Diprotected triflylguanidines: A new class of guanidinylation reagents
Diprotected triflylguanidines: A new class of guanidinylation reagents
复制标题
DOI：
10.1021/jo980425s
复制
发表时间：
1998-06-12
影响因子：
3.6
通讯作者：
Goodman, M
中科院分区：
文献类型：
--
作者：
Feichtinger, K;Zapf, C;Goodman, M
胍基是许多生物活性化合物的重要结构组分。1由于它们的强碱性，胍在生理条件下完全质子化。因此，施加在分子上的正电荷形成了配体与受体或酶与底物之间通过氢键和/或静电相互作用介导的特异性相互作用的基础。因此，在温和条件下以高产率制备胍类化合物的合成方法在药物化学中具有很大的意义。通常，胍的合成涉及用亲电子脒物质处理胺。最常用的试剂包括吡唑-1-甲脒衍生物、S-烷基异硫脲和保护的硫脲衍生物，后者主要与汞盐或Mukaiyama试剂结合使用。2-11我们现在希望报道N，N′-二-Boc-N′′-三氟甲酰基胍1和N，N′-二-Cbz-N′′-三氟甲酰基胍2作为双保护的三氟甲酰基胍，一类新的胍基化试剂的两个实例。这两种化合物都是稳定的结晶物质，可以非常容易和有效地制备受保护的胍。起始原料盐酸胍便宜且易于大量获得，试剂1由盐酸胍3经两步以51%的总收率获得（方案1）。3与Boc-酸酐在强碱性条件下反应产生中间体4，其易于用三氟甲磺酸酐转化为目标化合物1。在类似的反应顺序中，试剂2的合成从盐酸胍转化为N，N′-二-Cbz-胍5开始。与试剂1的合成相反，用氢化钠代替三乙胺作为碱进行最终磺化步骤。1和2都是稳定的结晶物质，在室温下储存至少三个月，活性无明显损失;因此，如果冷藏，这些化合物应无限期保持稳定。
The guanidino group is an important structural component in many biologically active compounds. 1 Because of their strongly basic character, guanidines are fully protonated under physiological conditions. The positive charge thus imposed on the molecule forms the basis for specific interactions between ligand and receptor or enzyme and substrate, mediated by hydrogen bonds and/or electrostatic interactions. Consequently, synthetic procedures that allow the preparation of guanidines with high yield and under mild conditions are of great interest in medicinal chemistry. Typically, the synthesis of guanidines involves treatment of an amine with an electrophilic amidine species. The most commonly used reagents include derivatives of pyrazole-1-carboxamidine, S-alkylisothioureas, and protected thiourea derivatives, the latter mostly used in conjunction with mercury salts or Mukaiyama’s reagent. 2-11 We now wish to report N, N′-di-Boc-N′′-triflylguanidine 1 and N, N′-di-Cbz-N′′-triflylguanidine 2 as two examples of diprotected triflylguanidines, a new class of guanidinylation reagents. Both compounds are stable crystalline substances that allow the preparation of protected guanidines with exceptional ease and efficiency. The starting material guanidine hydrochloride is cheap and readily available in large quantities.Reagent 1 is obtained in two steps from guanidine hydrochloride 3 in 51% overall yield (Scheme 1). Reaction of 3 with Boc-anhydride under strongly alkaline conditions produces intermediate 4, which is easily converted to target compound 1 with triflic anhydride. In a similar sequence of reactions, the synthesis of reagent 2 commences with the conversion of guanidine hydrochloride to N, N′-di-Cbz-guanidine 5. Contrary to the synthesis of reagent 1, the final sulfonation step is carried out with sodium hydride as a base in place of triethylamine. Both 1 and 2 are stable, crystalline substances which have been stored at room temperature for at least three months with no apparent loss of activity; hence, these compounds should remain stable indefinitely if refrigerated.