Nowe chiralne azirydynyloalkohole i aminoazirydyny jako efektywne katalizatory w syntezie asymetrycznej

Abstract

In present times asymmetric synthesis is one of the most dynamically expanding fields of modern organic synthesis. The direction for its development are the reactions which allow to obtain enantiomerically pure building blocks from prochiral substrates by using metal complexes with chiral ligands. In recent years, research on the synthesis and application of a new group of organic compounds - aziridine alcohols and aminoaziridines in asymmetric synthesis was conducted. The application of aziridine ring as a key structural element of the proposed systems results from the earlier experiments carried out at the Department of Organic and Applied Chemistry, which showed their particularly high-affinity to zinc ions. Firstly, a highly efficient synthesis of chiral aziridine alcohols based on the structure of achiral carboxylic acids with hydroxyl group was developed. In this way, enantiomerically pure ligands containing in their structure stereogenic center, located on the carbon atom of the aziridine ring, were obtained. Next, the catalytic activity of the resulting aziridine alcohols was examined in the asymmetric addition of diethylzinc and phenylethynylzinc to aromatic and aliphatic aldehydes. The further part of the research was oriented on the synthesis of enantiomerically pure 2-aziridine alcohols with two stereogenic centers. The key substrate for the synthesis of such compounds was an optically pure ester of N-trityl-aziridine-2-carboxylic acid, which can be obtained by conversion of readily available α-amino acid, i.e. L-serine. The choice of the N-trityl substituent resulted from the fact that the substituted aziridines have a much higher stability, which was important for the implementation of the individual reaction steps. The corresponding ligands were tested in the asymmetric addition of diethylzinc and phenylethynylzinc to various aldehydes. The chiral products were obtained with high enantiomeric excess and the addition stereochemistry depends on the presence of the stereogenic center located in the aziridine ring. The series of the above catalysts was extended to optically pure aziridinylethers. Moreover, optically pure aziridinylethers and aziridine alcohols were tested in asymmetric reactions, i.e. the Michael addition of diethylzinc to enones and the aldol condensation. Their high efficiency was demonstrated and expected products were obtained with high yields and enantiomeric excess. The reaction of the optically pure N-tritylaziridinyl-2-carboxylic acid ester with the two equivalents of Grignard reagents yielded the corresponding 2-aziridine alcohols, which were used in asymmetric synthesis. In addition, reaction of model β-aziridine alcohol with p-cresol derivative resulted in the bis-aziridine ligand (pincer structure). All chiral catalysts were tested in asymmetric epoxidation of chalcone. Furthermore, the bis-aziridine ligand was used in asymmetric additions of arylzinc systems generated from phenylboronic acid and diethylzinc to various aldehydes. In all cases, obtained results indicated high efficiency of tested catalysts. In the last part of the research, the reactions of the optically pure ester of N-trityl-aziridine-2-carboxylic acid with secondary and tertiary amines in the presence of trimethylaluminum led to the corresponding amides. Next, the carbonyl group was reduced and N-triphenylmethyl and N-unsubstituted aminoaziridines were obtained. All synthesized catalysts were tested in three different asymmetric reactions. In addition, benzyl amide was used in the synthesis of (S)-Lacosamide which is used as an anti-epileptic drug.