about accessing hordes of (useless) information simply by entering a few keystrokes in a giant search engine. At times, Wikipedia’s better than “Googling” simply by virtue of the fact that each topic is referenced (most of the time) and peer-reviewed. By analogy, can you imagine the quality of published work if the ACS didn’t require references in a submitted manuscript or operate a peer-reviews-type system?

Wikipedia is great for getting an objective “big picture,” rapidly in a fairly organized format, but it has its limitations. Do you need to know the origins of Evacuation day in Boston? Use Wikipedia. Do you need to know the economic impact of the 11-month British seizure of Boston? You’re better off consulting a textbook or bugging you local history scholar.

By contrast, my “ranking” professors largely despise search engines such as Wikipedia. I think they frown at the ease of accessing a tool that anyone can alter for finding physical constants (i.e. the density of aniline) or understanding conceptual material (i.e. Zimmerman-Traxler transition state models). I once heard a professor claim, “If it’s published on the internet, there’s really no way to verify if the information is true.” In a sense, he was correct. The internet is a terrific source for (mis)information, and Wikipedia is really no exception to this phenomenon. Hell, my wife (trained as a chemical engineer) has witnessed physical constants change on Wikipedia on several occasions.

Science is a largely unspoken art. Sure, there are lectures and textbooks that “guide the way.” However, every research scientist mines information from the stockpiles of primary literature in an effort to piece together relevant aspects of his or her project. I imagine that if I were to search for a procedure for using SOCl2 today (Lord knows I wouldn’t consult my PI), there are probably 49 other people in the world this week looking for a similar procedure. This means that 50 of us will spend valuable time crawling through the literature looking for a similar ballpark procedure. To make matters worse, on my campus, the SciFinder subscription is only available at a library where waiting for a computer is akin waiting for the Kansas City Royals to win a World Series. A lot of these problems could be fixed with the development of a free scientific database.

I think charging several hundreds of dollars for crappy textbooks is criminal. I also think that a scientist’s time is too valuable to be wasted crawling through primary literature looking for the proverbial needle in a haystack. Knowledge should be available to the general public, hence libraries. But, we live in a digital age where copious and sufficient information can be accessed with the click of a mouse. Don’t get me wrong. I believe in peer-reviewed publishing. However, the organization of that information (specifically scientific) is what kills me.

I propose the creation of a knowledge database. In the spirit of Dan Carlin’s last podcast, I say let it be produced by the militia—by the people for the people. You sign on. You contribute. You enter the associated references. Do you need to know the side reactions of a Pictet Spengler reaction? Maybe someone in Patrick Bailey’s group just added a reference from a recent paper last week. Need a technique for depositing silver nanoparticles? That would be easy to find if someone in Louis Brus’ team contributed a procedure. Earlier this morning, a friend of mine just came by my office looking for a quick, easy way to make trityl tetrafluoroborate. Imagine how easy it would’ve been for him to access a free database that references 50 different procedures (BTW, his group has complete access to SciFinder outside of the library). Don’t feel left out you biologists out in Internet-land. You could have access to PCR techniques, free sequencing software, and even references to protein crystal structures.

My argument is this: there is so much useful information that needs to be organized in a format that is free, navigational and easy to access. One person cannot do it alone; we all need to contribute for the betterment of science, in general. I envision a hybrid of Doug Taber’s Organic Chemistry Portal, Wikipedia and a condensed version of SciFinder. I’ll gladly contribute! How do we get the ball rolling?
January 27, 2009
19:56
Imidoyl Cyanides via Piperidines
» ‎ The Realm of Organic Synthesis

I spent a good part of my weekend at the library researching fragmentation reactions (hours of fun, I know). One of the several older papers I read came from Norbert De Kimpe's lab at Ghent University (Belgium). Apart from contributing to organofluorine, cyclopropane and medicinal chemistry, De Kimpe has also dabbled a bit in heterocyclic synthesis. The paper in question reports an interesting method for preparing imidoyl cyanide from a piperidine intermediate (Tetrahedron Lett. 2001, 42, 3921). Here’s the general reaction scheme:

