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).
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5 comments:
hmmm not sure i see anything wrong with the structures... hint?
I am surprised the referees let them get away with the title of this paper. racemic mixtures are not "non-chiral"!
I think he might be referring to the amino acids not being represented as zwitterions. Although I don't know if I would necessarily call that wrong.
I agree that calling these molecules nonchiral is wrong.
aa and anonymous:
You are both wrong. Those molecules are definitely non-chiral.
The compounds are definately achiral; you're creating a quaternary center from an sp2-hybrid without controling facial selectivity (nevermind that the cyclobutanone starting material is a meso compound). Additionally, the cyclization step is not stereoselectively controlled. The authors are correct in this regard.
Anonymous realized the zwitterionic nature of amino acids. I can tell you from personal experience that my PI has lectured me at length about drawing amino acids as the ammonium carboxylate (pKa values are one of the 10 commandments in our group).
All three molecules have a plane of symmetry passing through the carboxylate, amino function and both bridgehead carbons. Alternatively, if you can't picture that, make models of the molecules and their mirror images -- you'll see they are superimposable, and hence non-chiral.
The zwitterion thing is a bit hair-splitting in my view. Amino acids are often drawn like that for clarity sake even though we all understand that the actual structure is pH dependent. If you wanted to be really pedantic why not insist that all the hydrogen atoms on carbons are shown? It's just a representation of reality, not actual reality.
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