Synthesis of novel chiral ligands from aminoacids with aryl aldehydes

OLGA C. SÁNCHEZ M.; ANA FOI; FLORENCIA DI SALVO

Chascomús

Encuentro; IV Latin American Meeting on Biological Inorganic Chemistry - V WOQUIBIO; 2014

FCEN, UBA

INTRODUCTION The design of new molecules displaying biological activity has been investigated for a long time.1 For instance, inorganic compounds, like platinum complexes, present antitumoral activity and many ligands have been developed to increase such behavior.2 The presence of suitable ligands will provide useful physical properties such as, solubility in water, increased membrane permeability and thus, higher biological activity.3 Additionally, molecular chirality has an important role, as well. In living organisms practically all bioactive molecules such as, proteins and enzymes are chiral and exist in only one enantiomeric form. Consequently, the S and R enantiomers of a chiral compound will exhibit different physiological effects in the human body because they interact in a distinctive way with the enzymes and proteins.4 As a result, the choice of appropriate ligands in the metal complexes has a decisive role in order to alter and fine tune the biological properties. Based on these considerations, two novel water-soluble chiral ligands have been synthesized from aryl aldehydes via imine condensation with L-tyrosine and L-aspartic acid respectively. In order to get a better understanding of their properties, we are focused also, on studying their coordination chemistry properties using different oligometals like zinc, cobalt and copper. EXPERIMENTAL METHODS Solvents and starting materials were of the highest commercially available purity and used as received. Synthesis of N-(1,3-benzodioxol-5-ylmethyl)-L-tyrosine (HL1). A mixture of L-tyrosine (1.10 mmol) and NaOH (2.20 mmol) in methanol was stirred for 10 min to dissolve. A methanolic solution of piperonal (1.10 mmol) was added dropwise to the above solution. The color of the solution turned yellow. The stirring was continued for 3 hr heated to reflux. The solution was then treated with NaBH4 (3.0 mmol) with constant stirring, and then it became colorless. The clear solution was then acidified with a few drops of acetic acid (pH∼5-6). The ligand precipitated as a white solid (yield 76.89%). Synthesis of 2,4,6-Tris(L-aspartic acid) cyclohexane-1,3,5-trione (H3L2). A mixture of 2,4,6-Triformylphloroglucinol (0.1 mmol, 1 equiv.), L-aspartic acid (0.3 mmol, 3 equiv.) and NaOH (0.6 mmol, 6 equiv.) in 1 mL of ethanol was stirred to reflux under inert atmosphere for 24 h. The solvent was removed in vacuum from the reaction mixture to give the target molecules as a gummy mass. The crude products were purified by repeatedly dissolving them in water and re-precipitating by the addition of a large excess of ethanol. The solid was then dried in a vacuum desiccator (yield 90%). Both H3L2 and HL1 were fully characterized by NMR (1H, 13C, COSY, HSQC), MS and elemental analyses. The use of HL1 and H3L2 as ligands were studied with zinc, cobalt and copper acetate salts in different molar ratio at room temperature. The synthetic procedure was followed by 1H NMR experiments. However, the identity of the products obtained is still under investigation. RESULTS AND DISCUSSION The molecular structures of the chiral ligands presented in this work are shown in Fig. 1. HL1 was obtained as an air stable pure white solid with a high yield, in contrast to H3L2 that presented hygroscopic behavior. Both ligands present in their structure amino chelating sites as a result of the imine reduction process. Fig. 1 shows two coordination sites, the above mentioned and the carboxylate group, both in suitable geometry to chelate metal centers. In the case of H3L2, the presence of the amine is a consequence of a keto-enol tautomerism.6 In addition to this interesting property, this compound is obtained as a mixture of two keto-enamine tautomeric forms with C3h and Cs rotational symmetries respectively (Fig.1 bottom). In contrast to the previously reported related compounds,6 it was possible to obtain each isomer separately modulating the reaction conditions (Fig.2). The coordination capacity of H3L2 was demonstrated by in situ 1H NMR experiments with zinc acetate in different molar ratios. The resultant product is obtained as a light brown solid, air stable and, unlike the starting ligand, it is insoluble in water. Further spectroscopic investigations are carried out in order to reveal its structural identity. CONCLUSION In summary, two novel chiral ligands with amino and carboxylate groups with metal-chelting sites were synthesized. NMR experiments allowed the study of the two geometric isomers of H3L2 (C3h and Cs) obtained separately. Their use as ligands in coordination chemistry was demonstrated by preliminary results obtained from the reaction of H3L2 with M(II). These reactions are under investigation. REFERENCES 1. (a) E. Wong, et al,. Chem Rev. (1999) 99: 2451. (b) S.P.Fricker, Dalton Trans (2007) 4907 2. G. Natalie et al,. Coord Chem Rev. (2001) 383: 216-217 3. M.E. Cucciolito et al,. Inorg Chim Acta (2010) 363:741-747 4. Q. Shen et al,. Acta Pharm Sinica (2013) 34:998-1006 6. (a) J.H. Chong et al. Org Lett (2003) 5:3823-3826 (b) C.V. Yelamaggad et al., J. Org. Chem (2009).79:3168-3171. (b) B. Feldscher et al. Dalton Trans (2010).39:11675-11685 ACKNOWLEDGMENTS Financial support from ANPCyT (PICT 2012-1335 and 2011-2013), and CONICET (PIP 112 201001 00125). OCSM and AF thanks to CONICET for a PhD scholarship.