Multistep synthesis of 2,5-diketopiperazines on different solid supports monitored by high resolution magic angle spinning NMR spectroscopy

The solid-phase synthesis of 2,5-diketopiperazines containing the trans-4-h ydroxy-L-proline amino acid residue (Hyp) was performed on Ellman polystyre ne, polyoxyethylene-polyoxypropylene (POEPOP), polystyrene polyoxyethylene NovaSyn, and Wang resins, respectively. The reaction pathway allowed the in troduction of different functional groups around the bicyclic scaffold in a combinatorial approach, and it generated mixtures of isomers. A detailed c haracterization of the single reaction steps by high resolution magic angle spinning (HRMAS) NMR spectroscopy was performed. The NMR spectral resoluti on of the resin-bound intermediates and final products was greatly influenc ed by the polymer matrix. The POEPOP resin permitted to obtain HRMAS NMR sp ectra with a resolution comparable with that of the spectra of the molecule s in solution. Moreover, configurational and conformational isomers formed during the solid-phase reaction steps could be detected and easily assigned . Therefore, the combination of the HRMAS NMR technique with the use of non aromatic resins may become an extremely powerful tool in solid-phase organi c synthesis. This approach will allow the monitoring of multistep reactions and the conception of on-bead structural studies either on small molecules or on natural and/or synthetic oligomers.