Monday, December 21, 2009

Reaction of the Week #2 - Strecker reaction & amino acid synthesis

I selected the Strecker synthesis based on a recent Nature paper by Jacobsen and coworkers using an asymmetric Strecker synthesis to create unnatural α-amino acids. The classical Strecker reaction, first reported in 1850 (!), involves the reaction of a carbonyl acompound (ketone or aldehyde) with ammonia (to create the free amine) or primary or secondary amines to form an α-amino nitrile, which can be followed by acidification to hydrolize the nitrile group to a carboxylic acid.  (The intermediate may also be reduced to produce 1,2-diamines or undergo α-substitution chemistry following deprotonation at the α-position, provided there is an available proton). The mechanism/sequence concluding with acid-catalyzed, sans the formation of the iminium and acid stepwise, is shown below.

The entire sequence can be achieved in one pot.  This reaction and the synthesis of amino acids can be easily rendered asymmetric using a chiral Lewis acid or an organocatalyst (in the latter, the additive would coordinate to the imine would obviously have to be trisubstituted/neutral for this to occur) and another basic moiety at the appropriate distance would associate with the proton from HCN, pulling H away and direct the CN to whichever side of the imine it is closest to.  Anionic CN sources are generally a problem because of the toxicity of the CN anion, and so improvements and modifications to the reaction are continuously made.  Examples of reagents include Bu3SnCN, TMSCN (which is expensive and difficult to handle), Et2AlCN, and HCN; while KCN and NaCN are desirable as they are inexpensive and easily handled cyanide salts, they are not typically seen presumably due to their low solubility in organic solvents unless buffered aqueous medium is used, according to the authors of the Nature paper.

A neat caveat to α-amino nitriles is that if they are treated with a heavy metal salt (such as a Ag(I) salt), a Brönsted or Lewis acid, cyanide can be a leaving group to reform iminium which is trappable by a nucleophile - when the nucleophile is organometallic, the reaction is the Bruylants reaction.

Jacobsen and coworkers have developed a chiral catalyst derived from (S)-tert-leucine (read: inexpensive and accessible) to achieve asymmetric imine hydrocyanation.  Using 2 equivalents of TMSCN, 2 equivalents of MeOH, and 0.5 mol% of the catalyst in 0.2 M toluene at -30C for 20 hours, excellent yields were achieved with good to excellent ee with the exception of only a few of the reported substrates which were still in good yield.

A nice graphic that explains the enantioselectivity was presented in the paper:

Another example which is included in the entry in Kürti and Czakó text is in the synthesis of (-)-α-kainic acid, a neurotoxic compound that induces seizures (it is used in research commonly to induce seizures in rats).  It is a kainate receptor agonist (hence its name), and since the kainate receptor is one of the "ionotropic glutamate receptors" it is understandably a stimulant (glutamate is an excitatory neurotransmitter).  The Strecker reaction in this case is mediated by zirconium with the Schwartz reagent to form imine, which was not isolated but directly treated with cyanotrimethylsilane to produce the α-amino nitrile.  Hydrolysis to the acid and concomitant epimerization selectively led to (-)-α-kainic acid.

I hope you like the festive-colored kainic acid!


Constructive criticism welcome; criticism for judgement's sake, not.