Synthesis of Organofluorine Compounds and Chirality Sensing with Tropos Ligands

Abstract

Chiral organofluorine compounds play an important role in medicinal chemistry due to the beneficial effects of the fluorine moiety on the physiochemical and pharmacological profiles of drugs. The asymmetric synthesis of chiral organofluorines has therefore attracted increasing attention in recent years. In order to contribute to this rapidly growing direction, a catalytic asymmetric Friedel-Crafts reaction of indoles and trifluoropyruvates using a chiral copper(I)-bisoxazolidine complex was developed. Eleven ethyl 2-(3'-indolyl)-3,3,3-trifluoro-2-hydroxypropanoates were obtained in up to 99% yield and 94% ee within 4 hours. This reaction tolerates a wide range of substrates. Noteworthy, indoles carrying substituents on position 1 and 7 give higher yields and ee values than previously reported methods.

A practical method for difluoroenolate release from 2,2,4,4,4-pentafluorobutan-1,3-dione hydrates through LHMDS promoted carbon-carbon bond cleavage was introduced to convert trifluoromethyl ketones to pentafluorinated β-hydroxy ketones. This reaction tolerates both aromatic and aliphatic substrates, and it proceeds under mild conditions providing the pentafluorinated β-hydroxy ketones in up to 95% yield in 10 minutes. A catalytic variation of this reaction was then developed to extend this methodology to asymmetric synthesis. A wide range of α,α-difluoro-β-hydroxy ketones was obtained in up to 99% yield and 92% ee using a novel copper(II)-bisoxazoline catalyst under mild conditions. Reduction of the chiral aldol products can afford anti-1,3 diols with high yield and excellent diastereoselectivity. Alternatively, Baeyer-Villiger oxidation followed by hydrolysis forms 2,2-difluoro-3-hydroxy carboxylic acids in high yield and without any sign of racemization.

In contrast to the progress of asymmetric catalysis and combinatorial chemistry, fast analysis of the concentration and enantiomeric excess of a large number of samples is still challenging. To overcome this bottleneck, two stereodynamic palladium(II) complexes carrying tropos ligands DPPF or BDPDE were developed for chirality sensing of diamines and amino alcohols. This method is based on simple UV and CD measurements and provides an opportunity for fast analysis of the concentration and enantiomeric excess of chiral substrates. The use of tropos ligand derived metal complexes is adaptable to high throughput screening and has potential to accelerate the stereochemical analysis of libraries of chiral compounds.