Progress toward a novel ortho-functionalized cyclic phenylalanine dipeptide

Substance P, a neuropeptide found in various mammalian tissues, is involved a variety of physiological processes including the regulation of blood pressure, smooth muscle contraction, and cell growth. Assays have shown that the phenylalanine residues (Phe7 and Phe8) of Substance P are particularly important for receptor binding. Modeling studies, based on NMR data and P-methyl substitiution, seem to indicate a preferred conformation for the phenyl sidechains. This preferred conformation for these sidechains can be approximated, without backbone distortion, through the use of a sidechain ortho 0-CH2-O-CH2-CH2-O-CH2-0 linkage between the two residues.

We report progress toward the synthesis of an ortho-linked, cyclic phenylalanine dipeptide [cyclo(Boc-Phe-Phe-O-t-Bu)] for incorporation into a Substance P analog as described above. We also report the development of a synthetic method, based on the camphorsultam-derived synthesis of phenylalanine, for the formation phenylalanines containing novel sidechain functionality. These ortho-functionalized phenylalanines are then modified with the appropriate protecting groups, coupled to form the acyclic dipeptide, and cyclized via a crown ether-like SN2 coupling with ethylene glycol.