Tetrahydrofuran based sugar amino acids as foldamers and library scaffolds

Sugar amino acids (SAAs) have been extensively prepared in literature and utilised as dipeptide isosteres. The secondary structural preferences of delta-amino acids based upon tetrahydrofuran (THF) rings were ascertained by study of the corresponding homooligomers. Many of these were found to exhibit compact secondary structures (such as a repeating beta-turn and a left-handed 16-helix) in short sequences - foldamers. Pyranose SAAs have also been utilised as library scaffolds.

Chapter 2 describes the preparation of simplified delta-amino acid analogues of the existing SAA systems that adopt rigid secondary structures. Removal of the hydroxyl function at C-3 of L-gulonolactone and D-mannonolactone prior to THF formation gave efficient access to 3-deoxy THFs. The deoxygenated THFs of D-ribo and L-lyxo stereochemistry were utilised to provide access to the desired D-ribo, L-arabino and L-lyxo delta-amino acid precursors which contained the acid and amine functions orthogonally protected as an ester and azide respectively. Selective deprotection with solution phase coupling afforded the desired homooligomers. Information regarding the secondary structural preferences of these homooligomers was obtained by NMR (nOe, DMSO titrations, H/D exchange and variable temperature experiments), by solution IR and by circular dichroism (CD). The homooligomers were prepared in both protected and unprotected forms and two types of hydroxyl protection (silyl and acetyl) employed to allow investigation of any effects arising from different solvents and protecting groups. The homooligomers of the delta-amino acids with the 2,5-cis relationship adopted intramolecularly hydrogen bonded structures (by NMR and solution IR) which contained the nOes characteristic for the repeating beta-turn conformation. The removal of the hydroxyl function at C-3, the use of different solvents and different protecting groups did not perturb the conformation adopted by the 2,5-cis 3-deoxy homoligomers. By contrast, the 2,5-trans homooligomers did not adopt hydrogen bonded secondary structures (by solution IR) although poor signal dispersion by NMR restricted nOe study of the tetramers. CD spectra (in both TFE and water) showed that despite the absence of hydrogen bonding, a rigid conformation could be adopted by these homooligomers which was favoured when the bulky triethylsilyl group was present.

In chapter 3, the 3-deoxy D-ribo and L-lyxo THFs were utilised to prepare D-xylo, L-arabino and L-lyxo gamma-amino acids based on the 3-deoxy THF scaffold. Subsequent preparation of the corresponding unprotected and triethylsilyl protected tetramers allowed investigation of the secondary structural preferences of the cyclically rigidified gamma-amino acid homooligomers. No evidence was obtained for the formation of hydrogen bonded secondary structures. However, the observed dispersion of the amide protons of the protected oligomers in CDCl3, the presence of a broad peak by solution IR and partial rigidity by CD (in both TFE and water) lends hope that the formation of longer oligomers may lead to the formation of rigid structures, although not necessarily stabilised by hydrogen bonding interactions.

The L-lyxo and L-arabino TBDPS protected azides were validated as library scaffolds. Due to time restrictions only the L-lyxo azide was used as a scaffold and a 99-member library was successfully prepared. The library was screened for antimicrobial activity. Subsequent analysis of the five active library members showed that the active compounds were not the library members but impurities. A possible reaction side product was proposed but despite further testing of this compound (and several analogues), the compound(s) responsible for the biological activity were not identified.