An Efficient Synthesis of Dimemorfan from Dextromethorphan

Liu, Hui; Zheng, Wenyue; Ou, Xian-Fei; Ju, Xin

doi:10.1080/00304948.2015.1025015

Cited by 1 publication

(2 citation statements)

References 12 publications

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“…It is worth mentioning that, to the best of our knowledge, most thus synthesized enantioenriched 1-benzyl-OHIQ derivatives have never been reported before . Furthermore, these chiral amines in principle can be transformed to the corresponding dextromethorphan analogues of potential pharmaceutical importance, ,− such as dimemorfan (Scheme A), an effective antitussive with safety properties even more promising than those of dextromethorphan. , …”

Section: Resultsmentioning

confidence: 99%

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Asymmetric Synthesis of a Key Dextromethorphan Intermediate and Its Analogues Enabled by a New Cyclohexylamine Oxidase: Enzyme Discovery, Reaction Development, and Mechanistic Insight

Huang

Wang

et al. 2020

J. Org. Chem.

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Metrics & MoreArticle Recommendations * sı Supporting Information ABSTRACT: (S)-1-(4-Methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline [(S)-1-(4-methoxybenzyl)-OHIQ, (S)-1a] is a key synthetic intermediate in the industrial production of dextromethorphan, one of the most widely used over-the-counter antitussives. We report here that a new cyclohexylamine oxidase discovered by genome mining, named CHAO CCH12-C2 , was able to completely deracemize 100 mM 1a under Turner's deracemization conditions to afford (S)-1a in 80% isolated yield and 99% ee at a semipreparative scale (0.4 mmol). When this biocatalytic reaction was scaled up to a gram scale (5.8 mmol), without reaction optimization (S)-1a was still isolated in 67% yield and 96% ee. The relatively higher k cat determined for CHAO CCH12-C2 was rationalized as one major factor rendering this enzyme capable of oxidizing 1a effectively at elevated substrate concentrations. Protein sequence alignment, analysis of our co-crystal structure of CHAO CCH12-C2 complexed with the product 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline [1-(4-methoxybenzyl)-HHIQ, 2a], and the structure-guided mutagenesis study together indicated L295 is one of the critical residues for this efficient enzymatic oxidation process and supported the presence of two cavities as well as a catalytically important "aromatic cage" formed by F342, Y433, and FAD. The synthetic applicability of CHAO CCH12-C2 was further underscored by the stereoselective synthesis of various enantioenriched 1-benzyl-OHIQ derivatives of potential pharmaceutical importance at a semipreparative scale.

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Section: Resultsmentioning

confidence: 99%

“…9 Furthermore, these chiral amines in principle can be transformed to the corresponding dextromethorphan analogues of potential pharmaceutical importance, 3,38−42 such as dimemorfan (Scheme 1A), an effective antitussive with safety properties even more promising than those of dextromethorphan. 3,38…”

Section: ■ Introductionmentioning

confidence: 99%

Asymmetric Synthesis of a Key Dextromethorphan Intermediate and Its Analogues Enabled by a New Cyclohexylamine Oxidase: Enzyme Discovery, Reaction Development, and Mechanistic Insight

Huang

Wang

et al. 2020

J. Org. Chem.

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An Efficient Synthesis of Dimemorfan from Dextromethorphan

Cited by 1 publication

References 12 publications

Asymmetric Synthesis of a Key Dextromethorphan Intermediate and Its Analogues Enabled by a New Cyclohexylamine Oxidase: Enzyme Discovery, Reaction Development, and Mechanistic Insight

Asymmetric Synthesis of a Key Dextromethorphan Intermediate and Its Analogues Enabled by a New Cyclohexylamine Oxidase: Enzyme Discovery, Reaction Development, and Mechanistic Insight

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