Synthesis and conformational studies of a 1,1′-ferrocenophane lactam mimetic of substance P

The synthesis of a bis-phenylalanine mimetic 6 and its incorporation into Substance P (SP), giving a conformationally constrained organometallic SP analogue 8, is described. The lactam 6 was synthesized in five steps, via a HWE olefination reaction, enantioselective hydrogenation with [Rh(I)(COD)((S,S)Et-DuPHOS)]+OTf− and intramolecular cyclization with PyAOP as a coupling reagent. Comparative CD studies of 8 with native SP indicated that the flexibility around the amide bond of Phe(7)–Phe(8) sequence is crucial for the C-terminal (from residue Gln(4)) to adopt an α-helical conformation in the micellar environment created by SDS or in methanol.