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    Home > Medical News > Medical World News > 91 year old Nobel Prize winner Professor Corey of Harvard University latest JACS synthesis of chiral α - aminoketone

    91 year old Nobel Prize winner Professor Corey of Harvard University latest JACS synthesis of chiral α - aminoketone

    • Last Update: 2019-12-18
    • Source: Internet
    • Author: User
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    When it comes to organic synthetic chemist E J Corey (Elias James Corey), perhaps the first thing you think about is "reverse synthetic analysis" E Mr J Corey put forward this concept as early as 1960s, and won the Nobel Prize in chemistry in 1990 This reverse thinking synthesis method starts from the analysis of the chemical structure of the target molecule, according to the connection mode of different atoms in the molecule, referring to the known chemical reaction and possible reaction mechanism, successively cut off the key chemical bonds in the molecule, and then decompose it into a number of small molecules with simple structure, which are usually commercialized reagents Based on the reverse process of the above strategy, people can design a reasonable synthesis route, starting from simple raw materials, and gradually build complex molecules Now, this method has become a golden rule to guide people to synthesize complex natural products and drug molecules E Mr J Corey has made outstanding contributions to the research of total synthesis of natural products In addition, he has also established many novel and efficient synthesis methods Some organic chemical reactions are included in the named reaction (also known as "name reaction") named after Corey For example, ketones can be asymmetric catalytic reduced to the Corey Bakshi Shibata reduction (CBS reduction) reaction of chiral secondary alcohols; starting from aldehydes, the Corey Fuchs synthesis reaction of terminal alkynes can be finally synthesized As a professor of Harvard University in the United States, he is still active in scientific research at the age of more than 90, and his persistence and sincerity for chemical research have never changed Recently, Professor Corey's team has developed a highly efficient and practical method for the synthesis of chiral α - aminoketones using cinchona base chiral quaternary ammonium salt as organic molecular catalyst, which is expected to be used in the R & D and industrial production of related structural drugs This work was published in J am Chem SOC It was found that ketamine, which was used as general anesthesia in the past, had a good effect on some patients with refractory depression (no response to mainstream antidepressants) at low dose In March 2019, Johnson (Johnson & Johnson) group's Yang Sen Janssen (Pharmaceutical Companies) was used to treat Spravato with adult resistant depression FDA was approved for sale Its composition is the ketamine with S configuration, which is commercialized in the form of nasal spray Spravato works quickly, relieving depression within hours, compared with weeks for other mainstream drugs Most of the antidepressants used to act on the serotonin signal network, but spravato has different mechanisms Animal model experiments show that it can regulate glutamate receptor function, block the abnormal activity of the lateral habenular nucleus of the upper thalamus, temporarily restore the normal conduction of the signal of the neural loop within a short period of time after medication, long-term use is expected to reshape the synaptic connection between the neural loops, achieve the purpose of repairing large brain injury, and thus become the first anti inhibition with innovative mechanism in 30 years Yu therapy However, ketamine is also a kind of drug, commonly known as "powder K" Abuse of ketamine will produce dissociative hallucinations, which will cause irreversible damage to the heart, lungs and brain Considering the potential side effects of addiction, it is necessary to develop a simple and efficient method to construct the above structure, which can provide an effective way to quickly and flexibly adjust the structure of chiral ketamine and find derivatives with higher antidepressant activity and lower addiction In fact, as early as a few years ago, the research group has developed two kinds of methods for the synthesis of chiral α - aminocyclohexanone One is starting from the corresponding cyclohexene, after asymmetric epoxidation, azido nucleophilic reagent is used to open the epoxy ethyl nucleophilic ring to form α - azido cyclohexanone, and azido reduction is used to obtain the target product The other is the asymmetric electrophilic amination of 2,4-dinitrophenylhydroxylamine (2,4-dnponh2) with cyclohexanone derived enol silicone ether as raw material under the action of chiral Rh catalyst The former needs Ti (OiPr) 2 (N3) 2 or ibu2aln3 as azide reagent, while the latter needs special hydroxylamine 2,4-dnponh2 and the transition metal catalyst to introduce amino group into the molecule The cost of synthesis is high In order to put the method of constructing chiral α - aminocyclohexanone into large-scale industrial production, the first problem to be solved is to choose cheap and easily available amino sources to realize the above process In the past two decades, organic molecular catalysts have shown great advantages in the field of asymmetric catalytic synthesis Among them, cinchona bases and their derivatives can be used as ideal phase transfer catalysts and play an important role in the asymmetric functionalization of carbonyl compounds Taking the chiral quaternary ammonium salt B as an example, there is a close ion pair interaction between the cation part of cinchonidine and the reactant with anion or the transition state of reactant, forming a relatively stable intermediate At the same time, an effective chiral environment is generated by masking one side of the reactant with the modified quinoline group These catalysts can be used for enantioselective synthesis of amino acids with various cyclic and acyclic structures, and are widely used in asymmetric epoxidation of α, β - ketene, Michael addition and condensation of nitro alcohol It is assumed that the racemic α - bromoketone will be formed from cyclohexanone after α - bromination, and the chiral α - aminoketone product will be obtained with high enantioselectivity Starting from 2-bromo-2-phenylcyclohexanone 1, they transformed it into oxime 2 When 2 participated in the reaction, it formed α, β - unsaturated nitroso active intermediates, which had electrostatic interaction with the positive N atom in the chiral quaternary ammonium salt catalyst B at the same time, there was a stable van der Waals attraction between the quinoline group in B and the phenyl in the substrate The re surface of the nitroso active intermediate is masked, and the nucleophilic reagent can only approach the substrate from the Si surface (the front end of the paper in the figure below) The chiral α - azido oxime was formed by the asymmetric nucleophilic substitution of α - position of 2 with NaN3 as nucleophile After oxime hydrolysis and azido reduction, the chiral 2-amino-2-phenylcyclohexanone 4 was obtained with excellent enantioselectivity The enantioselectivity will not be affected obviously when azido is reduced to amino group They also investigated the substrate applicability of reduction of a series of chiral α - azido cyclones to corresponding α - aminoketones Different five to seven membered cyclones can produce azido reduction with good yield and enantioselectivity under the above optimized reaction conditions The acyclic α - azido ketone can also participate in the reaction smoothly, and the chiral quaternary ammonium salt catalyst after the reaction can also be simply recycled for the next reaction In addition, other C, O, N, s nucleophiles are also suitable for this α - Asymmetric nucleophilic substitution reaction The author also synthesized the chiral bupropion 19 by this method Previously, the drug can only be used as a prescription drug in the form of racemate Now people can use this synthesis method to study the biological activity of each enantiomer, which is expected to further improve its therapeutic effect Professor Corey has trained hundreds of students in his academic career for more than 60 years During his tenure at Harvard University, he never missed any class except one serious illness absence At the same time, he will pass on his passion for chemistry and encourage future generations to forge ahead on the road of chemical research.
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