The electron pushing for this transformation was rather interesting, so apart from submitting the mechanism to our Department’s weekly problem set, I figured I’d cover it on the blog. Bromination with elemental bromine results in 5-exo-tet cyclization to give the corresponding 1-pyrroldinium salt (a transformation previously reported by De Kimpe: Tetrahedron Lett. 1994, 35, 1925-1928). Treatment of the pyrroldinium species with KCN quenches the positive charge, which ends up causing an intramolecular C-N bond formation, followed by SN2 attack from the bromide ultimately giving the piperidine system.
Finally, treatment of the piperidine with a strong base (i.e. NaH) results in deprotonation at the reasonably acidic methine.
Here’s the challenging part to rationalize: proper orbital alignment in the transition state. Grob fragmentations fall into that category of “elimination-type” transformations. Because Grob reactions are notoriously E1cb-like, orbital alignment is critical for the reaction to proceed. In the chair diagram below, electron density between the C-N bond is aligned with the adjacent sp³-hybrid, which forms the C-Br bond. As the C-N bond breaks, the electron density flows into the proximal, “empty” lobe (more accurately called the sigma*-orbital) giving the double bond in the product.
From a purely utilitarian standpoint, the chemistry in the paper is great for a few reasons: good yields, high diastereoselectivity (in the piperidine synthesis) and use of commonly available chemicals found in most synthetic labs. The necessary evil, however, is the use of potassium cyanide, which, judging by its once notorious use in several state correctional systems, can pose serious health risks. But, as Chris Rock once said, "You can't be happy that fire cooks your food and be mad it burns your fingertips."
January 20, 2009
9:44
Playing the Devils Advocate: What has Monsanto done for you?
» ‎ The Realm of Organic Synthesis

Chemical ignorance among the general population is rampant. I recall once being lectured about trans-fats, yet this person didn't under stand the concept of a double bond or at the very least molecular packing. Anyhow, here’s my opportunity to rant and (maybe) get a couple of my readers to think. Long story short: I recently had an encounter with a new Facebook group entitled “Millions Against Monsanto,” which put me into a bit of a tizzy. For whatever it’s worth, I’ve posted their group graphic to the left. The opening paragraph of the group description caught my eye:

“Seeking to raise awareness about this dreaded corporation that has spread its genetically modified seed all over the world, pushed its bestselling broadleaf pesticide "round-up" for years, sued family farms for a "technology fee" because their fields had been contaminated with Monsanto seeds, and tricked farmers in other parts of the world into believing that using Monsanto seeds would increase yield when it has done exactly the opposite! Lets not forget the production of staples such as Agent Orange, recombinant Bovine Growth Hormone (rBGH), PCBs, Aspartame and so much more!”

If you’re a keen scientist, you might be hearing a “BS-detector” ringing in your ears. The truth is that Monsanto has made significant contributions in simplifying civilized life (however, I’ll comment more on that later). Not having earned my J.D. or an advanced degree in molecular biology, I won’t comment on the lawsuit business or the “recombinant Bovine Growth Hormone” business. However, the lack of “homework” done on this issue is dizzying and astounding. Here’s my attempt at address the chemical arguments.

PCBs: I’m willing to bet a six-pack that the average citizen of planet Earth could not tell you what “PCB” stands for without first running to Wikipedia. But, that will give us a good starting point, so let’s define PCBs as “polychlorinated biphenyls”—tasteless, odorless toxic compounds that were initially developed as coolants and insulating fluids (c. 1970’s). PCBs are usually lumped in with dioxins and furans in terms of toxicity (i.e. high purported carcinogenicity). Before grad school, I held a job at an analytical firm testing for PCBs in groundwater samples. Clearly their presence in drinking water poses a serious health concern to the general population.

