Unusual acid cleavage reactions are reported for derivatives containing acylated N-methyl-α-aminoisobutyryl (NMeAib) residues. The bond linking the NMeAib residue to the following amino acid is
cleaved. Through X-ray diffraction studies of the NMeAib containing molecules, we have shown that the
carbonyl oxygen atom of the preceding residue is in proximity to the carbonyl carbon of the NMeAib residue.
Thus, it can act as an internal nucleophile leading to a cleavage reaction by way of an oxazolinium ion
intermediate. Kinetic experiments for the cleavage reaction were carried out on a series of benzoyl dipeptide
derivatives (p-X-C6H4C(O)-NMeAib-Phe-OMe) where X is varied from NO2 to Cl. The value of ρ = −1.335
for the Hammett linear free-energy relationship strongly supports the intermolecular oxazolinium intermediate
proposed.
[formula: see text] We report the syntheses of peptidomimetic opioids containing the core structure N-alkyl-2-alkyl-2,3-dihydro-4-pyridone. By employing imines bound on a solid support and the Danishefsky diene, this [4 + 2] cyclocondensation reaction facilitates the synthesis of novel complex heterocycles. The central reaction is carried out under mild conditions and employs readily available building blocks. In this study we demonstrate the suitability of N-alkyl-2-alkyl-2,3-dihydro-4-pyridones as a central scaffold for peptidomimetics and establish the scope of this [4 + 2] cyclocondensation reaction with imino acids on a solid phase. We also combine the synthesis of diketopiperazines with the [4 + 2] cyclocondensation reaction to form a 9,9a-dihydro-2H-pyrido-[1,2a]- pyrazine-3,8(1,4-dialkyl)dione, a bicyclic molecule containing a pyridopyrazine core structure.
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