Transition Metal-catalyzed Amino Acid Racemization

D-Amino Acids were considered of no use to human body in the past, but in recent years, as to the development of chiral drugs and life science, a series of chiral drugs with D-amino acids as chiral synthesis source have kind of therapy that can not be replaced by L-amino acids. Therefore, D-amino acids preparation and applications gradually become the current research hotspot. But the current racemization rates of preparation of D-amino acids are too low, and the reaction speeds are also slower. In this research L-amino acids were racemized in organic acids catalyzed by several common transition metals, and we also made a theoretical study with Gaussian 03 program package to make a conclusion of the racemization reaction.The main contents are as follows.Considering the factors such as the R-of amino acids (straight-chain or ring-like), electron attracting or electron repeling and acid-base that influence the racemization reaction, we selected 4 of 19 kinds of amino acids with optical activity-- tryptophan, phenylalanine, glutamic acid and lysine as the research object. Secondly, the economic efficiency and catalytic effect on consideration, we selected manganese, iron, zinc and cadmium as catalyst.In the experimental part, firstly, we found that there were no significantly changes of 4 kinds of amino acids when heated for 4 hours in a higher temperature(117.9℃) indicating that this temperature had no effects to the 4 kinds of amino acids. Then the 4 kinds of amino acids were catalyzed by transition metals in acetic acid. From the results we can find that:the catalyze capacity of 4 kinds of metals were accordance, Mn2+>Fe2+>Zn2+>Cd2+, in which the capacity of Mn2+ was the best. The racemization value of Trp, Phe, Glu and Lys were 49.7%,60.1%, 81.1% and 70.8% which were much higher than those in literatures; but the rate of racemization were a little different:Fe2+ was the fastest with 1 h to 1.5 h while Mn2+ and Cd2+ were slower with 2.5 h to 3 h. But they were also much faster than those in strong bases or catalyzed by aldehyde with 5 h to 8 h. Because of their electron repeling properties Phe and Trp can not be racemized completely, although the recamization rates had increased significantly.In the theoretical part, on the racemization of Trp, we firstly made a structure optimization and frequency analysis by Gaussian 03 program on the level of B3LYP/LANL2DZ based on the crystal structure of metal-Trp compounds. Firstly, we made a thermodynamics data statistics, theΔrG(?) of the racemization reaction indicated that the catalytic ability was:Fe2+>Mn2+>Cd2+ Zn2+; while theΔrHF indicated that the reaction rate was:Fe2+>Mn2+≈Cd2+>Zn2+. Then we analyzed and compared Miilliken charges between reactants and products:after the racemization reaction, the electrons on the chirality carbon atom of L-Trp obviously reduced, which showed us that the catalytic ability was:Fe2+>Mn2+>Cd2+>Zn2+; Finaly, according to natural bond orbital theory, we made a NBO analysis of metal-Trp compounds which revealed the tendency of electrons transfer. The catalytic ability was:Mn2+>Fe2+>Zn2+>Cd2+。Taken together, the three above theoretical analysis showed the same law:recamization rate:Mn2+>Fe2+>Zn2+ Cd2+; speed of racemization:Fe2+>Mn2+>Cd2+>Zn2+ which suited the experimental results very well.There were no crystal data of metal-Phe, metal-Glu and metal-Lys, so we created a series of structures by GaussView program based on the crystal structure of metal-Trp compounds as initial structures. Then structure optimization and frequency calculation were made. Firstly, we also made a thermodynamics data statistics:the catalytic abilities of the four different metal ions to L-Phe, L-Glu and L-Lys were in accordance, theΔrG(?) of the racemization reaction indicated that the catalytic ability was:Fe2+>Zn2+>Mn2+>Cd2+; then Mulliken charges told us that catalytic effect was:Mn2+>Fe2+>Zn2+>Cd2+; Finally, NBO analysis revealed that catalytic effect was:Mn2+>Fe2+>Zn2+>Cd2+. Taken the three above method together, we knew that the catalytic abilities of the four different metal ions to the three kind of amino acids were in accordance:Mn2+>Fe2+>Zn2+>Cd2+, and the results also suited the experimental results very well. Catalytic rate of the four metal ions were a little different, but Fe2+ was the fastest while Cd2+ was the lowest.In conclusion, based on four kinds of typical amino acid, this paper reviewed a fast racemization method on the chemical experimental level and a law of racemization reaction by thermodynamics data statistics, Mulliken charges analysis and NBO analysis. The above results would play a great role in the preparation of D-amino acids which have a extensive application prospect.