Protected amino acid chlorides: Coupling reagents suitable for the most highly hindered systems

Abstract

Fmoc amino acid fluorides have proven to be generally useful for peptide synthesis, even in the case of hindered systems such as those incorporating adjacent Aib residues. In such cases, Fmoc-Aib-F has been shown to be more efficient than the corresponding acid chloride (Fig. 1) because the urethane-protected amino acid chloride is converted much more readily than the acid fluoride to the corresponding oxazolone. On the other hand Fmoc-amino acid fluorides appear to have reached their limits in attempted applications to very highly hindered substrates, e.g. the coupling of Fmoc-protected proteinogenic amino acids to MeAib substrates. The corresponding amino acid chlorides, although long disregarded due to deficiencies associated with available protocols, can, in fact, overcome these limitations. In the presence of bis(trimethylsilyl)-acetamide (BSA), urethaneprotected amino acid chlorides provide for a far more efficient process than the corresponding fluorides (Fig. 1). By switching to other forms of that are more compatible with the acid chloride functionality such as N-arenesulfonyl protectants for which the already high reactivity of the acid chloride unit is increased by inductive effects, it is possible to couple Aib to MeAib units within a few minutes. Indeed it is even possible to couple MeAib to MeAib, a reaction never achieved previously. Because of its facile removal the Pbf group was used as Thus, Pbf-MeAib-Cl (1 eq.) was coupled to (2 eq.) in toluene in the presence of DIEA (2 eq.) and BSA (1 eq.) within 2-3 h in a 70% yield. The structure of the resulting dipeptide (Pbf-MeAib-MeAib-OMe), purified by preparative HPLC, was confirmed by NMR analysis, mass spectrometry, and CHN analysis. Removal of the Pbf-group by means of 10% dimethylsulfide in trifluoroacetic acid (v/v) for 1 h at ambient temperature yielded the desired dipeptide, MeAib-MeAibOMe, in a yield of 87%.