Todd:Pictet-Spengler to PZQ

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==Abstract==
==Abstract==
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The Pictet-Spengler (PS) reaction has potential for the enantioselective synthesis of praziquantel (PZQ), the drug used worldwide for the treatment of the neglected tropical disease schistosomiasis. Following the recent identification of routes to enantiopure PZQ by classical resolution[[http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0001260 Todd, PLoS 2011], [http://www.nature.com/nchem/journal/v3/n10/full/nchem.1149.html Todd, Nature Chemistry 2011]] we report here the progress to date on the synthesis of PZQ using the PS reaction. The approach employs a known peptide acetal precursor in an chiral Lewis acid (CLA) -catalyzed cyclization.
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The Pictet-Spengler (PS) reaction has potential for the enantioselective synthesis of praziquantel (PZQ), the drug used worldwide for the treatment of the neglected tropical disease schistosomiasis. Following the recent identification of routes to enantiopure PZQ by classical resolution[[http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0001260 Todd, PLoS, 2011], [http://www.nature.com/nchem/journal/v3/n10/full/nchem.1149.html Todd, Nature Chemistry, 2011]] we report here the progress to date on the synthesis of PZQ using the PS reaction. The approach employs a known peptide acetal precursor in an chiral Lewis acid (CLA) -catalyzed cyclization.
[[Image:Intro.png|thumb|center|600px| '''Scheme: The general reaction scheme for the enantioselective Pictet-Spengler reaction to PZQ using chiral Lewis acid (CLA) catalysis'''.]]
[[Image:Intro.png|thumb|center|600px| '''Scheme: The general reaction scheme for the enantioselective Pictet-Spengler reaction to PZQ using chiral Lewis acid (CLA) catalysis'''.]]
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Besides an alternative separation of enantiomers based on chromatography,[[http://onlinelibrary.wiley.com/doi/10.1002/jps.20211/abstract Lui, J Pharm Sci, 20034]] there has been a single report each of diastereo-[[http://onlinelibrary.wiley.com/doi/10.1002/chin.200440213/full Zhang, J.Chem.Res., Synop 2004]] and enantioselective[[http://www.sciencedirect.com/science/article/pii/S0957416606002825 Czarnocki, Tet Asym 2006]] syntheses of PZQ. These routes are not, however, realistic for the large-scale syntheses of PZQ, partly because they use synthetic routes that are not currently used for the large-scale synthesis of the racemate - ''de novo'' process optimization for these approaches is not likely to happen given the low profit margin associated with drugs for neglected tropical diseases.
Besides an alternative separation of enantiomers based on chromatography,[[http://onlinelibrary.wiley.com/doi/10.1002/jps.20211/abstract Lui, J Pharm Sci, 20034]] there has been a single report each of diastereo-[[http://onlinelibrary.wiley.com/doi/10.1002/chin.200440213/full Zhang, J.Chem.Res., Synop 2004]] and enantioselective[[http://www.sciencedirect.com/science/article/pii/S0957416606002825 Czarnocki, Tet Asym 2006]] syntheses of PZQ. These routes are not, however, realistic for the large-scale syntheses of PZQ, partly because they use synthetic routes that are not currently used for the large-scale synthesis of the racemate - ''de novo'' process optimization for these approaches is not likely to happen given the low profit margin associated with drugs for neglected tropical diseases.
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A better approach is to take existing routes to the racemic drug, and make a key step asymmetric. PZQ was originally synthesized by a Reissert process,[[http://www.springerlink.com/content/k07547g60580m377/ Lobich, Cell Mol Life Science 1977]] and it is likely that this process is currently used in at least one commercial-scale synthesis of PZQ. This route has the disadvantage of requiring a large amount of cyanide.[[http://www.sciencedirect.com/science/article/pii/S004313540500134X Shen Water Res, 2005]] There are literature reports of catalytic, asymmetric Reissert processes,[[http://pubs.acs.org/doi/abs/10.1021/ja010654n Shibasaki JACS 2001], [http://www.sciencedirect.com/science/article/pii/S0040403905005228 Guingant, Tet Let, 2005]] but surprisingly there are no reports of this reaction being successfully applied to the system required for PZQ - isoquinoline. While the exact routes used to synthesize PZQ on a ton scale are not currently clear, it is likely that one of the main generics suppliers, Shin Poong, employs (or until recently employed) a published method that uses a Pictet-Spengler (PS) cyclization. [[http://www.sciencedirect.com/science/article/pii/S0040402098004013 Kim, Tet, 1998]] The key precursor to this cyclization, and hence the substrate for an asymmetric version of this reaction, is thus likely available in quantity, and can in any case be prepared by a recently-developed and more efficient route than that originally published.[[http://onlinelibrary.wiley.com/doi/10.1002/chem.201002046/abstract Domling Chem.Eur.J. 2010]] A large-scale route to (''R'')-PZQ is hence a viable possibility ''via'' a Pictet-Spengler sequence if a catalyst could be found to effect the required cyclization.<br>
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A better approach is to take existing routes to the racemic drug, and make a key step asymmetric. PZQ was originally synthesized by a Reissert process,[[http://www.springerlink.com/content/k07547g60580m377/ Lobich, Cell Mol Life Science 1977]] and it is likely that this process is currently used in at least one commercial-scale synthesis of PZQ. This route has the disadvantage of requiring a large amount of cyanide.[[http://www.sciencedirect.com/science/article/pii/S004313540500134X Shen Water Res, 2005]] There are literature reports of catalytic, asymmetric Reissert processes,[[http://pubs.acs.org/doi/abs/10.1021/ja010654n Shibasaki JACS 2001], [http://www.sciencedirect.com/science/article/pii/S0040403905005228 Guingant, Tet Let, 2005]] but surprisingly there are no reports of this reaction being successfully applied to the system required for PZQ - isoquinoline. While the exact routes used to synthesize PZQ on a ton scale are not currently clear, it is likely that one of the main generics suppliers, Shin Poong, employs (or until recently employed) a published method that uses a Pictet-Spengler (PS) cyclization. [[http://www.sciencedirect.com/science/article/pii/S0040402098004013 Kim, Tet, 1998]] The key precursor to this cyclization, and hence the substrate for an asymmetric version of this reaction, is thus likely available in quantity, and can in any case be prepared by a recently-developed and more efficient route than that originally published.[[http://onlinelibrary.wiley.com/doi/10.1002/chem.201002046/abstract Doemling Chem.Eur.J. 2010]] A large-scale route to (''R'')-PZQ is hence a viable possibility ''via'' a Pictet-Spengler sequence if a catalyst could be found to effect the required cyclization.<br>
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Unfortunately the key cyclization is beyond the current state of the art. There is a small number of reports in the literature of catalytic, asymmetric Pictet-Spengler reactions.[[http://pubs.acs.org/doi/abs/10.1021/ja057444l List, JACS, 2006], [http://onlinelibrary.wiley.com/doi/10.1002/anie.200701808/abstract Hiemstra, Angew. Chem. Int. Ed, 2007]] In all cases the aromatic ring involved in the cyclization is electron rich, usually by virtue of containing one or more methoxy substituents. To the best of our knowledge there are no reports of catalytic, asymmetric Pictet-Spengler reactions involving a simple phenyl ring as the reactive aromatic component. Besides the route described above, other racemic syntheses of PZQ have used the PS reaction.[[http://onlinelibrary.wiley.com/doi/10.1002/chem.201002046/abstract Domling Chem.Eur.J. 2010]]<br>
