Epimerization of peptide nucleic acids analogs during solid-phase synthesis: optimization of the coupling conditions for increasing the optical purity

Citation
R. Corradini et al., Epimerization of peptide nucleic acids analogs during solid-phase synthesis: optimization of the coupling conditions for increasing the optical purity, J CHEM S P1, (20), 2001, pp. 2690-2696
Citations number
48
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry & Analysis","Organic Chemistry/Polymer Science
Journal title
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1
ISSN journal
1472-7781 → ACNP
Issue
20
Year of publication
2001
Pages
2690 - 2696
Database
ISI
SICI code
1472-7781(20011021):20<2690:EOPNAA>2.0.ZU;2-8
Abstract
Peptide nucleic acid (PNA) analogs based on N-alpha-(thymin-1-ylacetyl)orni thine were previously shown to form triplexes with complementary RNA. In or der to obtain optically pure compounds for hybridization experiments, chira l monomers based on D- or L-ornithine, N-delta-Fmoc-N-alpha-(thymin-1-ylace tyl)ornithine 2 and N-delta-Fmoc-N-alpha(uracil-1-ylacetyl)omithine 3 were synthesized either by a one-step or by a simple three-step procedure starti ng from Ns-protected ornithine; the latter procedure led to enantiomericall y pure products. Oligomerization of 2 and 3 was carried out either in solut ion, or by solid-phase peptide synthesis (SPPS) on an MBHA-Rink amide resin . The oligomers turned out to contain large amounts of epimerization produc ts, especially those obtained by SPPS. Therefore, we examined carefully the parameters which may be involved in epimerization: the nature of the coupl ing reagent, of the base, and the addition mode. Coupling of the monomer L- 3 was performed under various conditions. Lower racemization was found to o ccur when using (7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflu orophosphate (HATU) as coupling agent and 2,4,6-trimethylpyridine (sym-coll idine, TMP) as base, without preactivation, leading to a residual 4% of the D-enantiomer. By applying a procedure based on the stepwise addition of th e base the D-enantiomer content was reduced to less than 1%. Using this pro cedure, a decamer of L-3 was synthesized, which was shown to contain less t han 2% of the D-ornithine derivative.