Oftentimes, in organic synthesis, the product of a chemical reaction or the starting material or key intermediate in a multi-step synthesis is only available in racemic form. The separation of these enantiomers could be effected through the use of enantiomerically enriched chiral auxiliaries. This project focuses on the separation of racemic mixtures of aldehydes and ketones, for several reasons: 1) these functionalities are prevalent, and 2) serve as ideal sites for temporary derivitization. One potentially useful application would involve chiral amines (figure, below) as auxiliaries in the formation of diastereomeric imines from racemic mixtures of aldehydes and ketones. The resulting mixture of diastereomers could be separable either by differential recrystallization or by normal chromatographic methods. Once resolved, the chiral auxiliary can be removed to yield the enantiomerically enriched aldehyde or ketone. The auxiliary can be recycled for use in further resolutions. This project outlines the synthesis of several chiral amines, and their use as potential resolving agents. The amines will be derivatives of aniline and a variety of terpenes including (-)-menthone, (+)-camphor, and (-)-camphorquinone, which are commercially available and relatively inexpensive. In addition, unsymmetrical Tröger’s base compounds (dibenzodiazocines) will be synthesized to serve as a second source of chiral amines.
The synthesis of chiral amines will be relatively straightforward. The first class of chiral amines to be synthesized will be the simple condensation products between o-nitroaniline (the meta- and para- isomers can also be employed) and an appropriate terpene ((+)-camphor, in this example) to form imine intermediates that are reduced to the desired chiral amine as illustrated in Scheme 1.
Scheme 1. 
One potential obstacle to this route is the possible formation of endo and exo amine products resulting from the reduction step. There is some precedent for the preferential formation of the exo product pictured above. Regardless, separation of these diastereomers should be possible. If this proves difficult, then the free aromatic amine could be used to form an imine with (+)-camphor (or some other terpene) resulting in diastereomeric imines that may prove more readily separable.
A second type of chiral amine will involve the condensation of o-phenylenediamine derivatives with (-)-camphorquinone to form chiral quinoxalines as shown in Scheme 2.
Scheme 2. 
Again, the formation of two regioisomeric products may create a separation problem. However, once separated, the quinoxaline product with the amine functionality closer to the bridgehead methyl group seems to be the most promising target. The imine formed via condensation with a racemic aldehyde or ketone in subsequent steps would place the chiral center of the auxiliary in close proximity to the carbonyl adduct allowing for greater chiral induction. The scheme above can be employed with a variety of nitrated o-phenylenediamine derivatives allowing for a rich variety of chiral amines to be produced. Initially, only the quinoxaline pictured in the scheme will be manufactured and tested as a resolving agent. If this analog proves useful, then other derivatives of o-phenyldiamine will be employed.
The final class of chiral amines to be produced will be unsymmetrical Tröger’s base analogs. The general synthesis is shown in Scheme 3. The most interesting step in the synthesis is the formation of the dibenzodiazocine moiety. The methyl group on the eight-membered ring will prefer to be in the endo position, allowing for the formation of only one of the two possible diastereomeric products to be formed. This synthesic route is interesting in that it presents a formalized methodology for the production of unsymmetrical chiral Tröger’s base analogs that has not been previously explored.
Scheme 3. 
The family of chiral amines produced will be used as auxiliaries in the resolution of racemic aldehydes and ketones as outlined below for the quinoxaline derivative and benzoin as the substrate. The use of imines for chiral resolutions has several advantages, and one potential problem. First, the advantages: 1) the chiral amines employed are aromatic, and the imines produced are relatively stable Schiff bases, and 2) these chiral amines cannot be epimerized (which is a disadvantage for many existing commercially available chiral amines).
| |
| |