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

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Date Issued:
2004
Summary:
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.
Title: Synthesis and structural characterization of intermediates towards the preparation of a polyphosphonate ester containing L-dopa for the potential treatment of Parkinson's disease.
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Name(s): Chamely-Wiik, Donna M.
Florida Atlantic University, Degree Grantor
Haky, Jerome E., Thesis Advisor
Carraher, Charles E., Thesis Advisor
Charles E. Schmidt College of Science
Department of Chemistry and Biochemistry
Type of Resource: text
Genre: Electronic Thesis Or Dissertation
Date Issued: 2004
Publisher: Florida Atlantic University
Place of Publication: Boca Raton, Fla.
Physical Form: application/pdf
Extent: 122 p.
Language(s): English
Summary: 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.
Identifier: 9780496082995 (isbn), 12108 (digitool), FADT12108 (IID), fau:9018 (fedora)
Note(s): Thesis (Ph.D.)--Florida Atlantic University, 2004.
Subject(s): Parkinson's disease--Treatment
Antiparkinsonian agents
Dopa
Organophosphorus compounds--Synthesis
Chemistry, Analytic
Held by: Florida Atlantic University Libraries
Persistent Link to This Record: http://purl.flvc.org/fcla/dt/12108
Sublocation: Digital Library
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Host Institution: FAU
Is Part of Series: Florida Atlantic University Digital Library Collections.