Enantioselective syntheses of isotopically labelled?-amino acids Preparation of specifically13C-labelled L-lysines

Abstract

[2-(13)C]-L-lysine, [3,4-(13)C2]-L-lysine and [5,6-(13)C2]-L-lysine are prepared from simple, commercially available, highly enriched starting materials as [2-(13)C]-glycine, ethyl [1,2-(13)C2]-bromo acetate, and [1,2-(13)C2]-acetonitrile. The introduction of the chiral center is based on a general method starting from the bis-lactim ether of cyclo-(D-Val-Gly). The synthesis of (2R)-[5-(13)C]-3,6-diethoxy-2,5-dihydro-2-isopropylpyrazine is described. The availability of our method for the preparation of specifically enriched bis-lactim ethers allows the synthesis of a great variety of site specific isotopically labelled (L- and D-)α-amino acids. Moreover, intermediate 4-[(2R,5S)-3,6-diethoxy-2,5-dihydro-2-isopropyl-5-pyrazinyl]butyronitrile is a valuable precursor in the synthesis of L-α-aminoadipic acid. The synthetic scheme in this publication makes both L-lysine and L-α-aminoadipic acid(13)C- or(15)N-labelled at any position, easily available. The isotopomers of lysine are obtained on a preparative scale in good yields, with 99%(13)C and high enantiomeric purity (>97% e.e.). Three isotopomers are characterized using various spectroscopic techniques,e.g.,(1)H NMR,(13)C NMR and Mass spectrometry.

Preparation of [1,2,3,4,5‐13C5]‐5‐Amino‐4‐oxopentanoic Acid (ALA) − Design of a Synthetic Scheme to Prepare Any 13C‐ and 15N‐Isotopomer with High Isotopic Enrichment

“…Preparation of the complete set of isotopomers of ethyl propenoate (12) from simple starting materials has been described earlier by our group. [16,17] 1,4-Addition of KCN to ethyl propenoate (12) leads to ethyl 3-cyanopro-Scheme 2. Synthesis of 5-chlorolevulinic acid (16) and ethyl levulinate (17) starting from ethyl propenoate (12); synthesis of 3-(1Ј,3Ј-dioxolan-2Ј-yl)propanenitrile (8) from acrolein (18) panoate (13) in high yield.…”

Preparation and Characterization of [5‐13C]‐(2S,4R)‐Leucine and [4‐13C]‐(2S,3S)‐Valine − Establishing Synthetic Schemes to Prepare Any Site‐Directed Isotopomer of L‐Leucine, L‐Isoleucine and L‐Valine

“…We have previously prepared the full isotopomeric set of the glycine part in the bis(lactim) ether of -valine-glycine [29] . This is the basic system of the Schöllkopf method for the preparation the full isotopomeric set of α-amino acids.…”

Synthesis of Isotopically Labeled α‐Amino Acids

“…While the Sch€ ollkopf bislactim ether has been used for the synthesis of a number of labeled amino acids [69,70], purification of these products from the valine byproduct and the level of diastereoselectivity during the alkylation or acylation step can sometimes be problematic [67]. Using oxazines, in particular the Williams oxazines supersedes some of these issues as the oxazine ring is cleaved under hydrogenation conditions and the isotopically labeled amino acid is isolated by ion-exchange chromatography.…”