Combined Fmoc-Alloc strategy for a general solid phase synthesis of phosphoserine peptides

A building block method for the SPPS of serine phosphopeptides has been developed using a combination of Fmoc and Alloc strategies. Alloc-Ser[PO(OCH2CH=CH2)2]-OH, prepared in a one-pot procedure from Alloc-Ser-OH, was introduced at the N-terminus of a sequence prepared by standard Fmoc-SPPS. Global cleavage of the allyl ester protecting groups followed by coupling of a tripeptide fragment led to tau phosphopeptide, 1, which was not available by post assembly phosphorylation strategies and is an important epitope of tau phosphoprotein in Alzheimer′s Disease. Fmoc SPPS ← Thr(tBu)-Glu(tBu)-Asn(Trt)-Leu-Lys(Boc)-His(Trt)-Wang + Alloc-Ser[PO(OAllyl)2]-OH ← ← H-Lys-Leu-Gly-Ser(P)-Thr-Glu-Asn-Leu-Lys-His-OH