University of Groningen Innovative multicomponent reactions and their use in medicinal chemistry Zarganes Tzitzikas, Tryfon IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2017 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Zarganes Tzitzikas, T. (2017). Innovative multicomponent reactions and their use in medicinal chemistry. University of Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 24-09-2021 CHAPTER 6 INDUSTRIAL APPLICATIONS OF MULTICOMPONENT REACTIONS (MCRS) Chapter contained in the Rodriguez-Bonne book Stereoselectve Multple Bond-Forming Transformatons in Organic Synthesis 2015 by John Wiley & Sons, Inc. Tryfon Zarganes – Tzitzikas, Ahmad Yazbak, Alexander Dömling Chapter 6 INTRODUCTION Multcomponent reactons (MCRs) can be defned as processes in which three or more reactants introduced simultaneously are combined through covalent bonds to form a single product, regardless of the mechanisms and protocols involved.[1] Many basic MCRs are name reactons, for example, Ugi,[2] Passerini,[3] van Leusen,[4] Strecker,[5] Hantzsch,[6] Biginelli,[7] or one of their many variatons. Several descriptve tags are regularly atached to MCRs they are atom economic, for example, the majority if not all of the atoms of the startng materials are incorporated in the product; they are efcient, for example, they efciently yield the product since the product is formed in one-step instead of multple sequental steps; they are convergent, for example, several startng materials are combined in one reacton to form the product; they exhibit a very high bond-forming-index (BFI), for example, several non-hydrogen atom bonds are formed in one synthetc transformaton. Since MCRs are ofen highly compatble with a range of unprotected orthogonal functonal groups, on a second level, the scafold diversity of MCR can be greatly enhanced by the introducton of orthogonal functonal groups into the primary MCR product and react them in subsequent transformatons, e.g. ring forming reactons. This two layered strategy has been extremely fruitul in the past leading to a great manifold of scafolds now routnely used in combinatorial and medicinal chemistry for drug discovery purposes.[8] A versatle example of this strategy are the Ugi-Deprotecton-Cyclizaton procedures (UDC) leading to a great scafold diversity, e.g. benzimidazoles, benzodiazepinedione, tetrazolodiazepinone, quinoxalinones, γ-lactams, and piperazines.[9] Similarly multple bond-forming transformatons (MBFTs) require the involvement of substrates exhibitng multple potental reacton sites and the selectve control of their reactvity in each individual bond-forming event. Some classes of densely functonalized small molecules have been shown to be partcularly suited for use in these transformatons, and in this context, 1,2- and 1,3-dicarbonyl compounds are exceptonal synthetc platorms.[10] The rapid and easy access to biologically relevant compounds by MCRs and their scafold diversity has recognized them by the synthetc community in industry and academia as a preferred method to design and discover biologically actve compounds. Although the list of MCR applicatons towards the synthesis of marketed drugs or drugs under development is much longer we will focus and discuss in the following chapters eight recent examples. 140 Industrial applicatons of multcomponent reactons (MCRs) APPLICATIONS OF MCRS Xylocaine The reacton of isocyanides, oxo components, and primary or secondary amines yields α-amino carbonamides, as disclosed by Ugi in 1959. The reacton has been employed by Ugi early on to synthesize the local anesthetc Xylocaine (Scheme 1).[11] It clearly shows the genius of Ivar Ugi who recognized the important applicatons of MCR chemistry several decades before the area of combinatorial chemistry was born. Xylocaine alters depolarizaton in neurons, by blocking the fast voltage gated sodium (Na+) channels in the cell membrane. While there are many synthetc approaches towards Xylocaine such as the one in (Scheme 1) Ugi’s approach is amongst the shortest and without doubts the most convergent and diverse one. e.g. many newer derivatves of the same class of anesthetcs can be synthesized by the same route by simple variaton of the three startng material classes, amine, oxo and isocyanide components (Scheme 2). 