Synthesis of Derivatives of ω-Isocyanato-α-methylamino, ω-Ureido-α-methylamino, and Nα-Methyl-α, ω-diamino Acids

Abstract

Homochiral N -methyl-2,3-diaminopropionic and N -methyl-2,4-diaminobutyric acid derivatives 8a,b were obtained via a stereoconservative four-step synthesis starting from hexa¯uoroacetone protected L-aspartic and L-glutamic acid 2a,b, respectively. Hexa¯uoroacetone protected 3-isocyanato--methylamino acids 4a,b ± the key intermediates of the synthesis ± are versatile building blocks for amino acid and peptide modi®cation and promising candidates for combinatorial chemistry. Upon reaction with alcohols, compounds 4 give activated N 3 -urethane protected 3-amino--methylamino acid derivatives 5±7; upon reaction with amines, 3-ureido--methylamino acid derivatives 10±12 and 3-methylamino-pyrrolidin-2-ones 13 are available.

α,β-Diamino Acids: Biological Significance and Synthetic Approaches

“…In fact, an N -acetamido l -asparagine derivative in the presence of Br 2 and NaOH or N -benzamido l -aspartic acid with diphenylphosphoryl azide (DPPA) provide exclusively imidazolidinone 203 (Scheme ) . However, a suitable combination of N -protecting groups and reagents efficiently converts asparagine and aspartic acid derivatives into α,β-diamino acid derivatives. 163b, Furthermore, it has been illustrated by different groups that a clever use of the reagents can provide orthogonally protected l -Dpr derivatives 206 and 207 by reacting isocyanate intermediates such as 205 , from the Curtius rearrangement of 204a , b , with benzyl alcohol or tert -butyl alcohol, respectively (Scheme ) 38 …”

Hexafluoroacetone as protecting and activating reagent: reactions of hexafluoroacetone with α-keto acids

“…Both compounds 2 and 4 do not meet the structural requirements to serve as precursors for a general synthesis of a-keto acid derivatives, i.e. they lack an unprotected carboxy group which is essential for the construction of side chains of high structural diversity [8][9][10]. These findings exclude the application of the hexafluoroacetone route for the generation of libraries of a-keto acids.…”

“…Using the standard protocol successfully applied to aspartic [8], malic [9] and thiomalic acid [10], 2-oxosuccinic acid 1 was reacted with an excess of hexafluoroacetone at room temperature. After work-up a crystalline compound was obtained.…”

“…Hexafluoroacetone has been successfully applied as a reagent for simultaneous protection and activation in a-amino [8], a-hydroxy [9] and a-mercapto acid chemistry [10]. On reaction of aspartic, malic and thiomalic acid with hexafluoroacetone the a-functionality and the adjacent carboxy group are simultaneously protected.…”

Synthesis of Ureido-Linked Glycosylated Amino Acids from N α-Fmoc-Asp/Glu-5-oxazolidinones and Their Application to Neoglycopeptide Synthesis

“…[6] This protocol is useful particularly for N a -methyl amino acids, [7] a-hydroxy acids, [8] and amercapto acids. [9] However, it cannot be extended to obtain isocyanates of HFA-protected activated a-amino acids because of intramolecular trapping of the generated x isocyanates by the ÀNH of the oxazolidinone ring.…”