From the 1930’s into the late 1970’s, Monsanto (in addition to General Electric and Westinghouse) produced PCBs for refrigerant use. However, during this period, production grew beyond the realm of North America; PCBs were produced in Germany (Bayer), France (Prodolec) and Japan (Kanegafuchi Chemical Co). Thus, Monsanto was not alone. That said, they do have a moral obligation to address the dumping incidents that happened over 50 years ago. It was the actions of this company that continue to cause problems in the water supply for communities such as Anniston, AL.
Roundup: Known chemically as glyphosphate, “Roundup” is derived from the amino acid glycene. Monsanto has gotten a bad rap over the past few years for pushing the sales of this product, which was widely believed to cause health problems. As of 2000, glyphosphate reportedly poses no purported health concern to the general human population (see: Regul. Toxicol. Pharmacol. 2000, 31, 117-65). However, more recent studies suggest that pregnant mammals exposed to glyphosphate can result in an increase of glucose-6-phosphate dehydrogenase (G6PDH) activity their fetuses (see: Environmental Research 2001, 85, 226-231, or Toxicology 2005, 283–291). Both of the cited studies concluded that the fetuses of preganant rats exhibited abnormalities in G6PDH when the mother was exposed to glyphosphate for 21 days. The obvious question is this: Why would you use chemicals if you were pregnant? As for “pushing” the sales of Roundup, that’s sort of the essence of a business.

Agent Orange: David Hanson wrote a great piece in C&EN about Agent Orange last March (definitely worth a quick read). To summarize, Agent Orange (code name for 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid) was developed by scientists for the USAF as a defoliant for use in the Vietnam War. The unfortunate side of this story was the dioxin byproduct formation (2,3,7,8-tetrachlordibenodioxin), which reportedly causes cancer and is commonly classified as an endocrine disruptor. To date, there are still ongoing legal battles over its use in the 1960’s and 70’s that involves everyone from the EPA to the USAF to the chemical companies who produced Agent Orange in the first place (notice how the word “company” has been purposely pluralized). If you’re going to boycott Monsanto for producing Agent Orange, you might as well throw out half of the chemicals in your house because Dow was just as guilty. The most recent bit of legal news surrounding this issue was the dismissal of a lawsuit in 2005 against Monstanto, Dow and about 20 other chemicals companies (Judge Jack Weinstein’s brief 200 page ruling).
As a brief aside, I recently listened to a history podcast about the Vietnam War and was surprised to learn that there were actually several types of defoliant prepared for use during this period. Each “agent” was prepared on an industrial scale then stored in 55-gallon drums marked with a color to identify the contents. Their names come from the color of the band used to mark each drum. Thus a drum with a pink mark was actually Agent Pink, whereas a drum marked in orange was Agent Orange.

Aspartame: I find this issue perpetually irritating. I cannot find a single, credible document that unequivocally states, “Aspartame will give you cancer.” I love my dear aunt to death, but she once got on my bad side by lecturing me on the dangers of aspartame while she was shoveling spoonfuls of Splenda into her cookie dough. I have more of a gripe with sucralose than I do with aspartame.

Monsanto had essentially nothing to do with the discovery of aspartame. Blame Searle scientist James M. Schlatter for his poor laboratory etiquette that ended up being mentioned in the manuscript published by the ACS (J. Am. Chem. Soc. 1969, 91, 2684-2691). The truth is that Monsanto acquired Searle in 1985, then sold the division (called NutraSweet) to Boston-based equity firm J. W. Childs in 2000. What’s interesting about Monsanto is that their company was founded on the production of saccharin, which ended up being sold to the Coca-Cola company.