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Unfortunately the key cyclization is beyond the current state of the art. There is a small number of reports in the literature of catalytic, asymmetric Pictet-Spengler reactions.[[http://pubs.acs.org/doi/abs/10.1021/ja057444l List, JACS, 2006], [http://onlinelibrary.wiley.com/doi/10.1002/anie.200701808/abstract Hiemstra, Angew. Chem. Int. Ed, 2007]] In all cases the aromatic ring involved in the cyclization is electron rich, usually by virtue of containing one or more methoxy substituents. To the best of our knowledge there are no reports of catalytic, asymmetric Pictet-Spengler reactions involving a simple phenyl ring as the reactive aromatic component. Besides the route described above, other racemic syntheses of PZQ have used the PS reaction.[[http://onlinelibrary.wiley.com/doi/10.1002/chem.201002046/abstract Doemling Chem.Eur.J. 2010]]<br>
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Besides the substrate ('''7a''') required for the synthesis of PZQ by a PS approach, three other peptide acetal starting materials are worthy of investigation: the benzoyl analog ('''7c''') and the dimethoxy-functionalised analogs of both these structures ('''7b''' and '''7d'''). The change from cyclohexanoyl to benzoyl might influence the ease of initial acetal cyclisation to generate an acyliminium ion, and the final product of the reaction, the benzoyl analog of PZQ ('''1c'''), may be easier to crystallise/purify. Interestingly this benzoyl analog is more potent as an anthelmintic than PZQ itself, yet is not used as the drug of treatment;[REF] regardless, it is possible to convert the benzoyl PZQ analog fairly easily to PZQ.[[http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0001260 Todd, PLoS 2011]] The two methoxy analogs are clearly of interest as they are more likely to participate in PS cyclizations. In fact the 6,7-di(MeO) analog of PZQ ('''7b''') is itself biologically active,[[http://onlinelibrary.wiley.com/doi/10.1111/j.1747-0285.2011.01288.x/abstract Domling 2012]] so again, the effective production of this molecule is an attractive possible alternative to enantiopure PZQ if the synthesis of (''R'')-PZQ itself proves intractable.<br>
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Besides the substrate ('''7a''') required for the synthesis of PZQ by a PS approach, three other peptide acetal starting materials are worthy of investigation: the benzoyl analog ('''7c''') and the dimethoxy-functionalised analogs of both these structures ('''7b''' and '''7d'''). The change from cyclohexanoyl to benzoyl might influence the ease of initial acetal cyclisation to generate an acyliminium ion, and the final product of the reaction, the benzoyl analog of PZQ ('''1c'''), may be easier to crystallise/purify. It would also be possible to convert the benzoyl PZQ analog fairly easily to PZQ.[[http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0001260 Todd, PLoS, 2011]] The two methoxy analogs are clearly of interest as they are more likely to participate in PS cyclizations. In fact the 6,7-di(MeO) analog of PZQ ('''7b''') is itself biologically active,[[http://www.sciencedirect.com/science/article/pii/S0960894X11016520 Rao, BMCL,2012]] so again, the effective production of this molecule is an attractive possible alternative to enantiopure PZQ if the synthesis of (''R'')-PZQ itself proves intractable.<br>
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==Literature: Examples of Catalytic, Enantioselective Pictet-Spengler Reactions==
==Literature: Examples of Catalytic, Enantioselective Pictet-Spengler Reactions==
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There is only currently [http://en.wikipedia.org/wiki/Pictet%E2%80%93Spengler_reaction a brief account of PS reactions on Wikipedia], and no page for the asymmetric version of the reaction. A review on [[Todd:Catalytic%2C_Asymmetric_Pictet-Spengler_Reaction | The Catalytic, Asymmetric Pictet-Spengler Reaction]]is currently being assembled .<br>
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There is only currently [http://en.wikipedia.org/wiki/Pictet%E2%80%93Spengler_reaction a brief account of PS reactions on Wikipedia], and no page for the asymmetric version of the reaction. A review on [[Todd:Catalytic%2C_Asymmetric_Pictet-Spengler_Reaction | The Catalytic, Asymmetric Pictet-Spengler Reaction]]is currently being assembled.<br>
==Results==
==Results==
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===1. Preparation of Cyclization Precursors===
===1. Preparation of Cyclization Precursors===
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The peptide acetal precursors '''7a-d''' to the PS reaction could be made using a [http://www.thesynapticleap.org/node/288 traditional stepwise approach][[http://www.sciencedirect.com/science/article/pii/S0040402098004013 Kim, Tet, 1998], [http://www.springerlink.com/content/55122gr811h23370/?MUD=MP Min, Arch. Pharm. Res., 1998]] or an Ugi 3-component coupling [[http://onlinelibrary.wiley.com/doi/10.1002/chem.201002046/abstract Domling Chem.Eur.J. 2010]] (Scheme 1). These were then shown to undergo PS reactions in the presence of excess acid, to give PZQ and its three analogs as racemates. Investigations of chiral acids were then undertaken collaboratively in a search for an effective catalyst system for optimization.<br>
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The peptide acetal precursors to the PS reaction ('''7a-d''') can be made using a [http://www.thesynapticleap.org/node/288 traditional stepwise approach][[http://www.sciencedirect.com/science/article/pii/S0040402098004013 Kim Tet, 1998], [http://www.springerlink.com/content/55122gr811h23370/?MUD=MP Min Arch. Pharm. Res., 1998]] or an Ugi 3-component coupling [[http://onlinelibrary.wiley.com/doi/10.1002/chem.201002046/abstract Doemling Chem. Eur. J. 2010]] (Scheme 1).<br>
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'''1a. Conventional Stepwise Synthesis'''
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The conventional stepwise synthesis successfully gave the cyclisation precursors ''(need method summary and description of yields)'' (See Supporting Information).
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Synthesis of these materials ''via'' Ugi multicomponent coupling was also successful and more convenient. Synthesis of the isocyanides '''6e''' ([http://www.ourexperiment.org/racemic_pzq/1564/Preparation_of_2phenylethyl_isocyanide__alternative_route__MW343.html MW34-3]) and '''6f''' ([http://www.ourexperiment.org/racemic_pzq/3915/Preparation_of_234Dimethoxyphenylethyl_isocyanide_MNR42.html MNR4-2]) was achieved ''via'' the Ugi formamide route from the corresponding amines following Doemling's 2-step procedure.[[http://onlinelibrary.wiley.com/doi/10.1002/anie.197205301/abstract Ugi, Angew Int, 1972],[http://worldwide.espacenet.com/publicationDetails/biblio?CC=WO&NR=2009115333A1&KC=A1&FT=D&date=20090924&DB=EPODOC&locale=en_ep Doemling PCT Int, 2009]] Attempts to use a Hoffman-type procedure did give the desired product ([http://www.ourexperiment.org/racemic_pzq/309/Preparation_of_2Phenylethyl_isocyanide_MW341.html MW34-1])in one step using chloroform as the source of C<sup>l</sup>, but this approach proved less efficient, especially on scale up ([http://www.ourexperiment.org/racemic_pzq/338/Scaleup__Preparation_of_2Phenylethyl_isocyanide_MW342.html MW34-2]). Details may be found in the Supporting Information.<br>
