An asymmetric synthesis of (+)-morphinans in high enantiomeric purity

Meyers, A. I.; Bailey, T. R.

doi:10.1021/jo00356a023

Cited by 46 publications

(8 citation statements)

References 2 publications

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“…The kinetic parameters of the mutant Y321I and Y321I/M226T proteins showed a high catalytic efficiency toward 1-(4-methoxybenzyl)-1, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline ( 13 ) and ( S )- N -(prop-2-yn-1-yl)-2, 3-dihydro-1 H-inden-1-amine [( S )- 8 ], respectively. Since ( R )- 8 is an irreversible inhibitor of monoamine oxidase for Alzheimer disease 27 , and ( S )- 13 is a key intermediate for the synthesis of the antitussive agent dextromethorphan 28 , several methods have been reported for the synthesis of ( R )- 8 29 30 31 and ( S )- 13 28 32 33 34 . Most methods are based on classical kinetic resolution with chiral acids 31 32 or focused on the asymmetric synthesis of ( R )-2, 3-dihydro-1-indanamine 29 30 .…”

Section: Discussionmentioning

confidence: 99%

New recombinant cyclohexylamine oxidase variants for deracemization of secondary amines by orthogonally assaying designed mutants with structurally diverse substrates

Yao

Cong

et al. 2016

Sci Rep

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To further expand the substrate range of the cyclohexylamine oxidase (CHAO) from Brevibacterium oxydans, a library of diverse mutants was created and assayed toward a group of structurally diverse substrates. Among them, mutants T198A and M226A exhibited enhanced activity relative to wt CHAO for most (S)-enantiomers of primary amines and some secondary amines. While mutants T198I, L199I, L199F, M226I and M226T were more active than wt CHAO toward the primary amines, mutants T198F, L199T, Y321A, Y321T, Y321I and Y321F enhanced the enzyme activity toward the secondary amines. In particular, mutant Y321I displayed an enhanced catalytic efficiency toward 1-(4-methoxybenzyl)-1, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline (13). Whereas a double mutant, Y321I/M226T, acted on (S)-N-(prop-2-yn-1-yl)-2, 3-dihydro-1H-inden-1-amine [(S)-8]. Since (R)-8 is an irreversible inhibitor of monoamine oxidase and (S)-13 is an intermediate of dextromethorphan, a cough suppressant drug, deracemizations of 8 and 13 were carried out with crude enzyme extracts of the respective mutants. This resulted in 51% and 78% isolated yields of (R)-8 and (S)-13, respectively, each with high enantiomeric excess (93% and 99% ee). The results demonstrated the application potential of the evolved CHAO mutants in drug synthesis requiring chiral secondary amines.

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Section: Discussionmentioning

confidence: 99%

New recombinant cyclohexylamine oxidase variants for deracemization of secondary amines by orthogonally assaying designed mutants with structurally diverse substrates

Yao

Cong

et al. 2016

Sci Rep

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“…The benzene ring can be hydrogenated in trifluoroacetic acid solution to provide 316 (Scheme 17.160) [424]. This product can also be obtained by ionic hydrogenation with cyclohexane through superacidic activation, as mentioned in Section 7.2.5.1.2 ) (Protonation) [340].…”

Section: Reactions With Oxidizing Reagentsmentioning

confidence: 99%

Six‐Membered Heterocycles: Quinoline and Isoquinoline

Alajarı́n

Burgos

2011

Modern Heterocyclic Chemistry

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“…For example, dextromethorphan (1), which is widely used as a non-opioid antitussive for over 50 years and has anticonvulsant and neuroprotective properties, [2] could be prepared from (S)-1-(4-methox-ybenzyl)-N-formyl-OHIQ (2) by Grewe cyclization and reduction of the N-formyl group (Scheme 1). [3] Scheme 1. Synthesis of dextromethorphan (1).…”

Section: Introductionmentioning

confidence: 99%

“…Kinetics Parameters of IR30 and IR40 towards 4 h. AE 0.1)3 10 À2 (1.8 AE 0.1)3 10 À2 (33.3 AE 2.4) 3 10 À2 5.4 3 10 À2 IR40 (8.7 AE 0.2) 3 10 À2 (4.7 AE 0.2) 3 10 À2 (19.5 AE 1.5) 3 10 À2 24.1 3 10 À2…”

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Imine Reductase‐Catalyzed Enantioselective Reduction of Bulky α,β‐Unsaturated Imines en Route to a Pharmaceutically Important Morphinan Skeleton

Yao

Sheng

et al. 2018

Adv Synth Catal

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The morphinan skeleton is an important sub-structure in many medicines such as dextromethorphan, and can be constructed from 1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (1-benzyl-OHIQ) derivatives. 1-Benzyl-3,4,5,6,7,8-hexahydroisoquinolines (1-benzyl-HHIQs), the precursors of 1-benzyl-OHIQs, constitute a type of bulky a, b-unsaturated imines. Until now, the application of imine reductases (IREDs) to a, b-unsaturated imines has only rarely been reported. In this study, through evaluation of 48 IREDs, both enantiomers of 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (1-(4-methoxybenzyl)-OHIQ) were obtained in high yield and excellent optical purity. Among the enzymes, the most steric hindrance-tolerant IRED from Sandarearacinus amylolyticus (IR40) was able to convert various phenyl substituted 1-benzyl-HHIQ to the corresponding 1-benzyl-OHIQ derivatives with excellent enantiometric excess. These results provide an effective route to synthesize these important compounds via enantioselective reduction of bulky a, b-unsaturated imine precursors, which can be readily prepared from 2-(1-cyclohexenyl) ethylamine and corresponding aryl acetic acids.

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An asymmetric synthesis of (+)-morphinans in high enantiomeric purity

Abstract: After workup and chromatography on silica gel (20% etherhexanes), 241 mg (57%) of alcohol 21 was obtained as a 75:25 mixture of erythro and threo isomers:

Cited by 46 publications

References 2 publications

New recombinant cyclohexylamine oxidase variants for deracemization of secondary amines by orthogonally assaying designed mutants with structurally diverse substrates

New recombinant cyclohexylamine oxidase variants for deracemization of secondary amines by orthogonally assaying designed mutants with structurally diverse substrates

Six‐Membered Heterocycles: Quinoline and Isoquinoline

Imine Reductase‐Catalyzed Enantioselective Reduction of Bulky α,β‐Unsaturated Imines en Route to a Pharmaceutically Important Morphinan Skeleton

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