6 Scheme 1. Synthesis of Xylocaine Almorexant Almorexant is a frst-in-class orexin receptor antagonist that was undergoing phase III clinical development for insomnia untl 2011. The tetrahydroisoquinoline derivatve was originally discovered from a series of Ugi/Pictet−Spengler reacton products. Originally developed by Actelion, from 2007 Almorexant was being reported as a potental blockbuster drug, as its novel mechanism of acton (orexin receptor antagonism) was thought to produce beter quality sleep and fewer side efects than the traditonal benzodiazepine and z-drugs, that dominate the mult- billion dollar insomnia medicaton market. [12] 141 Chapter 6 Scheme 2. Derivatves of Xylocaine Figure 1 . Structure of Almorexant The discovery synthesis of Almorexant starts with an Ugi three-component reacton (Ugi-3CR) between benzaldehyde (4), 2-(3,4-dimethoxyphenyl)ethanamine (5) and methyl isocyanide (6) afording product 7, which in a post Pictet−Spengler reacton with 3-(4-(trifuoromethyl)phenyl) propanal (8) in the presence of strongly acidic conditons gives the end product Almorexant (9). Clearly, the synthesis is not stereoselectve and yields four diferent stereoisomers of which only one is biologically highly actve (Scheme 3). 142 Industrial applicatons of multcomponent reactons (MCRs) Scheme 3. Discovery synthesis of Almorexant involving a one pot Ugi-3CR and Pictet-Spengler-2CR reacton Lefort et al. reported on two new efcient catalytc systems for the enantoselectve synthesis of intermediate 10 needed for the synthesis of Almorexant (Scheme 4).[13] The frst one relies on an asymmetric hydrogenaton of 11 using an iridium complex with a ferrocene-based ligand while the second one relies on an asymmetric transfer hydrogenaton of 11 using a ruthenium catalyst with a diamine ligand. Both catalysts were studied further and appeared to be suited for large- scale manufacturing (Scheme 5). In case Almorexant had not been stopped from phase III clinical development in 2011, a fnal choice would have been guided mainly by the cost of goods for the two routes, considering the availability of the producton units and the delivery tme of the raw materials. 6 Scheme 4. Almorexant and its key intermediate 143 Chapter 6 Scheme 5 . Asymmetric hydrogenaton of 11 with Ir/TaniaPhos and asymmetric transfer hydrogenaton with Noyori catalyst towards 10 Interestngly TaniaPhos catalysts used in the asymmetric hydrogenatons can be synthesized from the (R)-Ugi amine 15 in two steps.[14] The (R)-Ugi amine can be synthesized via a Mannich reacton between ferrocene 12, dimethyl amine (13) and acetaldehyde (14) (Scheme 6).[15] Scheme 6. Synthesis of (R)-Ugi amine 144 Industrial applicatons of multcomponent reactons (MCRs) (−)-Oseltamivir (Tamilfu®) New infectous diseases appear regularly in diverse parts of the globe, most recently swine fu, creatng new global health threats. The upcoming of new multple drug resistance seasonal fu and infectous and deadly infuenza pandemics in regular intervals of 20-40 years is of great concern. Current weaponry to fght infuenza can only build on a handful of chemotherapeutc optons besides immunizaton. While immunizaton is suitable to control seasonal fu it is not believed to work with new fu pandemics. The antinfuenza neuraminidase inhibitor (−)-oseltamivir is one of the few remaining chemotherapy optons and has been recently synthesized by the Hayashi group by a remarkably short and high yielding asymmetric synthesis (Scheme 7).[16] The synthesis consists of a one-pot MCR involving the Michael reacton of α-alkoxyaldehyde (16) and cis- nitroalkene 17, catalyzed by (S)-diphenylprolinol silyl ether (18), proceeded in the presence of HCO2H in chlorobenzene to aford the Michael product 19 in good yield with excellent diastereo and enantoselectvity. Ethyl acryl derivatve 20 and Cs2CO3 were added to the same pot generatng the desired product 21 and two diferent intermediates which were later converted into 21 by the additon of EtOH. In the next step the Michael reacton of toluenethiol (22), followed by epimerizaton at the α-positon of the nitro group, aforded the thiol Michael adduct 23a with the desired stereochemical confguraton. By additon of Zn and TMSCl to the same vessel, reducton of the nitro group gave the amine 23b, from which a retro-Michael reacton of the thiol group proceeded by treatment with base to aford Oseltamivir (Tamilfu®)