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''(need completion of summary of results here)''.  
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'''1b. Synthesis via Ugi Multicomponent Coupling'''
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''1b. i) Synthesis of the isocyanides''<br>
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Isocyanides [http://www.ourexperiment.org/racemic_pzq/1564/Preparation_of_2phenylethyl_isocyanide__alternative_route__MW343.html MW34-3] and [http://www.ourexperiment.org/racemic_pzq/3915/Preparation_of_234Dimethoxyphenylethyl_isocyanide_MNR42.html MNR4-2] were prepared via the Ugi formamide route from the corresponding amines following Domlings 2-step procedure.[[http://onlinelibrary.wiley.com/doi/10.1002/anie.197205301/abstract Ugi, Angew Int, 1972],[http://worldwide.espacenet.com/publicationDetails/biblio?CC=WO&NR=2009115333A1&KC=A1&FT=D&date=20090924&DB=EPODOC&locale=en_ep Domling PCT Int, 2009]]  Attempts to use a Hoffman type procedure produced the desired product ([http://www.ourexperiment.org/racemic_pzq/309/Preparation_of_2Phenylethyl_isocyanide_MW341.html MW34-1])in one step using chloroform as the source of Cl, but this proved less efficient especially on scale up ([http://www.ourexperiment.org/racemic_pzq/338/Scaleup__Preparation_of_2Phenylethyl_isocyanide_MW342.html MW34-2]).<br>
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*Care should be taken in the handling of the isocyanides as they have a strong odour with an unpleasant metallic taste<br>
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[[Image:Isocyanide.png|thumb|center|450px| '''Scheme: Formation of isocyanides MW34-4 and MNR4-2'''.]]
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''1b. ii) Ugi: Multicomponent Couplings''
''1b. ii) Ugi: Multicomponent Couplings''
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===2. Racemic Cyclizations===
===2. Racemic Cyclizations===
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It has been shown in the literature that cyclisation of the peptide acetal intermediate via the Pictet-Spengler reaction occurs in the presence of very strong Bronsted acids.  Previous examples include concentrated sulphuric acid [[http://www.sciencedirect.com/science/article/pii/S0040402098004013 Kim, Tet, 1998]] and methane sulfonic acid (MSA) [[http://onlinelibrary.wiley.com/doi/10.1002/chem.201002046/abstract Domling Chem.Eur.J. 2010]].
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It has been shown in the literature that cyclisation of the peptide acetal intermediate via the Pictet-Spengler reaction occurs in the presence of very strong Bronsted acids.  Previous examples include concentrated sulphuric acid [[http://www.sciencedirect.com/science/article/pii/S0040402098004013 Kim, Tet, 1998]] and methane sulfonic acid (MSA) [[http://onlinelibrary.wiley.com/doi/10.1002/chem.201002046/abstract Doemling Chem.Eur.J. 2010]].
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[[Image:Pictet-Spengler cyclisation.png|thumb|center|500px]]
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[[Image:MSA1.png|thumb|center|500px]]
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The four Ugi products ([http://www.ourexperiment.org/racemic_pzq/4029/Preparation_of_the_PZQ_peptide_acetal_Ugiintermediate_KAB52.html KAB5-2], [http://www.ourexperiment.org/racemic_pzq/5642/Preparation_of_the_dimethoxy_Ugiintermediate_MNR85.html MNR8-5], [http://www.ourexperiment.org/racemic_pzq/1555/Preparation_of_the_Nbenzoylprotected_Ugiintermediate_MW511.html MW51-1], [http://www.ourexperiment.org/racemic_pzq/4011/Preparation_of_the_dimethoxy_Ugiintermediate_MNR102.html MNR10-2]) were subjected to varying loading levels of methanesulfonic acid to study its effect on the cyclisation.  Initially the reactions were carried out in neat acid using 100 equivalents.  The reaction to afford PZQ ([http://www.ourexperiment.org/racemic_pzq/2443/Acidmediated_PictetSpengler_of_MW29_to_give_racPZQ_MNR131.html MNR13-1]) was the only one that did not give clean conversion to desired product at room temperature after 1 hour but all starting material was consumed.  It was however found that increasing the reaction temperature to 60 °C resulted in conversion to PZQ in 70% yield ([http://www.ourexperiment.org/racemic_pzq/3445/The_PictetSpengler_reaction_to_give_PZQ_KAB38_in_neat_acid.html KAB3-8]).  The other analogues converted to desired product in similar yields ([http://www.ourexperiment.org/racemic_pzq/2447/Acidmediated_PictetSpengler_of_MW51_to_give_Nbenzoylderivative_of_PZQ_MNR141.html MNR14-1], [http://www.ourexperiment.org/racemic_pzq/2419/Acidmediated_PictetSpengler_of_MNR82_to_give_dimethoxy_PZQ_analog_MNR112.html MNR11-2] and [http://www.ourexperiment.org/racemic_pzq/2421/Acidmediated_PictetSpengler_of_MNR82_to_give_dimethoxyNbenzoylderivative_of_PZQ_MNR121.html MNR12-1]).  It should be noted that these yields are un-optimised.  Reducing the level of methansulfonic acid to stoichiometric levels produced interesting results ([http://www.ourexperiment.org/racemic_pzq/2901/Acidmediated_PS_cyclisation_to_give_racemic_PZQ_KAB33_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB81_the_dimethoxy_PZQ_analogue_KAB12_and_the_Nbenzoyl_PZQ_analogue_KAB71.html KAB3-3, KAB7-1, KAB1-2 and KAB8-1]).  Following all four reactions by TLC it was clear to see consumption of starting material within 90 minutes however product spots were not observed for KAB3-3 and KAB7-1.  Instead, isolated from these reactions were the corresponding enediamides KAB13 and UNK01.  A similar result was found when carrying out the reactions using a catalytic 10 mol% of methanesulfonic acid.
[[Image:Table01_working.PNG|thumb|centre|700px]]
[[Image:Table01_working.PNG|thumb|centre|700px]]
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The formation and isolation of the enediamide can be explained by looking at the proposed mechanism of the cyclisation.  After formation of the first ring the iminium is formed by the loss of ethanol.  This iminium can then tautomerise to the stable enediamide.  Examples of when the phenyl ring is un-substituted don’t yield any of the desired product however examples where the ring is substituted with electron donation groups give exclusively the desired product with no enediamide being isolated. 
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[[Image:PS_mech.png|thumb|centre|700px]]
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'''2b Acid-catalysed Pictet-Spengler cyclisation.'''
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''2b i)Screening of racemic catalysts''
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Previously in the lab we’d tried several racemic Brønsted Acid and Thiourea Organocatalysts in an attempt to cyclise the Ugi intermediates. NMR studies using the thiourea ([http://www.ourexperiment.org/racemic_pzq/525 MW44])and phosphoramide ([http://www.ourexperiment.org/racemic_pzq/464 MW41]) catalysts did not yield any reaction. 
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'''2b Acid-catalised Pictet-Spengler cyclisation.'''
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''2b i)Screening of racemic catalysts''
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[[Image:MW44.png|thumb|center|500px]]
[[Image:MW44.png|thumb|center|500px]]
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[http://www.ourexperiment.org/racemic_pzq/525 Attempts to the Bronstedt-acid catalysed Pictet-Spengler cyclization using N,N’-bis[3,5-bis(trifluoromethyl)phenyl]thiourea (MW44)] -> no reaction
 
