Peptides derived from α-hydroxymethylserine: Aspects of solid-phase synthesis

Summary

The solid-phase synthesis of peptides derived from the sterically hindered α-hydroxymethylserine (HmS) was investigated. The acid-sensitive,O,O-isopropylidene (Ipr) protection of HmS is compatible with the Fmoc chemistry, represented here by the Fmoc-HmS(Ipr)-OH and Fmoc-HmS(Ipr)-F derivatives. Three analogs of the opioid pentapeptide DADLE with a single or two consecutive HmS residue(s) were synthesized using Wang resin as the solid support. The HATU method has been shown to effectively accomplish ‘difficult’ couplings with the HmS(Ipr) residue. Wang resin is not suitable, for the synthesis of sequences with a C-terminal HmS because of the easy formation of the diketopiperazine resulting from the cyclization of the susceptible dipeptide sequence AA-HmS(Ipr) bound to the resin. A further drawback of the Wang resin methodology is the increased danger of the undersired N→O-acyl shift, when long-lasting acidic cleavage is applied. These side reactions are totally suppressed when the 2-chlorotrityl polystyrene is used as a solid support. The mild conditions (AcOH/TFE/DCM) applied for the peptide detachment from this resin do not affect the Ipr protection, affording highly pure fragments with HmS(Ipr) residues suitable for post-cleavage condensation, cyclization or controlled side-chain deprotection. This approach is documented by the efficient synthesis of linear and cyclic analogs of the opioid hexapeptide DTLET containing two residues of HmS or HmS(Ipr) in positions 2 and 6.