Stereoselective syntheses of 3-mercaptoproline derivatives protected for solid phase peptide synthesis.
Stereoselective syntheses of 3-mercaptoproline derivatives protected for solid phase peptide synthesis.
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立体选择性合成受保护的 3-巯基脯氨酸衍生物，用于固相肽合成。
DOI：
10.1111/j.1399-3011.1996.tb00841.x
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Marshall,GR
中科院分区：
文献类型：
--
作者：
Kolodziej,SA;Marshall,GR
将顺式和反式-3-巯基脯氨酸（3-MPc和3-MPt）掺入生物活性肽的类似物中已被证明是降低肽骨架构象迁移率的有效手段。我们在此报告了一种新的立体选择性合成路线tol-1和l-2，3-MPt和3-MPc的衍生物适当保护固相肽合成。光学活性起始材料是先前报道的顺式-3-羟基脯氨醇衍生物1 - 3。将C1醇氧化成羧酸，形成甲酯并将C3醇脱保护，以68%的总产率得到1 - 6。仲醇与硫代乙酸在Mitsunobu条件下反应，得到硫代乙酸酯-7，产率为77%，构型完全反转。1 - 7 tol-1的转化以一锅法顺序完成，该顺序由三个步骤组成：硫醇乙酸酯的水解、硫醚的形成和甲酯的水解。从ml-3得到l-1的总产率为38%。1 - 2的合成需要1 - 6的差向异构化，其使用标准的Mitsunobu转化来完成，以得到反式-3-羟基脯氨酸衍生物1 - 8。l-8 tol-2的转化遵循l-1所述的方法，不同之处在于从l-10中除去甲酯需要在104 NHCl中酸解。从1 - 3得到1 - 2的总产率为18%。获得SPPS保护的3-MPt和3-MPc的纯对映体将极大地促进其用作研究肽-受体相互作用的构象限制。© Munksgaard 1996.
The incorporation ofcis‐andtrans‐3‐mercaptoproline (3‐MPc and 3‐MPt) into analogs of biologically active peptides has been shown to be an effective means for reducing the conformational mobility of the peptide backbone. We report herein a novel stereoselective synthetic route tol‐1 andl‐2, derivatives of 3‐MPt and 3‐MPc suitably protected for solid phase peptide synthesis. The optically active starting material was the previously reported cis‐3‐hydroxyprolinol derivativel‐3. Oxidation of the C1 alcohol to the carboxylic acid, formation of the methyl ester and deprotection of the C3 alcohol yieldedl‐6 in an overall yield of 68%. Reaction of the secondary alcohol with thiolacetic acid under Mitsunobu conditions gave the thiolacetatel‐7 in 77% yield with clean inversion of configuration. Conversion ofl‐7 tol‐1 was accomplished in a one‐pot sequence consisting of three steps: hydrolysis of the thiolacetate, formation of the thioether and hydrolysis of the methyl ester. The overall yield ofl‐1 froml‐3 was 38%. Synthesis ofl‐2 required an epimerization ofl‐6, which was accomplished using a standard Mitsunobu inversion to give the trans‐3‐hydroxyproline derivativel‐8. Transformation ofl‐8 tol‐2 followed that described forl‐1, except that removal of the methyl ester froml‐10 required acidolysis in refluxing 4NHCl. The overall yield ofl‐2 froml‐3 was 18%. The availability of pure enantiomers of 3‐MPt and 3‐MPc protected for SPPS will greatly facilitate their use as conformational constraints for studying peptide‐receptor interactions. © Munksgaard 1996.