Synthesis of stereoisomers of 2,4-diaminoglutaric and 2,5-diaminoadipic acids

Abstract

Stereoisomers of 2,4-diaminoglutaric and 2,5-diaminoadipic acids were synthesized from glutamic and 2-aminoadipic acids, respectively. The stereo, chemistry of the products was established by IH NMR spectroscopy and X-ray analysis.Key words: 2,4-diaminoglutaric acid, 2,5-diaminoadipic acid. nucleophilic substitution; stereoisomers; racemization.2,4-Diaminoglutaric acid (In) has been previously isolated as a natural product t,z and synthesized by different methods. 1"4 The (2S,4S)-enantiomer of la has been synthesized 4 and its complexing properties have been studied. 5 Methods for the synthesis of 2,5-diaminoadipic acid (lb) ~,~ and its stereoisomers s are also known. It is interesting to note that derivatives of acids la,b exhibit antitumor activity. 9,t~We have developed simple methods for the synthesis of diastereomers of compounds la,b from the corresponding monoaminodicarboxylic acids, viz., glutamic (2a) and 2-aminoadipic (2b) acids.Compound 2a is readily transformed into methyl 4-bromo-N-phthalylglutamate (3a). !1 Its reaction with potassium phthalimide (PP) in DMF followed by separation of the mixture of diastereomers afforded methyl 2,4-diphthalimidoglutarates (threo-4a and meso-4a), whose acid hydrolysis resulted in threo-and meso-la diastereomers (Scheme 1).An attempt to obtain the threo-forrn of 4a from erythro-3a was unsuccessful, since the reaction of the latter with PP in DMF ,,vas accompanied by racemization. Stirring of an equimolar mixture of meso-4aand PP in DMF for 3 h at ~ 20 ~ resulted in a mixture of diastereomers of 4a (meso/threo = 5 according to HPLC data). Evidently, PP is a very strong base, since the inversion of the carbanion follows the abstraction of the a-proton. The alternative mechanism of racemization of the phthalimide group involving nucleophilic substitution by the phthalimide ion is impossible, since heating of an equimolar mixture of meso-4aand potassium 4-nitrophthalimide in DMF for 6 h at 68 ~ did not afford (HPLC) diastereomers of methyl 2-phthalimido-4-(4-nitrophthalimido)glutarate (5),

Synthesis of 4‐Amino Derivatives of 5‐Oxoproline

“…Partial epimerization during acidic hydrolysis of C-4-substituted glutamic acids has been previously observed for some derivatives of 2,4-diaminoglutaric acid, [13d] and 4-thio-and 4-mercaptoglutamic acids. [11] The epimerization degree decreases with decreasing duration of acidic hydrolysis. Thus, when erythro-5 was hydrolyzed for 5 h, the overall yield of epimerization products threo-12 and cis-16 was about 10 %.…”

“…When there is a functional group (OH, SH, or NH 2 ) in position 4 of glutamic acid able to undergo ring formation, protecting groups removal by acidic hydrolysis can be accompanied by heterocyclic ring closure (Scheme 1). [11,13] Moreover, any of the process steps can be accompanied by racemisation. Scheme 1.…”

“…According to the above methods we prepared glutamic acid derivatives containing nitrogen, [9] oxygen, [10] sulfur, [11] and phosphorus [12] atoms in position 4. When there is a functional group (OH, SH, or NH 2 ) in position 4 of glutamic acid able to undergo ring formation, protecting groups removal by acidic hydrolysis can be accompanied by heterocyclic ring closure (Scheme 1).…”

Enhancing allosteric inhibition of dihydrodipicolinate synthase through the design and synthesis of novel dimeric compounds

“…A similar phenomenon was reported by Krasnov et al in the synthesis of adipic and glutaric acid stereoisomers. 32…”

Structure and Properties of 4‐Amino Derivatives of 5‐Oxoproline

“…Glutamic acid in aqueous solutions with pH values close to neutral is converted into pyroglutamic acid. [3] The derivatives of glutamic acid with 4-substituents, such as amino, [4] phenyl, [5] arylamino, [6] thiopyridinyl [7] and others, [8] are able to form lactams in acidic and neutral media. It should be noted that the amount of lactam formed increases when the glutamic acid contains aromatic and heterocyclic substituents.…”