ASYMMETRIC CATALYSIS AND SENSING WITH RIGID C2-SYMMETRIC LIGANDS AND DEVELOPMENT OF HEME-TARGETED ANTIMALARIALS

Abstract

The first general procedure for the ligand-catalyzed nucleophilic addition of diethylzinc to trifluoromethyl ketones was developed. A range of 2-aryl-1,1,1-trifluorobutan-2-ols have been prepared in up to 99% yield using 10 mol % of TMEDA to favor alkylation over β-hydride elimination. These findings provide a new route for the asymmetric synthesis of trifluoromethyl-derived tertiary alcohols which are important components in many pharmaceuticals. Accordingly, the first asymmetric variant of this reaction was introduced. Screening of 16 chiral ligands revealed that excellent yields and ee's up to 61% can be obtained with TBOX as catalyst.

The first general procedure utilizing a bisoxazolidine - copper(I) complex in the asymmetric Henry reaction was developed. A range of aromatic nitroaldol compounds have been prepared in up to 95% yield and up to 89% ee using 10 mol % of the bisoxazolidine catalyst. The reaction of aliphatic substrates proved even more successful, and the corresponding nitroaldol products were obtained in up to 97% yield and 97% ee. An interesting switch in enantioselectivity when employing the same chiral ligand with either copper(I) acetate or dimethylzinc was also discovered. In both cases, nitroaldol products are obtained in high yields and ee's but with opposite chiral induction.

1,8-bis(3'-(3,5-dimethylphenyl)-9'-acridyl)naphthalene N,N'-dioxide was introduced to new asymmetric catalysis and enantioselective sensing applications. The synthesis of the ligand was successfully scaled-up, and 1 gram of material was prepared. A chiral HPLC method was developed that allowed convenient preparative isolation of the enantiomers of this ligand. Initial progress made towards the asymmetric desymmetrization of meso-epoxides is promising from both a synthetic protocol development and enantioselective sensing standpoint. N-Oxide units of the ligand can also be protonated by a strong acid, which is accompanied by a significant UV-response. This finding opens entries towards the development of a Brønsted acid sensor.

Twelve heme-targeted antimalarials have been prepared by systematically varying side chain lengths, N-terminal branching and substitutions, and heteroatom substitution at the 4-position of quinoline. This study reveals that methodical variation of the side chain of chloroquine provides affordable heme-targeted antimalarials that may overcome the ever-increasing problem with worldwide drug resistance.