SPPS OF DIFFICULT SEQUENCES - A COMPARISON OF CHEMICAL CONDITIONS, SYNTHETIC STRATEGIES AND ONLINE MONITORING

The H-Ala-Arg-(Ala)(6)-Lys-OH sequence is a biologically interesting ' difficult sequence' presenting N-alpha-Fmoc deprotection and coupling problems. Different chemical conditions and synthetic strategies have been tested in order to overcome the problems due to sequence-dependen t interactions. In particular, it was confirmed that different solvent s in the deprotection step did not provide any significant improvement , but the use of a more efficient base in the deprotection mixture avo ided insufficient unblocking of N alpha-protecting group; problems due to partial coupling in the last steps of the synthesis were solved by double coupling techniques. Moreover, the synthesis of the model pept ide was carried out using both 'continuous flow' and 'batch' technique s. The present results demontrate that on-line monitoring of the depro tection step by absorbance measurements represents a very effective to ol to detect the onset of internal aggregations during the synthesis. (C) Munksgaard 1997.