Ferrocene-derived Protecting Groups

Boc and tert-butyl protecting groups are simultaneously cleaved [150-152]. The usefulness of Fem-Gly derivatives for peptide synthesis in solution is illustrated by the successful synthesis of [Leu j-Enkephalin and H-(Gly)g-OH in solution [152]. In a similar manner, the Fern group has also been used as a protecting group for Asn [151] and Cys [155,156] residues in peptide synthesis. 

Kane-Maguire and coworkers proposed the iron tricarbonyl cyclohexadienyl cation ([(Fe(CO)3(C5H7)], Fed) as an alternative to the Fern protecting group [157]. 

---

It is also possible to synthesize PNA monomers with an organometallic label at the C terminus. The secondary ferrocene amine derivative that has been used for the preparation of the bimetallic peptide derivatives 5 and 6 vide supra) could be coupled to the C terminus of the N-Fmoc-T-PNA monomer to yield 54 (Scheme 5.28). The N-Fmoc protecting group can be readily removed imder mild conditions and coupling to a second T-PNA monomer is possible, yielding the ferrocenylated PNA dimer 55 [139]. 

Figure 3.7 General structures of anticancer chiral ferrocenes functionalized in the cyclopenta-dienyl-derived ligand with (a) a nucleobase (R, =side chain Nb = nucleobase) and (b) an amino acid (R2 = Fmoc-protected amine group) [52,54].

Our group published the first organometallic derivatives of PNA monomers [138]. Ferrocene carboxylic acid 3 and benzoic acid chromium tricarbonyl 50 were coupled to the amino group of PNA monomers with different nucleobases (Thymine (T) a and Z-protected Cytosine (Z-C) b) using HBTU as the coupling agent to give compounds 51 and 52, respectively (Scheme 5.27). The activation barrier AG for the rotation about the tertiary amide bond has been determined for the ferrocenylated T-PNA monomer 51a to be 75 0.5 kj moD. For the same compound 51a, a T-T self-association constant = 2.5 0.2 has been... 

---