Conformational Analysis of beta-Lactam-Containing Ferrocene Peptides

The homochiral 3-amino-1-(4-methoxyphenyl)-4-phenyt-beta-lactam (equivalent to Alm) was conjugated with Boc-Ala to give Ala-Alin (9) after Boc deprotection (Boc = tert-butox.ycarbonyl, Ala = alanine). Coupling of Fc-COOH (1) and Boc-Fca (10) with dipeptide 9 resulted in the formation of Fc-CO-Ala-Alin (12) and the trisamide Boc-Fca-Ala-Alni (13), respectively (Fc = ferrocenyl, Fca = 1'-aminoferrocene-1-carboxylic acid). The reactions were accomplished by the HOBt/EDC procedure, and the products were obtained in good yields [HOBt = 1-hydroxybenzotriazole, EDC = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride]. Symmetrically 1,1'-disubstituted tetrapeptide Fn(CO-Ala-Alm)(2) (14) was prepared by reaction of ferrocene chloride 11 with 9 (Fn = 1,1'-ferrocenediyl). Spectroscopic and theoretical analyses revealed that compounds 12, 13, and 14 are stabilized in solution by medium-strong intramolecular hydrogen bonds. In all dominant conformations (DFT calculations) intrachain bonds spanning COFc and NHAlm are present (gamma-turns). Additional interchain hydrogen bonds NHAla center dot center dot center dot COBoc (13) and NHAla center dot center dot center dot COAla/NHAla center dot center dot center dot COAlm (14) give rise to ordered helical conformations of the ferrocene moieties. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451. Weinheim Germany, 2009)