Catalytic Asymmetric Mannich‐Type Reaction Enabled by Efficient Dienolization of α, β‐Unsaturated Pyrazoleamides†
Catalytic Asymmetric Mannich‐Type Reaction Enabled by Efficient Dienolization of α, β‐Unsaturated Pyrazoleamides†
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DOI：
10.1002/cjoc.202000432
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发表时间：
2020-09
影响因子：
5.4
通讯作者：
Hai‐Jun Zhang;Feng Zhong;Yan Xie;L. Yin
中科院分区：
文献类型：
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作者：
Hai‐Jun Zhang;Feng Zhong;Yan Xie;L. Yin
主要观察和结论(E)-α，β-不饱和吡唑酰胺类化合物在铜(I)-(R)-DTBM-SEGPHOS催化剂和乙二胺存在下，以二烯醇化反应制得以铜(I)-(1Z，3Z)-二烯醇化为主的铜(I)-(1Z，3Z)-二烯醇化产物，与乙二胺反应生成非对映异构体，具有较高的区域和对映选择性。在某些情况下，非对映选择性很低，可能是由于铜(I)-(1Z，3Z)-二烯醇酸盐与铜(I)-(1Z，3E)-二烯醇酸盐的比率很低。(Z)-烯丙基铜(I)物种被认为是有效的中间体，它可能与铜(I)-(1Z，3Z)-二烯醇酸盐形成平衡。有趣的是，本方法是对我们以前报道的一个很好的补充，在以前的报道中，(E)-β，γ-不饱和吡唑酰胺作为前亲核剂在铜(I)催化的不对称乙烯曼尼奇反应中得到了反乙烯产物。在前一反应中，铜(I)-(1Z，3E)-二烯醇酸盐通过α去质子化生成，可能与(E)-烯丙基铜(I)物种形成平衡。因此，在铜(I)催化剂存在下，(E)-α，β-不饱和吡唑酰胺生成同步化产物，(E)-β，γ-不饱和吡唑酰胺生成反产物。最后，利用(E)-β，γ-不饱和吡唑酰胺、(E)-α，β-不饱和吡唑酰胺、(R)-DTBM-SEGPHOS和(S)-DTBM-SEGPHOS成功地进行了四种立体异构体的立体发散合成。然后通过三步反应序列，以较高的产率合成了所有四个立体异构体n-Boc-2-Ph-3-Me-哌啶，它们可能成为药用活性化合物中的共同结构单元。
Main observation and conclusion(E)‐α,β‐Unsaturated pyrazoleamides undergo facile dienolization to furnish copper(I)‐(1Z,3Z)‐dienolates as the major in the presence of a copper(I)‐(R)‐DTBM‐SEGPHOS catalyst and Et3N, which react with aldimines to affordsyn‐vinylogous products as the major diastereoisomers in high regio‐ and enantioselectivities. In some cases, the diastereoselectivity is low, possibly due to the low ratio of copper(I)‐(1Z,3Z)‐dienolates to copper(I)‐(1Z,3E)‐dienolates. (Z)‐Allylcopper(I) species is proposed as effective intermediates, which may form an equilibrium with copper(I)‐(1Z,3Z)‐dienolates. Interestingly, the present methodology is a nice complement to our previous report, in which (E)‐β,γ‐unsaturated pyrazoleamides were employed as the prenucleophiles in the copper(I)‐catalyzed asymmetric vinylogous Mannich‐Type reaction and anti‐vinylogous products were obtained. In the previous reaction, copper(I)‐ (1Z,3E)‐dienolates were generated through α‐deprotonation, which might form an equilibrium with (E)‐allylcopper(I) species. Therefore, it is realized in the presence of a copper(I) catalyst that (E)‐α,β‐unsaturated pyrazoleamides lead tosyn‐products and (E)‐β,γ‐unsaturated pyrazoleamides lead toanti‐products. Finally, by use of (E)‐β,γ‐unsaturated pyrazoleamide, (E)‐α,β‐unsaturated pyrazoleamide, (R)‐DTBM‐SEGPHOS, and (S)‐DTBM‐SEGPHOS, the stereodivergent synthesis of all four stereoisomers is successfully carried out. Then by following a three‐step reaction sequence, all four stereoisomers ofN‐Boc‐2‐Ph‐3‐Me‐piperidine are synthesized in good yields, which potentially serve as common structure units in pharmaceutically active compounds.