[[Image:MW41.png|thumb|center|500px]]
[[Image:MW41.png|thumb|center|500px]]
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[http://www.ourexperiment.org/racemic_pzq/464 Attempts to the Bronstedt-acid catalysed Pictet-Spengler cyclization using BINOL-N-triflyl phosphoramide (MW41)] -> no reaction
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The BINAP-disulfonic acid ([http://www.ourexperiment.org/racemic_pzq/1755 MW56-4]and [http://www.ourexperiment.org/racemic_pzq/2524/Continuation_of_Acidcatalyzed_PictetSpengler_0f_MNR82_using_binaphthalenedisulfonic_acid_to_give_MNR11.html MNR11-8]
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) however gave what looked like promising results based on LCMS analysis but at this stage the reaction requires further investigation on a larger scale.
[[Image:MW56.png|thumb|center|500px]]
[[Image:MW56.png|thumb|center|500px]]
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[http://www.ourexperiment.org/racemic_pzq/1755 Acid-catalyzed Pictet-Spengler reaction with binaphthalenedisulfonic acid (MW56-1 to MW56-4)]
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Moving on triflic acid (TfOH) was screened as a catalyst for the Pictet-Spengler reaction using the four Ugi products from above.  At a catalyst loading of 5 mol %, the desired product for the two electron rich systems ([http://www.ourexperiment.org/racemic_pzq/5642/Preparation_of_the_dimethoxy_Ugiintermediate_MNR85.html MNR8-5], [http://www.ourexperiment.org/racemic_pzq/4011/Preparation_of_the_dimethoxy_Ugiintermediate_MNR102.html MNR10-2]) was isolated in excellent yields of 91 for [http://www.ourexperiment.org/racemic_pzq/4520/TfOH_catalysed_PS_reactions_to_give_the_dimethoxy_PZQ_analogues_KAB814__KAB15.html KAB1-5]and 96% for [http://www.ourexperiment.org/racemic_pzq/4520/TfOH_catalysed_PS_reactions_to_give_the_dimethoxy_PZQ_analogues_KAB814__KAB15.html KAB8-14].  Unfortunately, as with the previous examples, complete cyclisation was not observed for the other two examples ([http://www.ourexperiment.org/racemic_pzq/2696/Stoichiometric_acidmediated_PictetSpengler_of_MW294_to_give_racemic_PZQ_KAB31_and_KAB32.html KAB3-2] and [http://www.ourexperiment.org/racemic_pzq/4441/TfOH_catalysed_PS_reaction_to_give_the_Nbenzoyl_PZQ_analogue_KAB73.html KAB7-3])and intermediate enediamide was isolated as the major product.  Increasing catalyst loading did not help to push these reactions to completion ([http://www.ourexperiment.org/racemic_pzq/4127/TfOH_catalysed_PS_reaction_to_give_PZQ_KAB312_to_KAB316.html KAB3-12]). 
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[http://www.ourexperiment.org/racemic_pzq/1755 Acid-catalyzed Pictet-Spengler reaction with binaphthalenedisulfonic acid (MW56-1 to MW56-4)] - Starting material for unactivated comp., cycl for dimethoxy-intermediates (hemi-acetal or fragmentation from MS?)
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Experiments to the acid-mediated Pictet-Spengler of the PZQ intermediate with various Bronsted-acids (phenyl phosphonic acid, p-toluenic acid, TFA) -> no reaction
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[http://www.ourexperiment.org/racemic_pzq/262 Attempts to the acid-mediated Pictet-Spengler cyclization of the ‘Ugi intermediate’ MW29 (MW31)]
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[http://www.ourexperiment.org/racemic_pzq/470 Cleavage of the dimethoxy acetal of 2-((2,2-dimethoxyethyl)amino)-N-phenethylacetamide hydrochloride MW7 (MW42-1 to MW42-7)]
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[[Image:KAB_cats_TfOH.png|thumb|center|500px]]
[[Image:KAB_cats_TfOH.png|thumb|center|500px]]
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[[Image:Table02.PNG|thumb|center|500px]]
 
