Methods for syntheses of N-methyl-DL-aspartic acid derivatives

Abstract

A novel practical method for the synthesis of N-methyl-DL-aspartic acid 1 (NMA) and new syntheses for N-methyl-aspartic acid derivatives are described. NMA 1, the natural amino acid was synthesized by Michael addition of methylamine to dimethyl fumarate 5. Fumaric or maleic acid mono-ester and -amide were regioselectively transformed into beta-substituted aspartic acid derivatives. In the cases of maleamic 11a or fumaramic esters 11b, the alpha-amide derivative 13 was formed, but hydrolysis of the product provided N-methyl-DL-asparagine 9 via base catalyzed ring closure to DL-alpha-methylamino-succinimide 4, followed by selective ring opening. Efficient methods were developed for the preparation of NMA-alpha-amide 13 from unprotected NMA via sulphinamide anhydride 15 and aspartic anhydride 3 intermediate products. NMA diamide 16 was prepared from NMA dimethyl ester 6 and methylamino-succinimide 4 by ammonolysis. Temperature-dependent side reactions of methylamino-succinimide 4 led to diazocinone 18, resulted from self-condensation of methylamino-succinimide via nucleophyl ring opening and the subsequent ring-transformation.

Biocatalytic Enantioselective Hydroaminations for Production of N‐Cycloalkyl‐Substituted L‐Aspartic Acids Using Two C−N Lyases

“…N ‐substituted L‐aspartic acids are noncanonical amino acids that have wide applications in pharma‐ and nutraceutical fields, serving as drug candidates and chiral building blocks for pharmaceutically active molecules, artificial sweeteners and peptido‐mimetics . Therefore, the development of methodologies for the efficient synthesis of N ‐substituted aspartic acids in enantioenriched form is of high academic and industrial interest.…”

“…N-substituted L-aspartic acids are noncanonical amino acids that have wide applications in pharma-and nutraceutical fields, serving as drug candidates and chiral building blocks for pharmaceutically active molecules, artificial sweeteners and peptidomimetics. [1][2][3][4][5][6][7] Therefore, the development of methodologies for the efficient synthesis of N-substituted aspartic acids in enantioenriched form is of high academic and industrial interest. The most common chemocatalytic synthetic strategy is the Michael addition of suitable amines to maleic acid, fumaric acid, their ester or amide derivatives, or monoalkali salts.…”

“…The most common chemocatalytic synthetic strategy is the Michael addition of suitable amines to maleic acid, fumaric acid, their ester or amide derivatives, or monoalkali salts. [7][8][9] However, in these chemocatalytic reactions, racemic product mixtures are obtained. To achieve the desired single L-enantiomer, purification or resolution is needed, leading to unsatisfactory product yields lower than 50%.…”

Unsubstituted <i>β</i>-Alkyl Aspartates as Highly Biodegradable and Almost Nontoxic Surfactants

“…Several synthetic methods for the preparation of zwitterionic surfactants have obtained full recognition nowadays. They include chemical or enzymatic transformation of amino acids into their esters, conversion of amino acids into their derivatives with hydrophobic N-alkyl or N-acyl group at the nitrogen atom, as well as addition of fatty primary amines to the C=C double bonds of α, β-unsaturated acids or their derivatives [4]- [11].…”

The synthesis of (Z)-4-oxo-4-(arylamino)but-2-enoic acids derivatives and determination of their inhibition properties against human carbonic anhydrase I and II isoenzymes

“…The name maleimide (1) was derived from maleic acid (3) and imide functional group 1 . Maleimides are important structural blocks with unsaturated structures in organic synthesis.…”