Synthesis of (+/-)-homohistidine.
Synthesis of (+/-)-homohistidine.
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(i-)-高组氨酸的合成。
DOI：
10.1021/jo991630q
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Pei,T
中科院分区：
文献类型：
--
作者：
Pirrung,MC;Pei,T
对于一个研究组氨酸激酶抑制的项目，我们需要大量适合固相合成的几种组氨酸类似物。用于产生组氨酸同源物高组氨酸的方法已在早期报道。2.最近的高组氨酸的合成是从Z-谷氨酸开始，经9步完成的，总收率为40%。这里描述了从容易获得的尿刊酸制备高组氨酸，并转化为其BOC衍生物（方案1）。对尿刊酸进行酯化和氢化。虽然在早期的工作3中，咪唑的NH在随后的还原步骤中未受保护，但2的溶解性足够差，从而限制了合成规模。如Browne所报道的，4-三苯甲基化显著改善了其在醚溶剂中的溶解度，允许DIBAL-H在量上还原为醛。Strecker反应得到氨基腈，其水解也导致三苯甲基基团的去除，以73%的总产率产生高组氨酸（6）。用活化的BOC衍生物保护组氨酸可以先验地保护任一个或两个氮。预期R-氨基更亲核/反应性更强，但证明不可能用化学计量的BOC保护试剂选择性地衍生化该位点。据报道，用过量的BOC-N3处理组氨酸得到双-BOC衍生物，其可以在甲醇中进一步处理以形成R-氨基BOC衍生物。5用过量的BOC 2 O处理高组氨酸使两个氮衍生化，以17%的产率产生双-BOC-高组氨酸（8）。我们将这种低收率归因于BOC-咪唑啉对水性反应条件的反应性，因为还分离出一些R-BOC衍生物。这提出了一种通过使用过量的BOC 2 O，然后延长在水中的反应时间以水解咪唑啉来选择性地获得单-BOC衍生物的方法。这以56%产率产生目标R-BOC-高组氨酸（7）。
For a program studying the inhibition of histidine kinases, 1 we required quantities of several histidine analogues in forms suitable for solid-phase synthesis. Methods for the generation of the histidine homologue homohistidine have been earlier reported. 2 The most recent synthesis of homohistidine was achieved in nine steps with an overall yield of 40%, starting from Z-glutamic acid. Here is described a preparation of homohistidine from the readily available urocanic acid, and conversion to its BOC derivatives (Scheme 1). Urocanic acid was esterified and hydrogenated. While in earlier work3 the NH of the imidazole was left unprotected for the following reduction step, the solubility properties of 2 are sufficiently poor as to limit the synthesis scale. As reported by Browne, 4 tritylation significantly improves its solubility in ethereal solvents, permitting DIBAL-H reduction in quantity to the aldehyde. Strecker reaction gives an aminonitrile whose hydrolysis also causes removal of the trityl group, producing homohistidine (6) in 73% overall yield. The protection of histidines with activated BOC derivatives can a priori protect either or both nitrogens. The R-amino group is expected to be more nucleophilic/reactive, but it did not prove possible to derivatize selectively this site with stoichiometric BOC protection reagents. It has been reported that treatment of histidine with excess BOC-N3 gives the bis-BOC derivative, which can be further treated in refluxing methanol to form the R-amino BOC derivative. 5 Treatment of homohistidine with an excess of BOC2O derivatizes both nitrogens, producing the bis-BOC-homohistidine (8) in 17% yield. We attribute this low yield to the reactivity of the BOC-imidazolide toward aqueous reaction conditions, as some R-BOC derivative was also isolated. That suggested a method to obtain selectively the mono-BOC derivative by use of an excess of BOC2O, followed by an extended reaction time in water to hydrolyze the imidazolide. This produces the target R-BOC-homohistidine (7) in 56% yield.