SYNTHESIS AND X-RAY STRUCTURE OF THE CHIRAL, POLYDENTATE CATION BINDER N-[N-[(5-METHYL-2-THIENYL)METHYLIDENE]-L-METHIONYL]HISTAMINE

A synthetic route has been developed to obtain N-[N-[(5-methyl-2-thienyl)methylidene]-L-methionyl]histamine, optically pure (alpha-20 = 8.13-degrees/L mol-1 dm-1), from a sequence of reactions involving L-methionine, histamine, and 5-methyl-2-thiophenecarbaldehyde. The described procedure affords gram quantities in an overall yield of 40%, without the need of any chromatographic techniques. Moreover, the removal of the well-known tert-butyloxycarbonyl amino-protection group (BOC) with gaseous hydrochloric acid, in the present synthesis, had considerable advantages compared with the commonly applied trifluoroacetic acid method. The structure of N-[N-[(5-methyl-2-thienyl)methylidene]-L-methionyl]histamine in the solid has been determined by X-ray diffraction techniques. C16H22N4OS2 crystallizes in the monoclinic space group P2(1), with a = 5.233 (1), b = 9.556 (1), and c = 17.919 (1) angstrom; beta = 98.32 (1)-degrees; and Z = 2. Noteworthy aspects of the tertiary structure of the molecule are the fact that it is almost flat, the three arms connected to methionine-C-alpha, being the (thienylmethylidene)amino moiety, the ''imidazole-amide'' fragment, and the methionine side chain, spread out. pi-Conjugation causes the (thienylmethylidene)amino moiety to have a planar s-cis conformation, and the methionine side chain's all-trans conformation is due to vicinal interactions. The gauche conformation of the ''imidazole-amide'' does not have a clear origin, but is no artifact of the solid state. Intra- and intermolecular hydrogen bonds are prominently present, the former determining the relative orientations of the aforementioned arms and the latter linking the title molecules into two-dimensional, sheetlike entities.