Synthesis of Dipeptides with Ψ[CH(2)0] Amide Bond Mimetics

This chapter describes the synthetic procedures leading to ether dipeptide isosteres of the Phe-ψ[CH(2)O]-spiro-C(x) (9a-9e, Fig. 1) and Phe-ψ[CH(2)O]-Allylglycine (13, Fig. 2). Development of methods which lead to mimetics of amide bonds is central to the conversion of peptide leads into pharmaceutically viable molecules. Our strategy utilizes template 1, which provides derivatives 6b-6e upon alkylation with I, Cl-alkanes (C(3)-C(6)). Subsequent Finklestein conversion to iodides 7b-7e is then followed by cyclization to spirocyclic derivatives 5b-5e (Fig. 3). Figure 1. Synthesis of Phe ψ[CH(2)O]Spiro isosteres 9a-9e. Figure 2. Synthesis of Phe ψ[CH(2)O]Allylglycine 13 Figure 3. Synthesis of morpholinones 5b-5e.