Dramatic Effect of γ-Heteroatom Dienolate Substituents on Counterion Assisted Asymmetric Anionic Amino-Cope Reaction Cascades
Dramatic Effect of γ-Heteroatom Dienolate Substituents on Counterion Assisted Asymmetric Anionic Amino-Cope Reaction Cascades
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DOI：
10.1021/jacs.1c00745
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发表时间：
2021-04-12
影响因子：
15
通讯作者：
Njardarson, Jon T.
中科院分区：
文献类型：
--
作者：
Das, Pradipta;Delost, Michael D.;Njardarson, Jon T.
我们报告了当采用不同的γ-二烯醇化物杂原子取代基时，对锂离子使能的氨基-Cope样阴离子不对称级联的产物结果的显著影响。对于具有叠氮基、硫代甲基和三氟甲基硫醇取代基的二烯醇化物，Mannich/氨基-Cope/环化级联反应导致形成具有反关系的两个新立体中心的手性环己烯酮产物。对于氟化物取代的亲核试剂，Mannich/amino-Cope级联反应得到手性无环产物，其中两个新的立构中心处于顺式关系。溴化物和氯化物取代的亲核试剂似乎通过与氟化物相同的途径进行，尽管增加了3-外消旋环化的扭曲，以产生具有三个立体中心的手性环丙烷产物。当这类亲核试剂被γ-硝基取代时，曼尼希引发的级联反应现在转向β-内酰胺产物，而不是氨基-Cope途径。这些阴离子不对称级联是溶剂和抗衡离子依赖性的，锂抗衡离子与醚溶剂如MTBE和CPME组合是必不可少的。通过将亚胺双键的几何形状从E改变为Z，R-1和X立体中心的构型发生翻转。机理、计算、取代基和互补性研究表明，这些级联反应通过共同的曼尼希产物中间体进行，然后通过椅式（X = N-3、SMe或SCF 3）或船式（X = F、Cl或Br）过渡态进行，以提供氨基Cope类产物或β-内酰胺（X = NO）
We report a dramatic effect on product outcomes of the lithium ion enabled amino-Cope-like anionic asymmetric cascade when different gamma-dienolate heteroatom substituents are employed. For dienolates with azide, thiomethyl, and trifluoromethylthiol substituents, a Mannich/amino-Cope/cyclization cascade ensues to form chiral cyclohexenone products with two new stereocenters in an anti-relationship. For fluoride-substituted nucleophiles, a Mannich/amino-Cope cascade proceeds to afford chiral acyclic products with two new stereocenters in a syn-relationship. Bromide- and chloride-substituted nucleophiles appear to proceed via the same pathway as the fluoride albeit with the added twist of a 3-exo-trig cyclization to yield chiral cyclopropane products with three stereocenters. When this same class of nucleophiles is substituted with a gamma-nitro group, the Mannich-initiated cascade is now diverted to a beta-lactam product instead of the amino-Cope pathway. These anionic asymmetric cascades are solvent- and counterion-dependent, with a lithium counterion being essential in combination with etheral solvents such as MTBE and CPME. By altering the geometry of the imine double bond from E to Z, the configurations at the R-1 and X stereocenters are flipped. Mechanistic, computational, substituent, and counterion studies suggest that these cascades proceed via a common Mannich-product intermediate, which then proceeds via either a chair (X = N-3, SMe, or SCF3) or boat-like (X = F, Cl, or Br) transition state to afford amino-Cope-like products or beta-lactam in the case of X = NO