New synthetic pathways to polyfluoroalkyl-containing amino- and hydroxy acids with potential biological activity
Final Report Abstract
Bio-relevant molecules tackled with fluorine or fluorinated groups in strategic position are most interesting for modern drug design. Many fluorinated aromatics are commercially available for this purpose. In contrast, there is still a need for specifically fluorinated aliphatic and saturated (hetero)cyclic building blocks. This project focused on the development of new fluorinated amino acids as potential bio-isosteres of natural amino acids and on the investigation of the influence of fluorinated groups on the physical-chemical properties and the conformational behavior of such compounds. Based on our results of the first funding period, we concentrated on hitherto unknown 3-(polyfluoroalkyl)proline derivatives. Another topic was the synthesis of trifluoromethoxy substituted amino acids, representing a new type of fluorinated amino acids. Although the lipophilic character of this substituent makes such compounds most interesting as building blocks, very little is known about aliphatic members of this class of compounds The 2- and the 4-trifluoromethyl-prolines were known in literature and we were able to synthesize the 5-substituted regioisomers in the first funding period. Now we prepared cis- and trans-3-trifluoromethyl-proline, the last missing members of this family of potential building blocks for peptide synthesis, in racemic form. Moreover, the trans-isomer was accessible in both enantiomeric forms using a classical three-step deracemization methodology. To our regret, this type of racemate separation failed in case of the cis-isomer, probably because of steric constrains in the hydrolysis step of the successfully separated diastereoisomeric phenetylamides. Moreover, the racemic diastereomeric 3-(pentafluoroethyl)-prolines were produced on the same way. Furthermore, two additional new fluorinated proline analogues, namely trans-3-(bromodifluoromethyl)-3-hydroxyproline and trans-3-(difluoromethyl)-3-hydroxyproline were synthesized in racemic form. Using a methodically completely different approach, another proline analogue, trans-3-(carboxydifluoromethyl)proline was prepared in a new copper-catalyzed conjugate addition reaction of protected 2,3-dehydroproline with ethyl bromodifluoroacetate as the key-step of the three-stages sequence. This product can be regarded as a conformationally fixed difluoro glutamic acid analogue, but also as a nor-isopropyl-difluoro analogue of the natural kainic acid, which is a specific agonist of the glutamate receptor class (known as kainite receptors). Finally, the first member of the new group of trifluoromethoxy amino acids, and thus an oxygen analogue of trifluoromethionine, was prepared. In order to execute the scheduled synthesis, the first OCF3-substituted C2 building block, namely the tosylate of O-(trifluoromethyl)ethylene glycol was synthesized in three convenient steps from diethyleneglycol. Alkylation of N-acetylamino diethylmalonate and decarboxylative deprotection of the alkylation product delivered the racemic target compound. Also both enantiomers were accessible via an auxiliary directed asymmetric synthesis. In order to get information on the physical-chemical properties of this new type of fluorine-containing amino acids, pKa values and lipophilicity parameters were compared to those of some natural and some other fluorinated amino acids. Surprisingly, the pKa values are almost identical to those of valine, leucine and (difluoromethyl)alanine, while methionine, its oxygen analogue, and (trifluoromethyl)- and (trifluoroethyl)alanine are more acidic. Moreover, the measured logD value of the N-tosyl derivative of the new amino acid is almost identical to that of (trifluoroethyl)alanine and slightly lower than that of methionine, but much lower than that of all other mentioned amino acids. In summary, twelve new fluorinated amino acids have been prepared and its physical-chemical properties were investigated. Most of these proline analogues and the first trifluoromethoxy-substituted amino acid are available in multi-gram amounts and can serve as building blocks for peptide synthesis.
Publications
- Synthesis and physical chemical properties of 2-amino-4- (trifluoromethoxy)butanoic acid - a CF3O-containing analogue of natural lipophilic amino acids. Org. Biomol. Chem. 2017, 15, 672-679
I. S. Kondratov, I. G. Logvinenko, N. A. Tolmachova, R. N. Morev, M. A. Kliachyna, F. Clausen, C. G. Daniliuc, G. Haufe
(See online at https://doi.org/10.1039/c6ob02436j) - Straightforward synthesis of fluorinated amino acids by Michael addition of ethyl bromodifluoroacetate to α,β-unsaturated α-amino acid derivatives, J. Fluorine Chem. 2018, 211, 100-108
I. S. Kondratov, M. Y. Bugera, N. A. Tolmachova, C. G. Daniliuc, G. Haufe
(See online at https://doi.org/10.1016/j.fluchem.2018.03.014) - Synthesis of New fluorinated proline analogs from polyfluoroalkyl βketoacetals and ethyl isocyanoacetate, Chem. Commun. 2018, 54, 9683-9687
N. A. Tolmachova, I. S. Kondratov, V. G. Dolovanyuk, S. Pridma, A. V. Chernykh, C. G. Daniliuc, G. Haufe
(See online at https://doi.org/10.1039/C8CC05912H)
