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Assistance of DFT calculations on the design and rationalization of active pharmaceutical ingredients synthesis - Michael addition-isomerization steps in Oseltamivir synthesis.

ABSTRACT: The Michael addition step and the following C5 isomerization in Hayashi's synthesis of Oseltamivir was studied by means of a DFT mechanistic study. These steps are crucial for the viability of the process where the formation of a single stereoisomer is required. The results indicate that the addition reaction is under thermodynamic and not kinetic control and that the key factor determining the reaction stereoselectivity are the stereochemical constraints imposed by all substituents in the cyclohexane ring. The DFT results indicate that cyclohexylthiol should behave similarly to p-toluylthiol, the one actually employed, and tert-butylthiol should increase the ratio between isomers favoring the desired S configuration of the C5 atom. This work shows that DFT studies can be useful in the selection of a reactant to improve stereoselectivity of a chemical step.

SUBMITTER: Santos PP

PROVIDER: S-EPMC7336932 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Assistance of DFT calculations on the design and rationalization of active pharmaceutical ingredients synthesis - Michael addition-isomerization steps in Oseltamivir synthesis.

Santos Pedro Paulo PP Veiros Luís F LF

Tetrahedron 20200706 51

The Michael addition step and the following C5 isomerization in Hayashi's synthesis of Oseltamivir was studied by means of a DFT mechanistic study. These steps are crucial for the viability of the process where the formation of a single stereoisomer is required. The results indicate that the addition reaction is under thermodynamic and not kinetic control and that the key factor determining the reaction stereoselectivity are the stereochemical constraints imposed by all substituents in the cyclo ...[more]

PMID: 32836479

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Project description:The dark-colored viologen radical cations are unstable in air and easily fade, thus greatly limiting their applications. If a suitable substituent is introduced into the structure, it will have the dual function of chromism and luminescence, which will broaden its application field. Here, Vio1·2Cl and Vio2·2Br were synthesized by introducing aromatic acetophenone and naphthophenone substituents into the viologen structure. The keto group (-CH2CO-) on the substituents is prone to isomerize into the enol structure (-CH[double bond, length as m-dash]COH-) in organic solvents, especially in DMSO, resulting in a larger conjugated system to stabilize the molecular structure and enhance fluorescence. The time-dependent fluorescence spectrum shows obvious keto-to-enol isomerization-induced fluorescence enhancement. The quantum yield also increased significantly (T = 1 day, ΦVio1 = 25.81%, ΦVio2 = 41.44%; T = 7 days, ΦVio1 = 31.48%, and ΦVio2 = 54.40%) in DMSO. The NMR and ESI-MS data at different times further confirmed that the fluorescence enhancement was caused by isomerization, and no other fluorescent impurities were produced in solution. DFT calculations show that the enol form is almost coplanar throughout the molecular structure, which is conducive to stabilizing the structure and enhancing fluorescence. The fluorescence emission peaks of the keto and enol structures of Vio12+ and Vio22+ were at 416-417 nm and 563-582 nm, respectively. The fluorescence relative oscillator strength of Vio12+ and Vio22+ enol structures is significantly higher than that of keto structures (f value changes from 1.53 to 2.63 for Vio12+ and from 1.62 to 2.81 for Vio22+), indicating stronger fluorescence emission of the enol structure. The calculated results are in good agreement with the experimental results. Vio1·2Cl and Vio2·2Br are the first examples of isomerization-induced fluorescence enhancement of viologen derivatives, which shows strong solvatofluorochromism under UV light, making up for the disadvantage that it is easy for a viologen radical to fade in air, and providing a new strategy for designing and synthesizing viologen materials with strong fluorescence.

Dataset Information

Assistance of DFT calculations on the design and rationalization of active pharmaceutical ingredients synthesis - Michael addition-isomerization steps in Oseltamivir synthesis.

Publications

Assistance of DFT calculations on the design and rationalization of active pharmaceutical ingredients synthesis - Michael addition-isomerization steps in Oseltamivir synthesis.

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