Ferrocenyl alanine

In a slightly different approach, the introduction of a metal complex is also possible as a metallo amino acid. For example, ferrocenyl-alanine (Fer) was prepared as early as 1957 [67]. Also, stereoselective preparations [68-71] and its biological activity were reported [72], and the compound has been inserted into peptide sequences just as a normal amino acid would (see Fig. 7 for an example) [35, 71]. In this case, the metallocene constitutes the side chain. Alternatively, the amino and carboxylic acid function can be on two different Cp rings, yielding, in the simplest possible case, l -aminoferrocene-l-carboxylic acid (Fca, see Fig. 7 for an example). This compound has also been reported in the literature, although it was difficult to obtain in pure form [73,74], It has since been incorporated into oligomers... 

Fig. 7 Peptides containing ferrocenyl-alanine as one amino acid (Ac-Tyr-Gly-Gly-Fer-Leu-OH, top) and l -aminoferrocene-l-carboxylic acid (Boc-Ala-Fca-Ala-Ala-OMe, bottom)...

A number of other ferrocene-based amino acids were reported, for example, 1,2-ferrocenylbisalanine, ferrocenyl-/ -alanine and I,T-ferrocenylbis-/ -alanine, l,T-ferrocenylbisglycine, and ferrocenylenebisvaline. 

An enantioselective synthesis of ferrocenyl-modified alanines 91 and 93 was also reported.163 In this case, an organozinc derivative of serine 90 was coupled to iodoferrocene 89 or 1,1 -diiodoferrocene 92 using a palladium catalyst [Pd2(dba)3] to give the Boc-ferrocenyl-L-ala-nine methyl esters 91 and 93 in 60 and 64% yield, respectively (Scheme 26). 

The hydantoins (116 and 117) have been prepared from DL-j8-ferrocenyl-a-alanine and N - ferrocenyl methyl-AT-(a-carbethoxy-benzyl)urea, respectively.68 The Friedel Crafts reaction of ferrocene and 2-pyrroylchloride gave the ketone (118).112,113 The polarographic half-wave potentials of 118 and other related ferrocenes were measured113 and it was concluded that the ferrocene radical was more electropositive than the phenyl radical. 

Scheme 5.24 Synthesis of the methyl ester of N-Boc-l,l -ferrocenyl-Ws-alanine (44) and formation of cyclic peptides.

Frejd and coworkers then used lactam 45 as a structural H-Phe-Phe-OH mimic in peptides (116). The resulting conjugate 48 was expected to function as a structural mimic of substance P (Scheme 5.25). However, CD spectroscopic studies indicated that the constraints imposed by the l,l -ferrocenophane prohibited the peptide to adopt the characteristic a-hehcal secondary structure found for native SP in a biomimetic SDS (Sodium n-Dodecyl Sulfate) micellar environment. In another interesting paper, Frejd and coworkers prepared a [Leu ]-Enkephalin mimetic in which the H-Tyr-Gly-Gly-Phe-subunit has been replaced by a Gly-Gly-looped l,l -ferrocenyl-bis-alanine residue (49, Scheme 5.25) [117]. The ferrocene Cp rings of this constrained compound constitute a substitute for the aromatic phenol (Tyr) and phenyl (Phe) rings. NMR-spectroscopic studies revealed this... 

Scheme 5.25 Incorporation of derivatives of 1,1 ferrocenyl-fc/s-alanine 42 as dipeptide mimics into substance P (top, 48) and enkephalin (bottom, 49).

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