See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/343228169 The evolution of Tamiflu synthesis, 20 years on: Advent of enabling technologies the last piece of the puzzle? Article in Tetrahedron · July 2020 DOI: 10.1016/j.tet.2020.131440 CITATIONS READS 2 134 4 authors, including: Cloudius Ray Sagandira Francis Mathe Nelson Mandela University Nelson Mandela University 11 PUBLICATIONS 33 CITATIONS 1 PUBLICATION 2 CITATIONS SEE PROFILE SEE PROFILE Upenyu Guyo Midlands State University 33 PUBLICATIONS 418 CITATIONS SEE PROFILE Some of the authors of this publication are also working on these related projects: Development of a model for lean manufacturing critical success factors using structural equation modelling View project Bio materials View project All content following this page was uploaded by Upenyu Guyo on 05 August 2020. The user has requested enhancement of the downloaded file. Tetrahedron xxx (xxxx) xxx Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet Tetrahedron report XXX The evolution of Tamiflu synthesis, 20 years on: Advent of enabling technologies the last piece of the puzzle? * Cloudius R. Sagandira a, Francis M. Mathe a, Upenyu Guyo a, b, Paul Watts a, a Nelson Mandela University, University Way, Port Elizabeth, 6031, South Africa b Midlands State University, Senga Road, Gweru, Zimbabwe article info abstract Article history: Influenza is a serious respiratory disease responsible for significant morbidity and mortality due to both Received 11 May 2020 annual epidemics and pandemics; its treatment involves the use of neuraminidase inhibitors. Received in revised form (À)-Oseltamivir phosphate (Tamiflu) approved in 1999, is one of the most potent oral anti-influenza 29 June 2020 neuraminidase inhibitors. Consequently, more than 70 Tamiflu synthetic procedures have been devel- Accepted 23 July 2020 oped to date. Herein, we highlight the evolution of Tamiflu synthesis since its discovery over 20 years ago Available online xxx 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 Keywords: Enabling technologies the advent of enabling technologies. © Evolution 2020 Elsevier Ltd. All rights reserved. Influenza Tamiflu synthesis Contents 1. Introduction . ................................................. 00 2. Discovery and synthesis by Gilead sciences . .................................... 00 3. Roche industrial approach . ................................................. 00 4. Alternative synthetic approaches . ............................................ 00 4.1. Shikimic acid dependent approaches . ....................... 00 4.1.1. Azide-dependent routes . .. ....................... 00 4.1.2. Shikimic acid dependent azide-free routes . ....................... 00 4.2. Shikimic acid-independent approaches . ....................... 00 4.2.1. Tamiflu via Diels-Alder approach . ....................... 00 4.2.2. Tamiflu via a Horner-Wadsworth-Emmons (HeW-E) reaction/aldol condensation/Michael addition . ............ 00 4.2.3. Tamiflu synthesis from sugars . ....................... 00 5. Conclusions . ................................................. 00 Declaration of competing interest . ....................... 00 Acknowledgements . ....................... 00 References................................................................. ................................ ....................... 00 1. Introduction chemotherapeutic agent for influenza treatment [1e3]Influenza is a severe viral infection of the respiratory system regarded as the Tamiflu, also known as oseltamivir phosphate 1 is a potent most serious respiratory disease, which is responsible for signifi- cant morbidity and mortality due to both annual epidemics and predictable pandemics [1e3] More specifically, the avian influenza H5N1 has a mortality rate of about 60% [4] Unfortunately, little has * Corresponding author. been done to change the influenza infection patterns in past E-mail address: [email protected] (P. Watts). https://doi.org/10.1016/j.tet.2020.131440 0040-4020/© 2020 Elsevier Ltd. All rights reserved. Please cite this article as: C.R. Sagandira et al., The evolution of Tamiflu synthesis, 20 years on: Advent of enabling technologies the last piece of the puzzle?, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131440 2 C.R. Sagandira et al. / Tetrahedron xxx (xxxx) xxx decades despite influenza being the most studied viral infection before the arrival of the human immunodeficiency virus (HIV) [5,6] Now in this global society, a highly aggressive strains of the influ- enza virus such as the H5N1 can mutate to become easily trans- mitted from human to human and spark another deadly pandemic just as with current