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    Home > JACS: the E. J. Corey group of Harvard University synthesized chiral α - azido / α - aminoketone by racemic α - bromoketone

    JACS: the E. J. Corey group of Harvard University synthesized chiral α - azido / α - aminoketone by racemic α - bromoketone

    • Last Update: 2019-12-29
    • Source: Internet
    • Author: User
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    In recent years, researchers have found that ketamine (a, figure 1), a general anesthetic with α - aminoketone structure, also has antidepressant effect In 2019, S-ketamine, developed by Johnson & Johnson, was approved for the treatment of depression However, because of the side effects of dissociation and addiction, it is far from an ideal antidepressant (photo source: J am Chem SOC.) recently, physiologists have proposed a reasonable explanation for how ketamine can restore the normal function of brain circuits, thus arousing people's interest in the synthesis of such molecules Recently, the E.J Corey group of Harvard University reported two new methods for the synthesis of chiral α - aminoketones, which were directly catalyzed by alkene and enol silicone ether Recently, Corey group developed a method of enantioselective synthesis of chiral α - aminoketone by racemic α - bromoketone catalyzed by chiral quaternary ammonium salt, which was recently published in j.am Chem SOC (DOI: 10.1021 / JACS 9b12315) The author's idea of synthesis comes from the determination of the preferred geometry of the contact ion pair between the designed cinchona alkaloid, chiral quaternary ammonium ion B and anionic reagent or transition state It can be seen from single crystal X-ray diffraction that the dominant conformation (Figure 2), for example, the spatial arrangement between B and p-nitrophenoxy ion is C, while the application of C as the geometric model of ion pair provides reliable guidance for the discovery of the wide application of catalyst B in enantioselective synthesis, including the synthesis of acyclic, cyclic and functional amino acids, α, Asymmetric epoxidation of β - ketene, Michael addition of α, β - ketene and nitroaldol reaction Based on this, a new asymmetric α - amination method for ketones was developed (photo source: J am Chem SOC.) next, the author took 2-bromo-2-phenylcyclohexanone 1 as the raw material (scheme 1), transformed it into oxime, and then treated it with quaternary ammonium salt B / Nan 3 / TMG to obtain chiral α - azido 3, and then reduced it to chiral α - amino ketone 4 (photo source: J am Chem SOC.) the author found that fluorobenzene has better enantioselectivity than benzene or toluene In addition, the above conditions can also be used for other cyclic α - bromoketone substrates, especially 5 - 11 (Figure 3) It is important that the chiral quaternary ammonium salt catalyst can be recycled (photo source: J am Chem SOC.) in addition, the method can also asymmetric convert racemic acyclic α - bromoketone to corresponding chiral α - azido ketone (Figure 4) (photo source: J am Chem SOC.) based on the previous research, the author expects to azide racemic α - bromoketone 2 to produce R-enantiomer of aminoketone 4 under the phase transfer catalysis of quaternary ammonium salt B its high enantioselectivity (97.5:2.5) comes from Michael addition of azide anion and cation B and α, β - unsaturated nitroso intermediate complex (Figure) 5) The addition of azide anion occurs in front of the complex D The electrostatic attraction between the positively charged nitrogen center and the tetrahedral surface provides a stable transition state for the Michael addition of N3 – and promotes the reaction The van der Waals interaction between the quinoline ring and the phenyl of the vinylnitroso intermediate also favors the geometry of the complex D (photo source: J am Chem SOC.) later, the author also proved that the chiral α - azido ketone obtained by the above method can be converted into various N-protected α - aminoketones (Figure 6) (photo source: J am Chem SOC.) the above results can be extended to the synthesis of other valuable compounds For example, 4-NITROPHENOXY ion is used as nucleophilic reagent to convert (±) - α - bromooxime 17 to s-4-nitrophenoxy ether 18, and then react with t-butylamine to obtain the antidepressant r-bupropion (19, scheme 2) Its stereochemistry is also in accordance with figure 5 The model shown is consistent (photo source: J am Chem SOC.) finally, the author extended the developed asymmetric method to the synthesis of other chiral α - substituted ketones The conversion of 17 to 19 indicates that the strategy can be extended to other nucleophiles such as C, O, s and even neutral nucleophiles In - 20 ℃ or 0 ℃ fluorobenzene / H 2O, with 15 mol% quaternary ammonium salt B as catalyst, the author reacted the substrate (±) - α - bromoketone 2 with appropriate reagent to obtain the corresponding expected product (scheme 3) (photo source: J am Chem SOC.) conclusion: the research group of E J Corey has developed a highly selective method to convert racemic α - bromoketone into chiral α - azido ketone and α - aminoketone catalyzed by chiral quaternary ammonium salt This method can be applied to nucleophiles such as C, O, s and NHR Its advantages include: 1) easy recovery of catalyst; 2) easy operation; 3) no need of expensive transition metals or complex ligands; 4) predictable pathway; 5) versatility It can be expected that this method will be widely used in the fields of multi-step synthesis of complex molecules and candidate drug synthesis.
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