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Relevant Literature
 
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* [http://pubs.acs.org/doi/abs/10.1021/jo0524775 Youn 2006 JOC]
 
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===3. Synthesis/Acquisition of Candidate Catalysts===
 
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'''N,N’-bis-3,5-bis[3,5-bis(trifluoromethyl)phenyl]-thiourea'''
 
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This achiral version of a 'Jacobsens thiourea-catalyst' is a Bronsted-acid which is used for Screening pretests to evaluate if a reaction works under the choosen conditions without using expensive chiral versions of the catalyst. 
 
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[[Image:N,N’-bis-3,5-bis(trifluoromethyl)phenyl-thiourea.png|thumb|center|500px]]
 
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Procedure: [http://www.ourexperiment.org/racemic_pzq/547 Synthesis of N,N’-bis[3,5-bis(trifluoromethyl)phenyl-thiourea]
 
-
 
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* Acid-free, organocatalytic acetalization, M. Kotke and P. R. Schreiner, Tetrahedron 2006, 62, 2-3, 434-439; [http://dx.doi.org/10.1016/j.tet.2005.09.079 doi:10.1016/j.tet.2005.09.079].
 
-
 
-
* Synthetic Studies toward Aryl-(4-aryl-4H-[1,2,4]triazole-3-yl)-amine from 1,3-Diarylthiourea as Urea Mimetics, A. Natarajan, Y. Guo, H. Arthanari, G. Wagner, J. A. Halperin and M. Chorev, J. Org. Chem. 2005, 70, 16, 6362–6368; [http://dx.doi.org/10.1021/jo0508189 DOI: 10.1021/jo0508189].
 
-
 
-
 
-
'''(+/-)-BINOL-N-triflyl phosphoramide'''
 
-
 
-
Achiral version of a BINOL catalyst with an acidic NH-proton, commonly used for acid-catalysed asymmetric reaction 
 
-
 
-
[[Image:BINOL-N-triflyl phosphoramide.png|thumb|center|500px]]
 
-
 
-
Procedure: [http://www.ourexperiment.org/racemic_pzq/454 Preparation of (+/-)-BINOL-N-triflyl phosphoramide]
 
-
 
-
* [http://dx.doi.org/10.1021/ja062508t Design of Chiral N-Triflyl Phosphoramide as a Strong Chiral Brønsted Acid and Its Application to Asymmetric Diels-Alder Reaction, D. Nakashima and H. Yamamoto, J. Am. Chem. Soc. 2006, 128, 30, 9626–9627.]
 
