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

被引:16
作者
Corradini, R
Sforza, S
Dossena, A
Palla, G
Rocchi, R
Filira, F
Nastri, F
Marchelli, R
机构
[1] Univ Parma, Dipartimento Chim Organ & Ind, I-43100 Parma, Italy
[2] Univ Padua, Dipartimento Chim Organ, I-35131 Padua, Italy
[3] Univ Naples Federico II, Dipartimento Chim, I-80126 Naples, Italy
来源
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1 | 2001年 / Royal Society of Chemistry卷 / 20期
关键词
D O I
10.1039/b104146k
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
Peptide nucleic acid (PNA) analogs based on N-alpha-(thymin-1-ylacetyl)ornithine were previously shown to form triplexes with complementary RNA. In order to obtain optically pure compounds for hybridization experiments, chiral monomers based on D- or L-ornithine, N-delta-Fmoc-N-alpha-(thymin-1-ylacetyl)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 starting from Ns-protected ornithine; the latter procedure led to enantiomerically pure products. Oligomerization of 2 and 3 was carried out either in solution, or by solid-phase peptide synthesis (SPPS) on an MBHA-Rink amide resin. The oligomers turned out to contain large amounts of epimerization products, especially those obtained by SPPS. Therefore, we examined carefully the parameters which may be involved in epimerization: the nature of the coupling reagent, of the base, and the addition mode. Coupling of the monomer L-3 was performed under various conditions. Lower racemization was found to occur when using (7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) as coupling agent and 2,4,6-trimethylpyridine (sym-collidine, TMP) as base, without preactivation, leading to a residual 4% of the D-enantiomer. By applying a procedure based on the stepwise addition of the base the D-enantiomer content was reduced to less than 1%. Using this procedure, a decamer of L-3 was synthesized, which was shown to contain less than 2% of the D-ornithine derivative.
引用
收藏
页码:2690 / 2696
页数:7
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