Henry Rzepa's Blog Chemistry with a twist

May 26, 2010

Anatomy of an asymmetric reaction. The Strecker synthesis, part 2.

In the first part of the post on this topic, I described how an asymmetric sulfoxide could be prepared as a pure enantiomer using a chiral oxygen transfer reagent. In the second part, we now need to deliver a different group, cyano, to a specific face of the previously prepared sulfoxide-imine. The sulfoxide is now acting as a chiral auxilliary, and helps direct the delivery of the cyanide group to specifically one face of the imine rather than the other. After removal of the aluminum carrier for the cyano group and hydrolysis of the cyano group to a carboxylic acid group, we end up with an enantiomerically pure amino acid.

The Strecker synthsis: asymmetric delivery of cyanide anion. Click for 3D model of transition state

Two transition states can be computed (ωB97XD/6-311G(d,p)/SCRF[dichloromethane], see DOI 10042/to-4927) and the S,S(S) diastereomer is found to be  1.35 kcal/mol lower in total free energy than the R,S(S) isomer. This agrees with the observed specificity. Again, a reason for the specificity needs identifying, and again we use  AIM.

AIM analysis for the asymmetric delivery of cyanide to an imine, S,S(S) form.

In the favoured diastereomer, a BCP or bond-critical-point (green arrow above) can be found connecting a hydrogen from an aryl group to the oxygen of the Al-OMe group  via a weak hydrogen bond (H…O distance 2.25Å). In the disfavoured form, this interaction vanishes, and is instead replaced by a repulsive close N=CH…C-aryl contact of 2.49Å (for which there is no  BCP, red arrow below).

Disfavoured transition state. R,S(S) form.

The take home message from these two posts is that quite unusual interactions may often be responsible for asymmetric induction in a stereospecific reaction, and that helpful clues to these interactions may well be derived from an AIM analysis. Indeed, anyone doing stereospecific synthesis in the lab should be familiar with these methods! You have to be a jack-of-all-trades nowadays to keep up!

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