I find it puzzling that this Facebook group names every “bad” product, but fails to mention the good that Monsanto has done for civilization (the number of which is countless). I’ll name a few. Monsanto scientists help develop polyurethanes (a huge player in the polymer industry), which are used in the production of textiles, adhesives and varnishes (among others). William S. Knowles developed his asymmetric hydrogenation method (work that landed him the Nobel Prize in 2001) while working for Monsanto. Let’s also not forget my personal favorite: vinegar. Monsanto developed the first Rh-catalyzed methanol carbonylation method for preparing acetic acid.

I like people who “stir the pot” because it often results in the development of new ideas (presumably) for the betterment of society. But, if you’re going to make a solid stance, for the love of God, please do your homework. Disinformation is not helpful, it’s hurtful.
January 14, 2009
9:24
A New Route to 5-Amino Levulinic Acid
» ‎ The Realm of Organic Synthesis

Inventor Sven Aldenkortt was recently awarded US patent #7,319,164 for developing a process for producing 5-azido levulinic acid. You might be asking yourself about the utility of the compound. The azide moiety can be reduced to the corresponding amine, providing 5-amino levulinic acid hydrochloride, which is a useful synthon.

There have been several attempts at accessing 5-amino levulinic acid, each with its own set of disadvantages. Some cited procedures involve the use of toxic reagents or require complex workups (Tetrahedron Lett. 1984, 25, 2977-2980, Synthesis 1999, 568-570). The disadvantage in these cases is dealing with “unwanted chemicals” (which is code "waste"). At least one of the cited previous procedures required used of N-protecting groups (U.S. patent # 5,380,935), which is undesirable because it affects atom economy. A couple references cite use of photosensitizers such as C60 or rose Bengal (for example see: Synthesis 1995, 303-306). Having no experience with either chemical, I couldn't tell you if this is good or bad; Aldenkortt claims that they are a disadvantage.

I thought that Aldenkortt's route was interesting for 2 reasons. First, the chemistry doesn’t require any wacky reagents or random protocols. I often encounter across strange procedures that (at least in my mind) could be avoided with careful reagent/solvent/heating choice. There's something to be said for doing good chemistry with cheap reagents. Furthermore, there's nothing strange or wacky about crystallizing the products after workup (the purification method of choice in this invention). Second, the yields are quite high.

Anyhow, beginning with methyl 5-bromo levulinate (purportedly accessed by direct bromination of methyl levulinate in a whopping 9.5 %), Aldenkortt accessed 5-chloro levulinic acid in 24 h using 3M HCl. The azide was then installed using sodium azide in warm acetone (similar to a Finkelstein reaction where the resultant NaCl is simply filtered off). Finally, catalytic hydrogenation in acidic media gave the 5-amino levulinic acid hydrochloride.
The inventor notes that the serious pitfall in the process involves starting from methyl 5-bromo levulinate (apart from the notably poor yields resulting from direct bromination of either methyl levulinate or levulinic acid). Methyl 5-bromo levulinate is a nasty lachrymator that has the tendency to decompose and/or isomerize in the presence of acid. It turns out that 5-chloro levulinic acid is actually stable, crystalline and won’t make you cry.

The inventor notes that 5-azido levulinic acid has an impact energy (i.e. the total energy absorbed until fracture) of 40 J, which may have “utility as a priming fuse” in motor vehicle airbags.
January 04, 2009
13:19
Good Stuff Coming out of Harvard
» ‎ The Realm of Organic Synthesis

By and large, I regard Andrew Myers as an “important” figure in the realm of organic synthesis. Do a quick author search on SciFinder, and you’ll find that Myers has made several pivotal contributions to synthetic organic chemistry. Apart from the Myers Group’s extensive natural product work, they have also dabbled in C-F bond formation, synthon development and medicinal chemistry (I’m leaving several other instances out).

