Synthesis of N-Fmoc-(2S,3S,4R)-3,4-dimethylglutamine: An Application of Lanthanide-Catalyzed Transamidation

• Published in: Journal of organic chemistry 2005-08, Vol.70 (16), p.6218-6221
• Main Authors: Çalimsiz, Selçuk, Lipton, Mark A
• Format: Article
• Language: English
• Subjects: Aliphatic compounds; Amination; Catalysis; Chemistry; Depsipeptides - chemistry; Exact sciences and technology; Glutamine - analogs & derivatives; Glutamine - chemical synthesis; Glutamine - chemistry; Lactams - chemical synthesis; Lanthanoid Series Elements - chemistry; Molecular Structure; Organic chemistry; Preparations and properties
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo050518r

N-Fmoc-(2S,3S,4R)-3,4-dimethylglutamine (6) was synthesized from tert-butyl N-Boc-(2S,3S,4R)-dimethylpyroglutamate (13). This synthesis involved selective deprotection of a Boc group from a lactam nitrogen in the presence of a tert-butyl ester, Fmoc protection of the lactam, and a lanthanide-catalyzed transamidation reaction of the Fmoc-protected lactam, using ammonia and dimethylaluminum chloride. The scope of Lewis acid-catalyzed transamidation of acylated lactams was explored through the variation of lanthanide, lactam, acyl group, amine, and aluminum reagent. The reactivity of various metal triflates was found to vary in the following qualitative order:  Yb ∼ Sc > Er ∼ Eu ∼ Sm > Ce ∼ AgI > CuII ∼ Zn. Intriguingly, catalysis was only observed when ammonia was the nitrogen nucleophile; addition of other amidoaluminum complexes to acyl lactams was found to be insensitive to the addition of lanthanides.