Spirocyclic sulfates of 2-and 3-(hydroxyalkyl)cyclopropanols, obtainable through the Kulinkovich reaction from β-and γhydroxy carboxylic acid esters, respectively, were synthesized for the first time. The possibility of regio-and stereoselective alkylating the spirocyclic sulfates by using Normant homocuprates has been demonstrated.
Racemization in proteins and peptides at sites of L-asparaginyl and L-aspartyl residues contributes to their spontaneous degradation, especially in the biological aging process. Amino acid racemization involves deprotonation of the alpha carbon and replacement of the proton in the opposite stereoconfiguration; this reaction is much faster for aspartate/asparagine than for other amino acids because these residues form a succinimide ring in which resonance stabilizes the carbanion resulting from proton loss. To determine if the replacement of the hydrogen atom on the alpha carbon with a deuterium atom might decrease the rate of racemization and thus stabilize polypeptides, we synthesized a hexapeptide, VYPNGA, in which the three carbon-bound protons in the asparaginyl residue were replaced with deuterium atoms. Upon incubation of this peptide in pH 7.4 buffer at 37 °C, we found that the rate of deamidation via the succinimide intermediate was unchanged by the presence of the deuterium atoms. However, the accumulation of the D-aspartyl and D-isoaspartyl forms resulting from racemization and hydrolysis of the succinimide was decreased more than five-fold in the deuterated peptide over a 20 day incubation at physiological temperature and pH. Additionally, we found that the succinimide intermediate arising from the degradation of the deuterated asparaginyl peptide was slightly less likely to open to the isoaspartyl configuration than was the protonated succinimide. These findings suggest that the kinetic isotope effect resulting from the presence of deuteriums in asparagine residues can limit the accumulation of at least some of the degradation products that arise as peptides and proteins age.
An efficient procedure has been developed for the transformation of (7S)-7-(3-bromoprop-1-en-2yl)-5,5-dimethyl-4,6-dioxaspiro[2.5]octane [available from diethyl (S)-malate] into methyl 2-[(4S)-2,2-dimethyl-5-methylidene-1,3-dioxan-4-yl]acetate, and conditions for diastereoselective reduction of the double C=C bond in the latter have been optimized. The reduction product has been converted into (3S,4S)-3-[tertbutyl(dimethyl)siloxy]-4-methyldecanoic acid which is a building block for the synthesis of arenamides A and C, natural compounds possessing pronounced antitumor activity and efficiently inhibiting nitrogen(II) oxide and prostaglandin E 2 (PGE 2 ). * Stereodiad (propionate) block is a three-carbon fragment with vicinal hydroxy and methyl substituents in polyketide molecules.
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