For my own selfish reasons, I’ve found Myers to be particularly helpful in navigating my way through synthesis and organometallic chemistry classes in graduate school. Many of his lecture notes are published online and serve as an excellent substitute for purchasing Boger’s Modern Organic Synthesis. Given his educational background, experience and commitment to synthetic organic chemistry, I’d go so far as to call him a “guru.” There, I said it.
His work gets picked up on occasion by C&EN. Most recently, Stephen Ritter wrote a little blurb about Myers’ new “pathway to tetracycline antibiotics” (December 22, 2008, page 35). The molecule in the article looked interesting (from a retrosynthetic perspective), so after attempting to disconnect the molecule with my mind, I cheated and pulled the primary reference (J. Am. Chem. Soc., 2008, 130, 17913–17927). It turns out that this article is a smorgasbord of physical organic, synthesis and medicinal chemistry all rolled into a brief 15 pages.

The chemistry in question involves intermolecular Michael addition followed by a tandem aldol-type chemistry. The potential Michael donor is deprotonated with n-BuLi in the presence of TMEDA (presumably to sequester the lithium metal and make a stronger nucleophile). Inclusion of the cyclohexenone to the reaction mixture results in conjugate addition, which Myers and co-workers proved mechanistically by trapping experiments. Finally, warming to room temperature resulted in nucleophilic acyl substitution followed by tautomerization to give the multi-cyclic compound. Granted this is a representative example, but these cyclizations occur in yields so good, you’ll literally want to slap yo’ mamma (it’s a figure of speech in my part of the country). Check out the article if you get a second.
December 29, 2008
16:21
A New Route to Roseophilin
» ‎ The Realm of Organic Synthesis
In an effort to educate my readers, I’ve put together an analogy. Admittedly, you probably won’t see this sort of problem on any SAT (maybe a MENSA-qualifying exam one day), but here it goes:

Stoltz : Wolff/Cope :: Frontier : ____________
- (a) Wynn/Trump
- (b) Jahn-Teller
- (c) Nazarov
- (d) Knoevenagel/Diels-Alder
- (e) Corey
I enjoy reading work from Alison Frontier’s group; they handle a good array of challenging projects that contribute to the overall (practical) growth of synthetic organic chemistry. Admittedly, I’ve even gone so far as to ask a prof in our department to invite her for a guest seminar. The Frontier group invests a large amount of research effort towards Nazarov chemistry—that would be answer (c)—those pesky 4-pi, conrotary, electrocyclization reactions that are often covered in physical organic chemistry to highlight the importance of orbital overlap.

Nazarov chemistry can be used to construct cyclopentanones from divinyl or allyl-vinyl ketones. I became interested in Nazarov chemistry when I saw Frontier’s total synthesis of merilactone A (J. Am. Chem. Soc. 2008, 130, 300-308). Despite the modest yield, Frontier eloquently demonstrated an Ir(III)-catalyzed Nazarov cyclization (historically, Nazarov reactions require an excess of Lewis acid). I continue to check in on her publications from time to time.
Frontier and Bitar have recently carried the Nazarov chemistry into the formal synthesis of roseophilin (Org. Lett. 2009, 11, 49-52), an antitumor antibiotic of medium-size, and fairly complex functionality. Fuchs and co-workers are credited with the first formal synthesis of racemic roseophilin (Tetrahedron Lett. 1997, 38, 2601-2604), and over the past 10 years (or so), several other groups have thrown their respective hats into the ring (Trost, Boger, Fürstner, Dudley, etc.). While several of these synthetic routes focus on Paal-Knor conditions, Frontier’s approach made use of Nazarov chemistry to access the [3.3.0] bicycle.

Frontier’s Nazarov conditions required catalytic use Sc(III) salts and 1 molar equivalent of lithium perchlorate. Presence of the LiClO4 is believed to convert the Sc(OTf)3 to Sc(ClO4)3—a highly active catalyst in Nazarov cyclizations (Tetrahedron Lett. 1994, 35, 3319). In methodological studies prior to this synthesis, Frontier noted a similar effect (Org. Lett. 2006, 8, 5661). While I like the method Frontier developed, I wonder if there was a way around the dichloroethane.
Tsuji-Trost allylation of the enone gave the tricyclic roseophilin frame in 82%. I have a few comments to make about this step. First, the large amount of palladium(II) acetate and air-sensitive ligand makes this specific allylation chemistry slightly undesirable. Second, the product contained ~20% of a diene side product, which taken into accound, adjusts the yield to ~66%. Also, sodium hyride is not terribly practical given the pKa of the active methylene moiety; a better bet may have been to use K2CO3.
All in all, a good chapter in the roseophilin saga.