-
 
-
 
-
'''1,1-Binaphthyl-2,2-disulfonate'''
 
-
 
-
Strong acidic achiral BINOL catalyst wearing two sulfonic acid groups 
 
-
 
-
[[Image:Binaphtyl-disulfonic acid procedure.gif|thumb|center|500px]]
 
-
 
-
Procedure:
 
-
 
-
[http://www.ourexperiment.org/racemic_pzq/567 1. Step: 1,1’-Binaphthalene-2,2’-diyl-O,O’-bis(N,N’-dimethylthiocarbamate)]
 
-
 
-
[http://www.ourexperiment.org/racemic_pzq/583 2. Step: 1,1’-Binaphthalene-2,2’-diyl-S,S’-bis(N,N’-dimethylthiocarbamate)]
 
-
 
-
[http://www.ourexperiment.org/racemic_pzq/587 3. Step: 1,1’-Binaphthalene-2,2’-disulfonic acid]
 
-
 
-
 
-
* Pyridinium 1,1′-Binaphthyl-2,2′-disulfonates as Highly Effective Chiral Brønsted Acid−Base Combined Salt Catalysts for Enantioselective Mannich-Type Reaction, M. Hatano, T. Maki, K. Moriyama, M. Arinobe and K. Ishihara, J. Am. Chem. Soc. 2008, 130, 16858–16860; [http://dx.doi.org/10.1021/ja806875c DOI: 10.1021/ja806875c].
 
-
 
-
* A Powerful Chiral Counteranion Motif for Asymmetric Catalysis, P. García-García, F. Lay, P. García-García, C. Rabalakos, B. List, Angew. Chem. Int. Ed. 2009, 48, 4363 –4366; [http://www3.interscience.wiley.com/journal/122382952/abstract DOI: 10.1002/anie.200901768].
 
-
 
-
===4. Screening/Evaluation of Catalysts in Asymmetric PS Reactions===
 
-
 
-
==Pictet-Spengler reactions - Cyclization - SECTION NEEDS TO BE ASSIMILATED IN ABOVE==
 
-
 
-
==Summary==
 
-
 
-
Results:
 
-
Use of catalytic vs stoich achiral acid? Results.
 
-
Use of chiral acids. Little reaction. What is the evidence for any hemiaminals? Starting material – lots in unactivated. Messy NMR, so some reaction.
 
-
Discussion of range of acidity – what we have tried compared to what not.
+
[[Image:Table02.PNG|thumb|center|600px]]
 +
Continuing on, metal triflates were then studied with the potential of employing bisoxazoline ligands (BOX ligands) to generate chiral catalysts.[[http://pubs.acs.org/doi/abs/10.1021/om00105a047 Nishiyama, Organometallics, 1989]]  Copper and silver triflate were investigated with the silver triflate being more extensively screened.  Again as for the previous examples, electron rich systems (MNR8 and MNR10) cyclised and the desired products were isolated in 78 % of [http://www.ourexperiment.org/racemic_pzq/4755/AgOTf_catalysed_PS_reaction_to_give_the_dimethoxy_PZQ_analogue_KAB16.html KAB1-6] and 87% for [http://www.ourexperiment.org/racemic_pzq/4684/AgOTf_catalysed_PS_reaction_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB815.html KAB8-15] with a catalyst loading of 10%.  No further attempts at this stage were taken to reduce the catalyst loading any further.  Also, as before, increasing the catalyst loading did not help to push KAB5-2 and MW51-1 to completion (see experiments [http://www.ourexperiment.org/racemic_pzq/3757/The_metal_triflate_catalysed_PictetSpengler_to_give_racemic_PZQ_KAB39__KAB310.html KAB3-9 and KAB3-10]).  A negative control was also carried out using AgCl (table entry 6, [http://www.ourexperiment.org/racemic_pzq/4510/AgCl_catalysed_PS_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB813.html KAB8-13]).  This confirmed that the metal alone was not catalysing the cyclisation. 
 +
[[Image:Table03.PNG|thumb|center|700px]]
==Experimental Protocols for Catalyst Screening==
==Experimental Protocols for Catalyst Screening==
Line 215: Line 136:
[http://www.ourexperiment.org/data/files/3274/IMG_1283.jpeg MNR8 reaction to KAB1-2 TLC (60% EtOAc:Hex)] Starting material Rf = 0.2, Product Rf = 0.1, Enamide Rf = 0.33
[http://www.ourexperiment.org/data/files/3274/IMG_1283.jpeg MNR8 reaction to KAB1-2 TLC (60% EtOAc:Hex)] Starting material Rf = 0.2, Product Rf = 0.1, Enamide Rf = 0.33
<br><br>
<br><br>
-
[http://openwetware.org/images/e/e1/HPLC_kab1_25EtOH_05ml.pdf Chiral HPLC trace of KAB1 using 25% EtOH in hexane + 0.2% TEA.]
+
[http://openwetware.org/images/e/e1/HPLC_kab1_25EtOH_05ml.pdf Chiral HPLC trace of KAB1 using 25% EtOH in hexane + 0.2% TEA.] using a CHIRALCEL OD-H column and a flow rate of 0.5 mL/min
<br><br>
<br><br>
2-benzoyl-9,10-dimethoxy-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one ('''KAB8-16''')
2-benzoyl-9,10-dimethoxy-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one ('''KAB8-16''')
Line 225: Line 146:
[http://www.ourexperiment.org/data/files/3556/IMG_1410.jpg MNR10 reaction to KAB8-16 TLC (60% EtOAc:Hex)] Starting material Rf = 0.23, Product Rf = 0.15, Enamide Rf = 0.33
[http://www.ourexperiment.org/data/files/3556/IMG_1410.jpg MNR10 reaction to KAB8-16 TLC (60% EtOAc:Hex)] Starting material Rf = 0.23, Product Rf = 0.15, Enamide Rf = 0.33
<br><br>
<br><br>
-
[http://openwetware.org/images/a/a3/HPLC_kab8.pdfChiral HPLC trace of KAB8 using 25% EtOH in hexane + 0.2% TEA.]
+
[http://openwetware.org/images/a/a3/HPLC_kab8.pdf Chiral HPLC trace of KAB8 using 25% EtOH in hexane + 0.2% TEA.] using a CHIRALCEL OD-H column and a flow rate of 0.5 mL/min
-
 
