Solid-phase synthesis and spectroscopic studies of TRH analogues incorporating cis- and trans-4-hydroxy-L-proline.
Solid-phase synthesis and spectroscopic studies of TRH analogues incorporating cis- and trans-4-hydroxy-L-proline.
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掺入顺式和反式 4-羟基-L-脯氨酸的 TRH 类似物的固相合成和光谱研究。
DOI：
10.3891/acta.chem.scand.45-1047
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发表时间：
1991
期刊：
影响因子：
--
通讯作者：
G. Francis
中科院分区：
文献类型：
--
作者：
G. Stavropoulos;K. Karagiannis;D. Vynios;D. Papaloannou;D. Aksnes;N. Age Frøystein;G. Francis
本文报道了TRH类似物Glp-His（Nim-Trt）-Hyp-OH的高效固相合成法。采用Na-Fmoc保护的氨基酸和DCC/HOBt活化。庞大的和温和的酸敏感的2-氯三苯甲基树脂，用作固体支持物，完全抑制二氧代哌嗪的形成。该三肽是合成TRH类似物的关键中间体，其包含顺式和反式-4-羟基-L-脯氨酸。在三苯基膦-偶氮二甲酸二乙酯（TPP-DEAD）存在下，将三肽转化为Glp-His（Nim-Trt）-cHyp内酯，其中Hyp残基的C-4处构型反转。内酯的一锅MeOH-TPP-DEAD酯交换，随后Nim-脱三苯甲基，得到Glp-His-cHyp-OMe。该酯经氨解和皂化分别得到相应的酰胺和酸。Glp-His-cHyp-OH及其非对映体Glp-His-Hyp-OH（通过Nim-脱三苯甲基化关键三肽获得）的高场1H NMR研究表明，脯氨酰残基C-4处的构型对于确定分子的优选三维结构至关重要。
An efficient solid-phase synthesis of the TRH analogue Glp-His(Nim-Trt)-Hyp-OH is described. Na-Fmoc protected amino acids and DCC/HOBt activation were employed. The bulky and mild-acid-sensitive 2-chlorotrityl resin, utilised as the solid support, completely suppressed dioxopiperazine formation. The tripeptide is a key intermediate in the synthesis of TRH analogues incorporating cis- and trans-4-hydroxy-L-proline. The tripeptide was converted, with inversion of configuration at C-4 of the Hyp residue, to Glp-His(Nim-Trt)-cHyp lactone in the presence of triphenylphosphine-diethyl azodicarboxylate (TPP-DEAD). One-pot MeOH-TPP-DEAD transesterification of the lactone, followed by Nim-detritylation, provided Glp-His-cHyp-OMe. This ester gave the corresponding amide and acid on ammonolysis and saponification, respectively. A high-field 1H NMR investigation of Glp-His-cHyp-OH and its diastereomer Glp-His-Hyp-OH, obtained by Nim-detritylation of the key tripeptide, showed that the configuration at C-4 of the prolyl residues is critical for the determination of the preferred three-dimensional structure of the molecules.