Happy New Year from the RoOC staff—me.
9:30
Just Being a Wise-@ss
» ‎ The Realm of Organic Synthesis

I’m glad to see companies are selling “organic” products for your health and beauty. Why? Because washing your hair with chromium was so passé.
December 21, 2008
18:33
Wagering on Chemistry
» ‎ The Realm of Organic Synthesis

As I write this, I’m sitting at McCarran Airport in Las Vegas. The city was crippled yesterday (Wednesday) with the first snowfall since 1979 (so much for global warming), which consequently caused the airport to close at 3 pm. In turn, there are people everywhere, waiting to get out of this vacuum of trust funds and mortgage payments. That sounded bitter, and I’m way off topic.

In the spirit of Vegas, I started thinking about the similarities between chemistry and gambling, more specifically blackjack. Gambling has played a pivotal role in many discoveries. The classic example, though controversial, is Columbus’ “discovery of America.” Love him or hate him, he placed a heavy wager on finding a new way to India. Jonas Salk rolled the proverbial dice when he tested his polio vaccine on himself. I’m suddenly recalling that George and Ira Gershwin song “They all Laughed” (best performed by Ella Fitzgerald and Louis Armstrong).

Think about the traits of a good blackjack player for a moment. You have to be well educated in the game (i.e. know your odds of success, know basic strategy, etc.). All good blackjack players will manage their playing money well; why risk more than you can afford? And, most critically, professionals usually don’t go on hunches. They have a plan and stick to it. If they keep getting bad cards they either switch tables or call it a night.

How is this any different than chemistry? A good chemist will know the chances of a success for a given reaction in the general sense. In my mind, a good chemist will manage money well (it’s more prudent to spend $50 here and there for chemicals you know you’ll use versus dropping $200 on long shot chemistry). And, all good chemists know when to throw in the towel and call it a night.

Nothing groundbreaking; just a though.
December 05, 2008
16:08
Taking a Peak at Basiliolide B
» ‎ The Realm of Organic Synthesis

Chi-Sing Lee and co-workers recently published a route to basiliolide B that features a pretty cool transformation (Org. Lett. ASAP; doi: 10.1021/ol8022787). This target has been the focus of research efforts of the Stoltz (Org. Lett. 2008, 10, 25–28) and Dudley (Tetrahedron Lett. 2008, 49, 2899–2901) not only because of its biological activity—an irreversible SERCA (Ca²⁺) pump inhibitor—but also due to its stereochemical complexity (I count six stereogenic centers, three of which are quaternary).

Lee’s retrosynthesis featured the (seemingly) obvious disconnect of the 7-membered lactone in the target and deconstruction of the hexene ring via base-catalyzed Diels-Alder (essentially the primary focus of the paper). They then hypothesized that the methyl enoate could derive from the alpha-hydroxy furan system (a transformation that was essentially claimed in one step). It was this later step that really caught my attention.
In the manuscript, Lee and credits the transformation of the alpha-hydroxy furan to the corresponding lactone to Achmatowiz (Tetrahedron 1971, 27, 1973–1996). Using a model system, the team from China demonstrated the transformation using a bromonium source (i.e. NBS) and sodium acetate in THF and water. Subsequent Jones oxidation gave the quinone-type (??) compound. Given the excellent yield, the optimized Achmatowiz reaction conditions were applied en route to basiliolide B.
The mechanism of the Achmatowiz reaction, sadly, won’t be found in Kürti and Czakó’s bible. In fact, it appears a bit amorphous. One could rely on a bit of chemical intuition to get a ballpark guestimate of how the mechanism proceeds. Admittedly, I was stumped, however. So, I opted to take the scholarly way out and I chase down a few references.