+
-
 
+
-
-----------------------------------------------------------------------------
+
-
Analytical.
+
-
1H, 13C of Ugi S/M + links.
+
-
TLC of typical cyclizations.
+
-
HPLC of the reaction products.
+
-
Any other tips - e.g. concentrations/temperatures/solvents tried.
+
-
* Typical reaction protocol: dissolve peptide-acetal starting material in toluene to 1% (w/v). Add catalyst. Heat to 90 °C. Monitor by TLC. The faster the reaction mixture reaches temperature = fewer side-reactions (appears as fragmentation by TLC). Generally pre-heat the oil bath.\
+
-
* TLC stain: KMnO4. Enamide intermediate stains bright yellow. Starting materials first turn white, fade, then appear yellow. Product spot stains bright yellow.
+
-
* Dimethoxy N-benzoyl reaction mixture Rfs (EtOAc/hexane, v/v, X:X) - starting material:  Rf = 0.4, product: Rf = 0.3, enamide intermediate: Rf = 0.5. Unknown intermediates: Rfs = 0.35, X, X and X. Unknown intermediate spots appear, but eventually fade completely.
+
-
No isolated enamide, but some example NMRs with relevant peaks in.
+
==Outlook==
==Outlook==
Line 292: Line 201:
* WHO Business Plan 2008-2013 - Drug development and evaluation for helminths and other neglected tropical diseases [http://www.who.int/tdr/publications/about-tdr/business-plans/bl6-business-plan-2008-2013/en/index.html http://www.who.int/tdr/publications/about-tdr/business-plans/bl6-business-plan-2008-2013/en/index.html]<br>
* WHO Business Plan 2008-2013 - Drug development and evaluation for helminths and other neglected tropical diseases [http://www.who.int/tdr/publications/about-tdr/business-plans/bl6-business-plan-2008-2013/en/index.html http://www.who.int/tdr/publications/about-tdr/business-plans/bl6-business-plan-2008-2013/en/index.html]<br>
 +
 +
==Supporting Information==
 +
 +
 +
'''Synthesis of cylisation precursors using conventional stepwise approach'''
 +
[[Image:Stepwise_MW.png|thumb|center|650px| '''Scheme: Stepwise Formation of Pictet-Spengler Starting Materials''']]
 +
Synthesis of 3e: MW???
 +
Synthesis of 3f: MW9-3-79
 +
Synthesis of 4e: MW7-2-27
 +
Synthesis of 4f: MW14-3-79 (74%)
 +
Synthesis of 7a: MW29-4 (98%)
 +
Synthesis of 7b: MW32-3 (93%)
 +
''(What about &c and d by this route?)''
 +
 +
Synthesis of Ugi Isocyanides
 +
[[Image:Isocyanide.png|thumb|center|450px| '''Scheme X''': Formation of Isocyanides 6e and 6f.]]
 +
 +
Synthesis/Acquisition of Candidate Catalysts
 +
 +
'''N,N’-bis-3,5-bis[3,5-bis(trifluoromethyl)phenyl]-thiourea'''
 +
 +
This achiral version of a 'Jacobsens thiourea-catalyst' is a Bronsted-acid which is used for Screening pretests to evaluate if a reaction works under the choosen conditions without using expensive chiral versions of the catalyst. 
 +
 +
[[Image:N,N’-bis-3,5-bis(trifluoromethyl)phenyl-thiourea.png|thumb|center|500px]]
 +
 +
Procedure: [http://www.ourexperiment.org/racemic_pzq/547 Synthesis of N,N’-bis[3,5-bis(trifluoromethyl)phenyl-thiourea]
 +
 +
* Acid-free, organocatalytic acetalization, M. Kotke and P. R. Schreiner, Tetrahedron 2006, 62, 2-3, 434-439; [http://dx.doi.org/10.1016/j.tet.2005.09.079 doi:10.1016/j.tet.2005.09.079].
 +
 +
* Synthetic Studies toward Aryl-(4-aryl-4H-[1,2,4]triazole-3-yl)-amine from 1,3-Diarylthiourea as Urea Mimetics, A. Natarajan, Y. Guo, H. Arthanari, G. Wagner, J. A. Halperin and M. Chorev, J. Org. Chem. 2005, 70, 16, 6362–6368; [http://dx.doi.org/10.1021/jo0508189 DOI: 10.1021/jo0508189].
 +
 +
 +
'''(+/-)-BINOL-N-triflyl phosphoramide'''
 +
 +
Achiral version of a BINOL catalyst with an acidic NH-proton, commonly used for acid-catalysed asymmetric reaction 
 +
 +
[[Image:BINOL-N-triflyl phosphoramide.png|thumb|center|500px]]
 +
 +
Procedure: [http://www.ourexperiment.org/racemic_pzq/454 Preparation of (+/-)-BINOL-N-triflyl phosphoramide]
 +
 +
* [http://dx.doi.org/10.1021/ja062508t Design of Chiral N-Triflyl Phosphoramide as a Strong Chiral Brønsted Acid and Its Application to Asymmetric Diels-Alder Reaction, D. Nakashima and H. Yamamoto, J. Am. Chem. Soc. 2006, 128, 30, 9626–9627.]
 +
 +
 +
'''1,1-Binaphthyl-2,2-disulfonate'''
 +
 +
Strong acidic achiral BINOL catalyst wearing two sulfonic acid groups 
 +
 +
[[Image:Binaphtyl-disulfonic acid procedure.gif|thumb|center|500px]]
 +
 +
Procedure:
 +
 +
[http://www.ourexperiment.org/racemic_pzq/567 1. Step: 1,1’-Binaphthalene-2,2’-diyl-O,O’-bis(N,N’-dimethylthiocarbamate)]
 +
 +
[http://www.ourexperiment.org/racemic_pzq/583 2. Step: 1,1’-Binaphthalene-2,2’-diyl-S,S’-bis(N,N’-dimethylthiocarbamate)]
 +
 +
[http://www.ourexperiment.org/racemic_pzq/587 3. Step: 1,1’-Binaphthalene-2,2’-disulfonic acid]
 +
 +
 +
* Pyridinium 1,1′-Binaphthyl-2,2′-disulfonates as Highly Effective Chiral Brønsted Acid−Base Combined Salt Catalysts for Enantioselective Mannich-Type Reaction, M. Hatano, T. Maki, K. Moriyama, M. Arinobe and K. Ishihara, J. Am. Chem. Soc. 2008, 130, 16858–16860; [http://dx.doi.org/10.1021/ja806875c DOI: 10.1021/ja806875c].
 +
 +
* A Powerful Chiral Counteranion Motif for Asymmetric Catalysis, P. García-García, F. Lay, P. García-García, C. Rabalakos, B. List, Angew. Chem. Int. Ed. 2009, 48, 4363 –4366; [http://www3.interscience.wiley.com/journal/122382952/abstract DOI: 10.1002/anie.200901768].

