Hydroxylysine synthesis

Hydroxylysine (328) was synthesized by chemoselective reaction of (Z)-4-acet-oxy-2-butenyl methyl carbonate (325) with two different nucleophiles first with At,(9-Boc-protected hydroxylamine (326) under neutral conditions and then with methyl (diphenylmethyleneamino)acetate (327) in the presence of BSA[202]. The primary allylic amine 331 is prepared by the highly selective monoallylation of 4,4 -dimethoxybenzhydrylamine (329). Deprotection of the allylated secondary amine 330 with 80% formic acid affords the primary ally-lamine 331. The reaction was applied to the total synthesis of gabaculine 332(203]. 

Benzyl-oxygen bonds may be cleaved under conditions mild enough to leave an allylic hydroxy group (759) or an easily reduced N—OH bond intact (65,80). N-Hydroxyamino acids can be prepared in good yield by hydrogenolysis of benzyl hydroxamates as shown in the synthesis of N -hydroxylysine (6) from 5 (777). 

Eeistner GJ (1995) Proferrioxamine Synthesis in Erwinia amylovora in Response to Precursor or Hydroxylysine Peeding Metabolic Profiling with Liquid Chromatography-Elecfrospray Mass Spectrometry. BioMetals 8 318... 

Maurer PJ, Miller Ml (1982) Microbial Iron Chelators Total Synthesis of Aerobactin and its Constituent Amino Acid, if -Acetyl-lf -hydroxylysine. J Am Chem Soc 104 3096... 

Hi. Lysine. Gamma radiolysis of aerated aqueous solution of lysine (94) has been shown, as inferred from iodometric measurements, to give rise to hydroperoxides in a similar yield to that observed for valine and leucine. However, attempts to isolate by HPLC the peroxidic derivatives using the post-column derivatization chemiluminescence detection approach were unsuccessful. This was assumed to be due to the instability of the lysine hydroperoxides under the conditions of HPLC analysis. Indirect evidence for the OH-mediated formation of hydroperoxides was provided by the isolation of four hydroxylated derivatives of lysine as 9-fluoromethyl chloroformate (FMOC) derivatives . Interestingly, NaBILj reduction of the irradiated lysine solutions before FMOC derivatization is accompanied by a notable increase in the yields of hydroxylysine isomers. Among the latter oxidized compounds, 3-hydroxy lysine was characterized by extensive H NMR and ESI-MS measurements whereas one diastereomer of 4-hydroxylysine and the two isomeric forms of 5-hydroxylysine were identified by comparison of their HPLC features as FMOC derivatives with those of authentic samples prepared by chemical synthesis. A reasonable mechanism for the formation of the four different hydroxylysines and, therefore, of related hydroperoxides 98-100, involves initial OH-mediated hydrogen abstraction followed by O2 addition to the carbon-centered radicals 95-97 thus formed and subsequent reduction of the resulting peroxyl radicals (equation 55). 

Ascorbic acid or vitamin C is found in fruits, especially citrus fruits, and in fresh vegetables. Man is one of the few mammals unable to manufacture vitamin C in the liver. It is essential for the formation of collagen as it is a cofactor for the conversion of proline and lysine residues to hydroxyproline and hydroxylysine. It is also a cofactor for carnitine synthesis, for the conversion of folic acid to folinic acid and for the hydroxylation of dopamine to form norepinephrine. Being a lactone with two hydroxyl groups which can be oxidized to two keto groups forming dehydroascorbic acid, ascorbic acid is also an anti-oxidant. By reducing ferric iron to the ferrous state in the stomach, ascorbic acid promotes iron absorption. 

Scheme 27 Synthesis of Glycosylated Hydroxylysine Building Blocks and Glycopeptide in Solution Using the Glycosyl Halide as Donorl74 ...

Synthesis of 1,2-frans-O-Linked Glycosyl Hydroxylysine via the Epoxide... 

PJ Maurer, MJ Miller. Microbial iron chelators total synthesis of aerobactin and its constituent amino acid,N6-acetyl-N6-hydroxylysine. J Am Chem Soc 105 240-245, 1983. 

Fig. 5. Synthesis of 1,2-trans glycosides using a participating group at C-2 for example, synthesis of glycosylated hydroxylysine derivative (p-D-Gal-( 1 >0)-IIyl) using (a) insoluble promoter-silver silicate (56) (b) soluble promoter-silver trifluo-romethanesulfonate (57).

Holm, B., Broddefalk, J., Flodcll, S., Wellner, E., and Kihlberg, J. (2000) An improbed synthesis of a galactosylated hydroxylysine building block and its use in solid-phase glycopeptide synthesis. Tetrahedron Lett. 56,1579-1586. 

UV characteristics of the natural product, while further hydrolysis (under acid conditions) yielded asteroidic acid (190)—the chromophoric fragment—together with e-hydroxylysine (191) and acetic acid (97). For the synthesis of asteroidic acid (190), /V-salicyloylglycine (192) was condensed with triethyl orthoacetate to afford 2-(o-hydroxy)phenyl-4-(l -ethoxy)ethylidene-5-oxazolone (193). This product on treatment with base underwent Cornforth rearrangement,... 

Hydroxyproline and hydroxylysine occur most noticeably in collagen. These are formed by modification of proline and lysine residues by specific enzymes after synthesis of the collagen chains. It is interesting to note that proly/hydroxylase, which hydroxylates proline, requires ascorbate (vitamin C) as a coreactant. Other chemical modifications known to occur commonly are the attachment of sugars (glycosylation) to asparagine, serine, and threonine residues and the phosphorylation of serine. Chemical modifications are also associated with the transport of proteins out of the cells in which they are synthesized. 

AA serves as an important cofactor for enzymes. Lack of AA in food causes scurvy in humans due to inefficient collagen synthesis, caused by the inactivation of the Fe(II)-activating prolyl hydroxylase and lysyl hydroxylase which catalyze the formation of hydroxyproline and hydroxylysine as essential components for collagens. Prolyl hydroxylases can also hydroxylate conserved prolyl residues in the alpha subunit of the hypoxia-inducible transcription factor, which signals for proteasomal degradation of the transcription factor . The proper action of these hydrolases requires dioxygen, thus they can act... 

Malkar, N B, Lauer-Fields, J L, Fields, G B, Convenient synthesis of glycosylated hydroxylysine derivatives for use in solid-phase peptide synthesis. Tetrahedron Lett., 41, 1137-1140, 2000. 

Markedly diminished synthesis of type I collagen presence of hydroxylysine-enriched collagens associated with delayed helix formation. 

In protozoa, alanine is generally the amino acid present at the highest concentration. High levels of glycine, serine and threonine have been reported. Amino acids other than those required for protein synthesis have also been detected. These include 2-aminobutyrate, 2-aminoadipate, hydroxylysine, 3-methylhistidine, norleucine, norva-line, ornithine and taurine. Amino acid levels fluctuate according to culture conditions. 

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