EXPLORING THE ASYMMETRIC ENVIRONMENT OF VARIOUS CHIRAL CATALYSTS USING A MODIFIED ION-TRAP MASS SPECTROMETER: TOWARDS THE DEVELOPMENT OF A RAPID CHIRAL CATALYST SCREENING METHOD

摘要

Since the tragedy of the drug Thalidomide® in the late 1950 to early 1960’s, chirality has been recognized as an important aspect that must be controlled in the drug development process in the pharmaceutical industry. Since then, there has been a considerable movement towards single enantiomer drugs. This demand has presented many challenges for the synthetic organic chemist. Chiral catalysts offer one solution to this problem, as they afford the unique ability to preferentially synthesize one enantiomer. Unfortunately, the design of new chiral catalysts is often empirical, with luck and trial and error necessary due to factors that govern enantioselectivity. Therefore, it would be highly beneficial to develop a method that is capable of screening multiple chiral catalysts early in the catalyst development cycle. Using a modified ion-trap mass spectrometer, the chiral environment of various chiral catalysts may be examined, free from solvent and ion-pairing affects. Thus, the catalyst’s inherent asymmetric environment (enantioselectivity) may be probed using simple chiral molecules, including alcohols, ethers, and epoxides of various steric demands. Using these probes, various C2-symmetric bis-oxazolines and di-imines catalysts were examined. Use of the binaphthyl-based diamine, BINAM, condensed with various 3,5-disubstituted benzaldehydes, provided selectivity close to the privileged catalyst, bis-oxazoline. In general, the chiral probes 1-phenyl-2-propanol, 1-mehtoxyethylbenzene, and styrene oxide offer the best look at the catalyst’s enantioselectivity potential. With the use of the ion-trap mass spectrometer as a mass filter, the purity of the catalyst is not paramount, thus, multiple catalysts may be screened simultaneously, with the constraint that the catalysts must be of different m/z. This thesis presents results found during the exploration of various C2 and C1-symmetric chiral catalysts, in the development of the new chiral screening method utilizing various chiral probes.