Diastereoselective Synthesis of 2,3,6-Trisubstituted Piperidines

We report the diastereoselective and chromatography-free syntheses of four 2-phenyl-6-alkyl-3-aminopiperidines. Ring construction was accomplished through a nitro-Mannich reaction linking a nitroketone and phenylmethanimine, followed by a ring-closure condensation. Relative stereocontrol was achieved between C-2 and C-3 by kinetic protonation of a nitronate or by equilibration of the nitro group under thermodynamic control. Stereocontrol at C-6 was accomplished by utilizing a variety of imine reduction methods. The C-2/C-6-cis stereochemistry was established via triacetoxyborohydride iminium ion reduction, whereas the trans relationship was set either by triethylsilane/TFA acyliminium ion reduction or by Lewis acid catalyzed imine reduction with lithium aluminum hydride.

本研究报道了四种2-苯基-6-烷基-3-氨基哌啶的对映选择性合成，该合成过程无需色谱分离。环状结构的构建是通过硝基-Mannich反应实现的，该反应将硝基酮与苯甲醛亚胺连接，随后进行环闭合缩合反应。通过硝酸盐的动力学质子化或在热力学控制下硝基的平衡，实现了C-2与C-3位点的相对立体控制。C-6位点的立体控制则通过多种亚胺还原方法实现。C-2/C-6位点的顺式立体化学是通过三乙氧基硼氢化物亚胺离子还原确立的，而反式关系则可通过三乙基硅烷/三氟乙酸酰亚胺离子还原或通过路易斯酸催化的锂铝氢化物亚胺还原来设定。