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).
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 4th-20th 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?
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 19th or early 20th 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.
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.
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).
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