Achmatowiz and co-workers originally ran their reactions with elemental bromine in methanol and suggested the formation of an isolatable 2,5-dimethoxyfuran intermediate, a transformation covered by Elming years earlier (see: Advances in Organic Chemistry, 1960, 2, 67). Tee and Swedlund appear to have proposed a reasonable mechanism (Can. J. Chem. 1983, 61, 2171-2176) where the bromonium provides the driving force for the oxygen addition to make a new C-O bond. Their method was demonstrated on a furan (minus the alpha,hydroxy substituent) and seemed pretty reasonable. In any case there was no mention of regioselectivity.

Here’s what I’ve been able to piece together: bromine addition creates an oxo-carbenium-type intermediate where the acetate can add to the 5-membered ring in the 5-position. It’s not clear if the reaction then proceeds through the ring opening or undergoes SN2 thus displacing the bromide.
If we assume, then, that the diacetate is formed, the rest of the mechanism appears quite easy. Mild acid helps hydrolize the secondary acetate while opening the ring giving the intermediate hemiketal. Collapse of the hemiketal into the dicarbonyl intermediate followed by 6-exo-trig cyclization gives the lactone. The enol is explained by tautomerization.

It’d be nice to see a more indepth study of this mechanism to gain more information (RDS, intermediate trapping/isolation, etc.). All in all, it seems like a pretty interesting transformation.
P.S. The primary article for this post was found courtesy of ChemFeeds (which is becoming my new favorite website). If you haven’t yet checked out Mitch’s baby, please do so. It’s a really useful tool in reviewing literally hundreds of articles in ~ 1 h.
November 24, 2008
10:37
Death by Chocolate?
» ‎ The Realm of Organic Synthesis

For those of you who don’t know, Dr. Joe Vinson is iconic to the chemical community (believe it or not, even more so than Soderquist). The American Chemical Society frequently hosts his seminars on some of life’s guilty little pleasures, coffee and chocolate. I recently had the chance to sit in on his “Science of Chocolate” seminar. And after and hour of lecturing about the history and chemical make up of chocolate, he took questions from the audience. When I used to housesit for my aunt, I remember her telling me to be careful not to feed the dog chocolate because it could kill them. I also recall coming across a warning by the ASPCA about the dangers of cocoa bean fertilizer.

With my curiosity, I decided to ask the expert. “Why is chocolate toxic to dogs?” There was a bit of laughter behind me after I posed the question. Vinson claimed that the theobromine was responsible. “You would think that for a 100 pound dog it would be okay to feed them chocolate safely. But you can’t.” He then took the next question while I sat there completely unsatisfied with the response.

So (like my daschund and miniature pinscher) I went digging. Despite the name, theobromine has nothing to do with halogens. Theobromine (or more IUPAC-y, 3,7-dimethylxanthine) is a structural derivative of caffeine. In fact, several species of plants synthesize caffeine by converting xanthosine into theobromine. The biosynthesis is concluded by N-methylation of theobromine by caffeine synthase (using S-adenosyl-L-methionine or SAM). Recently, Crozier and co-workers mentioned that several groups have reported identical biosynthetic routes to caffeine (Coffea Arabica – coffee; Camellia sinensis – tea; Theobroma cacao – cacao; see Phytochemistry 2008, 69, 841-856). At any rate, both theobromine and caffeine are stimulants (caffeine much more so).
It appears that theobromine metabolism has only been moderately studied in the scientific community; most research has revolved around human metabolism. Arnaud and Welsch (two research chemists at Nestlé in Switzerland) used ¹⁴C-labeled theobromine to determine the metabolic breakdown of the alkaloid in rats (J. Agric. Food Chem., 1979, 27, 524-527). They determined that theobromine and methyl uracil were the major radioactive components in the urine (accounting for 85% of total radioactivity). Other side products included 7-methylxanthine, 7-methyluric acid, 3-methyluric acid and several others. Interestingly, they noted large similarities in the chemical composition of urine samples in both humans and rats that had been given theobromine. However, there were quantitative differences between the two species. Along with their paper, they actually printed pictures of 2D-TLC plates of urine samples of humans and rats.