Severe Acute Respiratory Syndrome Corona- virus 2 (SARS-CoV-2) Infection (COVID19) pandemic, [7,8] which has brought the world to its knees. The surge in drug-resistant influenza strains resulting from naturally occurring mutations re- Fig. 2. Structures of oseltamivir carboxylate 2. minds us of the need for continued research to discover more potent neuraminidase inhibitors [9e13] The current anti-influenza À drugs are useful templates in the development of new neuramin- studies into ( )-shikimic acid free synthetic routes in both industry idase inhibitors through structure-activity relationship studies. As and academia. Fortunately, this has been addressed by the devel- fi fi the research towards new and better treatment remains a top opment of more ef cient extraction and puri cation processes or priority, it is equally important to improve the availability of the alternatively by fermentation using a genetically engineered E.coli e current anti-influenza drugs by developing better synthetic pro- bacteria [25,28 30] Furthermore, Yoshida and Ogasawara cedures to guard the world against influenza. Drugs such as osel- demonstrated an enantioconvergent synthesis of shikimic acid via tamivir phosphate (Tamiflu) 1a, amantadine HCl 1b, rimantadine a palladium mediated elimination reaction [31] Although more HCl 1c, zanamivir 1d and peramivir 1e have been developed for the studies utilising alternative starting materials are still ongoing, they fi treatment of influenza over the years [1e3] and more recently, have not been as ef cient as the current shikimic acid based pro- baloxavir marboxil 1f was developed (Fig. 1)[14] The last four are duction route. The use of the potentially hazardous azide chemistry FDA approved and are currently the recommended influenza drugs for the introduction of amino and acetomido groups to the ring was, by Centres for Disease Control and Prevention (CDC) [15] Of all the and is still, a major concern [1,2,32] Azide chemistry poses many drugs, Tamiflu is the most commonly used since its FDA approval in safety concerns because of its hazardous and highly exothermic e 1999 making its synthesis an important research area (see Fig. 2). nature, which become more pronounced at a large scale [2,33 37] Tamiflu was discovered by Gilead Sciences in 1995, patented in As a result, numerous studies towards azide-free synthetic routes 1996, co-developed with F. Hoffmann-La Roche Ltd and marketed were done, which unfortunately have not been as good as the by F. Hoffmann-La Roche and commercially launched in November current production route. Herein, this review highlights the evo- fi fl 1999 [16e21] In the early years of its discovery, (À)-shikimic acid lution towards ef cient and safe synthetic routes of Tami u since fi was used as starting material for the synthesis of Tamiflu and its rst approval 20 years ago. Since there has been over 70 pub- e e furthermore, the current and only industrial synthetic route still lished synthetic routes and some review articles, [1 3,22 26]a uses (À)-shikimic acid. In response to an increasing threat of an few selected representative routes will be used to give a clear ac- influenza pandemic, diverse synthetic approaches have been count of the past, present and the future with the arrival of enabling fl developed and very insightful reviews of their relative merits have technologies [38] such as ow chemistry. been published [1e3,22e27] However, there were legitimate (À)-shikimic acid availability concerns in the early years of the 2. Discovery and synthesis by Gilead sciences development of this drug. Shikimic acid, which is a natural product isolated from a plant of Chinese star anise was unavailable in Oseltamivir carboxylate 2 was the first molecule identified by consistent purity and enough quantity, which prompted extensive Gilead scientists for development, but the ethyl ester prodrug Fig. 1. Commercially available drugs for the treatment of influenza. Please cite this article as: C.R. Sagandira et al., The evolution of Tamiflu synthesis, 20 years on: Advent of enabling technologies the last piece of the puzzle?, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131440 C.R. Sagandira et al. / Tetrahedron xxx (xxxx) xxx 3 oseltamivir phosphate (Tamiflu) 1a was ultimately chosen as the developed. The use of potentially explosive azide-containing in- clinical candidate based on its potent in vitro and in vivo activities termediates is another drawback associated with this synthetic and its good oral bioavailability after extensive diversity-oriented route, which restricted the synthesis to milligram scale. discovery chemistry studies by Kim et al. [16e21]. Due