A Synthesis of Oseltamivir (Tamiflu) Starting from <scp>d</scp>-Mannitol

Ko, Ji S; Keum, J. E.; Ko, Sun Young

doi:10.1021/jo101517g

Cited by 44 publications

(8 citation statements)

References 69 publications

(20 reference statements)

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“…Microbial production of ASA has only been observed in preliminary laboratory experiments, but the availability of ASA as the substrate for the OSP synthesis might significantly improve the production of the NAI or other oseltamivir carboxylates. Attractive alternative strategies have been developed for the chemical synthesis of OSP from non-SA sources; 80 however, current technologies for influenza NAI synthesis demand the availability of the key aromatic intermediates SA and ASA obtained efficiently by biotechnological processes.…”

Section: Resultsmentioning

confidence: 99%

Current perspectives on applications of shikimic and aminoshikimic acids in pharmaceutical chemistry

Quiroz¹,

Carmona²,

Bolívar³

et al. 2014

RRMC

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Aromatic metabolism comprises the shikimic acid (SA) and the aminoshikimic acid (ASA) pathways. The SA pathway is the common route for the biosynthesis of aromatic amino acids and other metabolites in bacteria, higher plants, fungi, and Apicomplexa parasites, but this pathway is absent in mammals. A variant of the SA pathway known as the ASA pathway branches off from the normal pathway in some bacteria, and its final product, 3-amino-5-hydroxybenzoic acid, is the precursor for many aminoglycoside antibiotics such as kanamycin, neomycin, butirosin, and spectinomycin. The SA pathway includes the key intermediate SA, which is the precursor for the chemical synthesis of the drug oseltamivir phosphate, known commercially as Tamiflu ® , an efficient inhibitor of the neuraminidase enzyme of the seasonal influenza viruses types A and B, avian influenza virus H5N1, and human influenza virus H1N1. Meanwhile, the intermediate of the ASA pathway, ASA, is an attractive candidate for use as the core scaffold for the synthesis of combinatorial libraries and is a potential alternative to SA as a precursor for oseltamivir phosphate synthesis. In this review, we discuss the relevance of the key intermediates SA and ASA as scaffold molecules for the synthesis of diverse chemicals. We highlight the current and potential pharmaceutical applications of these molecules and discuss the main strategies for the production of these aromatic compounds from natural sources and the application of metabolic engineering strategies in diverse bacterial strains for production through biotechnological processes.

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Section: Resultsmentioning

confidence: 99%

Current perspectives on applications of shikimic and aminoshikimic acids in pharmaceutical chemistry

Quiroz¹,

Carmona²,

Bolívar³

et al. 2014

RRMC

View full text Add to dashboard Cite

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“…Later, a similar synthetic approach was reported by the same research group using methionine as the starting material [113]. The Ko research team simplified the mannitol-based synthesis by protecting the carboxylic acid of 117 as a lactone [114]. A Dieckmann condensation was used by Shibasaki and coworkers for the construction of the oseltamivir ring intermediate 144 [115], which was also reported by Corey and coworkers [96].…”

Section: Oseltamivirmentioning

confidence: 99%

Influenza Neuraminidase Inhibitors: Synthetic Approaches, Derivatives and Biological Activity

2016

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Despite being a common viral disease, influenza has very negative consequences, causing the death of around half a million people each year. A neuraminidase located on the surface of the virus plays an important role in viral reproduction by contributing to the release of viruses from infected host cells. The treatment of influenza is mainly based on the administration of neuraminidase inhibitors. The neuraminidase inhibitors zanamivir, laninamivir, oseltamivir and peramivir have been commercialized and have been demonstrated to be potent influenza viral neuraminidase inhibitors against most influenza strains. In order to create more potent neuraminidase inhibitors and fight against the surge in resistance resulting from naturally-occurring mutations, these anti-influenza drugs have been used as templates for the development of new neuraminidase inhibitors through structure-activity relationship studies. Here, we review the synthetic routes to these commercial drugs, the modifications which have been performed on these structures and the effects of these modifications on their inhibitory activity.

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“…Affordable and abundantly available sugars such as d -xylose, [ 101 ] d -ribose, [ 102 ] D-mannitol, [ 103 ] D-glucal, [ 104 ] and d -glucose [ 105 ] have also been used as starting material for Tamiflu 1a synthesis [ 1 , 2 , 24 , 26 ] However, sugar dependent synthetic procedures are characteristically long (12–22 steps) accompanied with extensive chromatographic purification (9–16 operations) and low yields (2.6–15%). Herein, Liu and coworkers’ D-glucal procedure, [ 104 ] Wong et al.…”

Section: Alternative Synthetic Approachesmentioning

confidence: 99%

“…Just as with Ko et al. D-mannitol procedure, [ 103 ] Liu and coworkers [ 104 ] explored a Claisen rearrangement strategy in the construction of oseltamivir’s cyclohexene backbone from D-glucal 125 and the addition of diamino groups onto the cyclohexene backbone was accomplished via tandem intramolecular aziridination and ring opening ( Scheme 20 ) [ 104 ] The D-glucal 125 was protected via conversion to 4,6-benzylidene acetal with p- anisaldehyde diethyl acetal in the presence of catalytic pyridinium p -toluene sulphonate (PPTS) and silylation of the 3-hydroxy group as the tert -butyldimethylsilyl ether. Subsequent reductive cleavage of an acetal followed by treatment with diisobutylaluminium hydride (DIBAL-H) afforded free alcohol 126 in 65% yield.…”

Section: Alternative Synthetic Approachesmentioning

confidence: 99%

The evolution of Tamiflu synthesis, 20 years on: Advent of enabling technologies the last piece of the puzzle?

et al. 2020

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Influenza is a serious respiratory disease responsible for significant morbidity and mortality due to both annual epidemics and pandemics; its treatment involves the use of neuraminidase inhibitors. (−)-Oseltamivir phosphate (Tamiflu) approved in 1999, is one of the most potent oral anti-influenza neuraminidase inhibitors. Consequently, more than 70 Tamiflu synthetic procedures have been developed to date. Herein, we highlight the evolution of Tamiflu synthesis since its discovery over 20 years ago in the quest for a truly efficient, safe, cost-effective and environmentally benign synthetic procedure. We have selected a few representative routes to give a clear account of the past, present and the future with the advent of enabling technologies.

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A Synthesis of Oseltamivir (Tamiflu) Starting from d-Mannitol

Cited by 44 publications

References 69 publications

Current perspectives on applications of shikimic and aminoshikimic acids in pharmaceutical chemistry

Current perspectives on applications of shikimic and aminoshikimic acids in pharmaceutical chemistry

Influenza Neuraminidase Inhibitors: Synthetic Approaches, Derivatives and Biological Activity

The evolution of Tamiflu synthesis, 20 years on: Advent of enabling technologies the last piece of the puzzle?

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