Synthesis and analysis of the sterically constrained l-glutamine analogues (3S,4R)-3,4-dimethyl-l-glutamine and (3S,4R)-3,4-dimethyl-l-pyroglutamic acid

The nonproteinogenic amino acids (3S,4R)-3,4-dimethyl-l-pyroglutamic acid and (3S,4R)-3,4-dimethyl-l-glutamine—found in the cyclic depsipeptides callipeltin B, callipeltin A, and papuamide A—were synthesized from a common intermediate derived from l-pyroglutamic acid. The diastereoselective introduction of the methyl groups was accomplished by cuprate addition and enolate alkylation, followed by a kinetic epimerization of the C-4 methyl substituent. (3S,4R)-3,4-Dimethyl-l-glutamine shows a conformational restriction of its side chain which may be related to its biological function in the natural products where it is found.