Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
Nat Commun. 2014 Nov 18;5:5474. doi: 10.1038/ncomms6474.
Non-aromatic nitrogen- and oxygen-containing heterocycles such as piperidines and pyrans are prevalent components of natural products and pharmaceutical drugs. Although it has been a workhorse as a synthetic method for assembling unsaturated sp(2)-hybridized substrates, transition metal-catalysed cross-coupling chemistry is traditionally not a suitable approach to prepare chiral non-aromatic heterocycles. Several mechanistic issues hamper the coupling of stereogenic secondary sp(3)-hybridized carbon-metal centres. Moreover, use of unsymmetrical allylic boronates in the Suzuki Miyaura cross-coupling is further complicated by the possibility of forming two regioisomeric products. Here we address this two-pronged problem and demonstrate that chiral enantiomerically enriched heterocyclic allylic boronates can be coupled with high stereochemical retention with a wide variety of aryl and alkenyl halides to independently afford both regioisomeric 2- and 4-substituted dihydropyrans and dehydropiperidines in high selectivity. A divergent mechanism is proposed where regiochemistry is governed by the nature of the ligands on the palladium catalyst. This scalable method is applied to the efficient preparation of the neuroactive alkaloid anabasine and the antidepressant drug paroxetine.
非芳族含氮和含氧杂环，如哌啶和吡喃，是天然产物和药物的常见成分。尽管它一直是用于组装不饱和 sp(2)-杂化底物的合成方法，但过渡金属催化的交叉偶联化学传统上不是制备手性非芳族杂环的合适方法。几个机制问题阻碍了立体手性仲 sp(3)-杂化碳-金属中心的偶联。此外，在 Suzuki-Miyaura 交叉偶联中使用不对称烯丙基硼酸酯时，由于可能形成两种区域异构体产物，情况变得更加复杂。在这里，我们解决了这个双重问题，并证明手性对映体富集的杂环烯丙基硼酸酯可以与各种芳基和烯基卤化物进行高立体化学保留的偶联，独立地以高选择性得到两种区域异构体 2-和 4-取代的二氢吡喃和脱水哌啶。提出了一种发散机制，其中区域化学由钯催化剂上配体的性质决定。这种可扩展的方法已应用于神经活性生物碱藜芦碱和抗抑郁药帕罗西汀的有效制备。