By comparison, it appears that the canid (or canine) biochemistry for metabolizing theobromine is strangely unique relative to humans (and rats for that matter). The consensus opinion appears to be that dogs are unable to metabolize and then excrete theobromine efficiently. Upon ingestion of a theobromine-containing substance, dogs have been reported to excrete “small quantities of an unidentified but apparently unique metabolite” (Drug Metab. Disposition 1984, 12, 154-160). It also appears that the toxicity associated with the inability to metabolize theobromine causes an increased concentration of intercellular free calcium, which is consistent with significant CNS stimulation and tachycardia (J. Agric. Food Chem., 2005, 53, 4069-4075). Physiologically, theobromine ingestion in dogs is linked to epileptic seizures, heart attacks and death.

Bottom line: stick to the peanut butter. It’s much safer.
November 21, 2008
9:25
You're Carding me for Cough Medicine?
» ‎ The Realm of Organic Synthesis

Due to a really bad tickling cough, I haven’t been able to sleep in about a week. When my cough began 2 weeks ago, I started taking generic, run of the mill cough medicine. Then as the coughing got worse, I switched to a cough medicine with dextromethorphan. Besides the fact that I had to present multiple forms of ID to the awful cashier at Wal-Mart (apparently there's a “problem wiff meff” in my fair city…vida infra), it did the trick for the day, but really didn’t help at night.
I don’t usually get bad coughs. The last time I was “blessed” with the plague, the University nurse practicioner wrote me two scripts for azithromycin and cough medicine with codeine (surprisingly I wasn’t asked to take a pregnancy test—usually par for the course at our health center). Apparently codeine, though a controlled substance, is an excellent cough suppressant (though its true therapeutic value has been called into question; Pulmonary Pharmacology 1996, 9, 293–297). I remember that codeine cough syrup seemed to help last time, but we’ll see what happens.

The reason why codeine is a controlled substance in the US is because of it is classified as a narcotic and is structurally similar to morphine. Several webpages I’ve read note that codeine is manufactured by chemoselective methylation of the phenol in morphine (extracted from opium plants). Codeine is apprently less potent than morphine, however one of the first biotransformations codeine undergoes upon entering the body is (you guessed it) demethylation. I think Wikipedia claims that ~12% of the codeine ingested into your body is converted to morphine.
All of this relates back to synthetic organic chemistry. Morphine (a lot like quinine) is a “proof of concept” synthetic target; it's often used to put new synthetic methodologies to the test due to its structural complexity.
Morphine contains a complicated pentacyclic skeleton with a central quaternary center and thus represents an excellent challenge to synthetic chemists. Among the best syntheses are Fukuyama’s approach (intramolecular Mannich-type reaction; Org. Lett. 2006, 8, 5311-5314) and Trost’s one of several routes (particularly Pd-catalyzed asymmetric allylation; J. Am. Chem. Soc. 2005, 127, 14785–14803). I like Fukuyama’s synthesis for two reasons. First, the molecular complexity dramatically increases over the course of one reaction. In refluxing, acidic methanol, they were able to form the final two rings in one step. Second, you cannot go wrong (economically speaking) with refluxing methanol and hydrochloric acid. They’re cheap reagents and my hat's off to someone who doesn’t go out and buy a specialized chemical (e.g. using DAST instead of TBAF).
Hope everyone has a great weekend!

P.S. Sorry about the lack of posts this past month. “The Man” has given me a date I’m trying to stick to, so it translates to extra time in the lab.

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