Enantioselective cyclopropanation of heterocycles and the use of high-pressure techniques for the conformational analysis of peptide foldamers

Cyclopropanated heterocycles have been shown to be invaluable building blocks for the synthesis of a broad variety of natural products and other biologically relevant compounds. The first part of the present thesis describes the enantioselective cyclopropanation of furan and pyrrole derivatives, as well as their further transformations of the derived compounds. Furan-3-carboxylic acid methyl ester 91 was used as starting material for the total synthesis of (-)-Paeonilide 27, however, only in 83% ee, as enantiopure material was not accessible at that time. In the course of this project an enantioselective cyclopropanation reaction of 91 was developed, which leads to cyclopropane 15 in > 99% ee and multi gram quantity. Key features for the success were the application of azabox ligand 8 as the chiral ligand and the modification of the ratio of catalyst to ligand from 1:1 to 1:2. On the other hand, cyclopropanation products of N-Boc-pyrrole 101, which already have been applied for various synthetic endeavors, could not be accessed by enantioselective cyclopropanation so far. In the present work, a strategy for the enantioselective cyclopropanation of 101 with the use of tert butyl diazoacetate as carbene source and again azabox ligand 8 was developed. Cyclopropane 103 can be obtained in > 99% ee and multi gram quantity, along with doubly cyclopropanated 104 (max. 41% ee). The application of tert butyl diazoacetate and the ligand 8 turned out to be crucial for achieving high enantiomeric excess of the product. In the course of this project tert butyl substituted azabox ligand 8 was identified to be superior to a great variety of other ligands for the asymmetric cylopropanation of both 91 and 101. Cyclopropane 103 was applied for a short and efficient synthesis of the biologically active GABA analogue (S)-(+)-homo-b-proline 109. Starting from N-Boc-pyrrole 101, (S)-(+)-109 could be prepared in three steps and 37% yield. However, the occurrence of epimerzation during the acid catalyzed cyclopropane ring opening step prohibited access to enantiomerically pure 109. In the second part of the present thesis the structural and conformational behavior of a/b-peptide foldamers were investigated by the application of high pressure NMR (up to 2 kbar) and FTIR (up to 6.5 kbar) spectroscopic methods. Short tripeptides 217a and 217b containing a central cyclopropane amino acid, were analyzed in terms of their catalytic performance related to the application of pressure. The fact that 217a acts as a highly efficient organocatalyst for intermolecular aldol reactions, while its enantiomer 217b gives poor results, led us to the investigation of this feature. A plausible model for explaining the discrepancy of catalytic performance of 217a and 217b was proposed. While 217b shows clear indications for a strong internal hydrogen bond that separates the two catalytic functional groups, 217b shows a significantly higher degree for flexibility that allows it for reaching an optimal conformation for catalysis. Experiments under high pressure conditions revealed a sixfold increase in reaction rate upon a pressure jump from 1 bar to 5 kbar, but this was rather assigned to the general effect of pressure than to a change of the equilibrium of conformations of 217a. In addition to short tripeptides 217a and 217b, the 13 residue a/b-peptide foldamer 226 was examined under variable pressure and temperature. Conformational studies by NMR, FTIR and CD spectroscopy revealed a partial unfolding of the helical structure of 226 at elevated pressures and temperatures, which was shown to be reversible.