Synthesis and structural characterization of intermediates towards the preparation of a polyphosphonate ester containing L-dopa for the potential treatment of Parkinson's disease

We have synthesized intermediates towards the preparation of a polyphosphonate ester containing L-dopa for the potential treatment of Parkinson's disease. A synthetic strategy was devised to be more reproducible than the original strategy. We discovered some very interesting chemistry of one of the intermediates produced from this new scheme. We synthesized L-N-(butyloxycarbonyl)-3-(3-hydroxy-ethyl-4-(benzyloxy)-phenyl)alanine benzylester, a compound containing a secondary alcohol moiety that had a unique set of characteristics. Upon reduction of the N-(tert-butyloxycarbonyl)-3-(3-acetyl-4-benzyloxyphenyl)-L-alanine benzylester, which contained a ketone moiety, to produce the secondary alcohol, we discovered that the materials that were formed included a pair of diastereomers of the secondary alcohol, each diastereomer also exhibiting two individually stable conformational isomers. We believe that the conformational isomers were generated by rotation of the C-N bond of the BOC carbamate, and were so stable that they could be separated by HPLC and NMR techniques. Energy optimization studies and molecular modeling techniques were performed using HyperChem, and rotational barrier energy values were calculated for the different conformational isomers for each of the diastereomers. HPLC and NMR techniques were also used to obtain information about these materials. Using the calculated data from these studies, and analyzing the HPLC chromatograms and NMR spectra we were able to fully determine the assignments for the diastereomers and the individual conformational isomers. We discovered that the SS form was synthesized preferentially over the SR form and that in both cases the E conformation was energetically more stable than the Z form. Octanol/water partition coefficient values (Log P0ct) were also determined and compared to L-dopa and dopamine. We concluded that the values for the dimeric compound that we synthesized and many of its potential products of degradation were significantly higher than that for both L-dopa and dopamine. This may be an indication that this material has a higher degree of lipophilicity than L-dopa itself, having more potential to cross the blood brain barrier. We believe that these intermediate materials serve as good indication of how a polyphosphonate ester containing L-dopa would compare as a potential drug for Parkinson's disease.