An Efficient Approach to Chiral C8/C9-Piperazino-Substituted 1,4-Benzodiazepin-2-ones as Peptidomimetic Scaffolds
An Efficient Approach to Chiral C8/C9-Piperazino-Substituted 1,4-Benzodiazepin-2-ones as Peptidomimetic Scaffolds
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DOI：
10.1021/jo8015456
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发表时间：
2008-11-07
影响因子：
3.6
通讯作者：
Gemma, Sandra
中科院分区：
文献类型：
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作者：
Butini, Stefania;Gabellieri, Emanuele;Gemma, Sandra
一种有希望的干扰生物过程的方法是通过小分子作为肽模拟物调节蛋白质-蛋白质相互作用。1，4-苯并二氮杂卓支架c已被广泛报道为肽模拟的药物系统。虽然已经公开了几种C6-8取代的苯并二氮杂卓的合成途径，但很少报道在C9取代的1，4-苯并二氮杂卓。在此，我们描述了一种在C8/C9引入环状可质子化官能团的通用方法。在C8和C9引入哌嗪系统，使通用的苯并二氮杂卓骨架获得独特的官能化，拓宽了分子苯并融合侧的定制选择，并有可能发现新的肽模拟物，可能能够调节蛋白质-蛋白质相互作用。偶联活化的氨基酸与反应性差的苯胺在温和的条件下，同时避免外消旋，容易获得这些化合物。利用三苯基膦和六氯丙酮在低温和无酸/碱条件下快速形成酰氯，获得了有效的氨基酸活化。该方法成功地导致高反应产率，不产生外消旋化（ee > 98%，如通过使用手性溶剂化剂所证明的），并且与底物中存在的酸敏感保护基团相容。
A promising way to interfere with biological processes is through the modulation of protein-protein interactions by rneans of small molecules acting as peptidomimetics. The 1,4-benzodiazepine scaffold c has been widely reported as a peptide-mimicking, pharmacogenic system. While several synthetic pathways to C6-8 substituted benzodiazepines have been disclosed, few 1,4-benzodiazepines substituted at C9 have been reported. Herein, we describe a versatile approach to introduce cyclic, protonatable functionality at C8/C9. Introduction of the piperazine system at C8 and C9 gave access to a unique functionalization of the versatile benzodiazepine skeleton, broadening tailoring options on the benzofused side of the molecule, and the possibility of discovering novel peptidomimetics potentially able to modulate protein-protein interactions. Coupling of activated amino acids with poorly reactive anilines under mild conditions, while avoiding racemization, gave easy access to these compounds. Efficient amino acid activation was obtained by exploiting the rapid formation of acid chlorides under low temperature and acid/base free conditions, using triphenylphosphine and hexachloroacetone. This procedure successfully resulted in high reaction yields, did not produce racemization (ee > 98%, as demonstrated by using chiral solvating agents), and was compatible with the acid sensitive protecting groups present in the substrates.