Current revision

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Contents

Synthesis of (R)-Praziquantel via a Catalytic, Asymmetric Pictet-Spengler Reaction

Katrina A. Badiola, School of Chemistry, The University of Sydney, NSW 2006, Australia
Murray N. Robertson, School of Chemistry, The University of Sydney, NSW 2006, Australia
Matthew H. Todd, School of Chemistry, The University of Sydney, NSW 2006, Australia
Michael Woelfle, School of Chemistry, The University of Sydney, NSW 2006, Australia (Current address...)

(additional authors - add alphabetically. Please consider adding yourself and helping to write this paper, particularly if you have already helped out over at relevant The Synaptic Leap site)

(This article is a continually-updated summary of the results to date from the Electronic Lab Notebook: Pictet-Spengler Route to Praziquantel. The project is open source, meaning anyone can participate. This paper may be added to and edited by anyone. The project, and this page are currently active - when this changes <= these words will be changed (and you can see when the last edit of this page was at the bottom). References for this page may be found in full at the Mendeley page). If you want to get in touch to ask questions, you can use the talk page here, or directly insert a question on this page with your initials, or ask something at the Synaptic Leap or discuss with us via our Google+ pages: Mat, Murray, Kat.

Abstract

The Pictet-Spengler (PS) reaction has potential for the enantioselective synthesis of praziquantel (PZQ), the drug used worldwide for the treatment of the neglected tropical disease schistosomiasis. Following the recent identification of routes to enantiopure PZQ by classical resolution[Todd, PLoS, 2011, Todd, Nature Chemistry, 2011] we report here the progress to date on the synthesis of PZQ using the PS reaction. The approach employs a known peptide acetal precursor in an chiral Lewis acid (CLA) -catalyzed cyclization.

Scheme: The general reaction scheme for the enantioselective Pictet-Spengler reaction to PZQ using chiral Lewis acid (CLA) catalysis.
Scheme: The general reaction scheme for the enantioselective Pictet-Spengler reaction to PZQ using chiral Lewis acid (CLA) catalysis.

Introduction

The anthelmintic drug praziquantel (PZQ, 1a, Scheme 1) is widely used in the treatment of schistosomiasis and remains the only viable drug for the mass treatment of this disease.[Doenhoff, Curr Opin Infect Dis 2008] PZQ is synthesized and administered as a racemate, even though the inactive (S)-enantiomer is associated with side effects and is responsible for the bitter taste of the pill.[Miculka, PLoS, 2009] Administration of the pure active enantiomer is listed as a priority in the WHO business plan 2008-2013.[WHO Business Plan 2008-2013] Production of PZQ as a single enantiomer while keeping the price approximately as low as the racemate is a challenge - preparation of single enantiomers is more expensive than preparation of racemates, unless relevant stereochemistry is contained within available natural products, which is not the case for PZQ.

Efficient approaches to enantiopure PZQ via resolution of a synthetic precursor were recently developed, both by a collaborative open science community and a contract research organisation.[Todd, PLoS 2011] Resolution approaches are viable candidates for the large-scale preparation of PZQ on economic grounds. Yet there remain potentially very efficient approaches based on asymmetric catalysis that would have the advantage of not requiring either disposal or separation/recycling of the inactive enantiomer. The challenge is twofold: firstly to demonstrate a path to (R)-PZQ using asymmetric catalysis, and then to optimize the process to ensure the catalyst loading does not make such a route prohibitively expensive.

Besides an alternative separation of enantiomers based on chromatography,[Lui, J Pharm Sci, 20034] there has been a single report each of diastereo-[Zhang, J.Chem.Res., Synop 2004] and enantioselective[Czarnocki, Tet Asym 2006] syntheses of PZQ. These routes are not, however, realistic for the large-scale syntheses of PZQ, partly because they use synthetic routes that are not currently used for the large-scale synthesis of the racemate - de novo process optimization for these approaches is not likely to happen given the low profit margin associated with drugs for neglected tropical diseases.

A better approach is to take existing routes to the racemic drug, and make a key step asymmetric. PZQ was originally synthesized by a Reissert process,[Lobich, Cell Mol Life Science 1977] and it is likely that this process is currently used in at least one commercial-scale synthesis of PZQ. This route has the disadvantage of requiring a large amount of cyanide.[Shen Water Res, 2005] There are literature reports of catalytic, asymmetric Reissert processes,[Shibasaki JACS 2001, Guingant, Tet Let, 2005] but surprisingly there are no reports of this reaction being successfully applied to the system required for PZQ - isoquinoline. While the exact routes used to synthesize PZQ on a ton scale are not currently clear, it is likely that one of the main generics suppliers, Shin Poong, employs (or until recently employed) a published method that uses a Pictet-Spengler (PS) cyclization. [Kim, Tet, 1998] The key precursor to this cyclization, and hence the substrate for an asymmetric version of this reaction, is thus likely available in quantity, and can in any case be prepared by a recently-developed and more efficient route than that originally published.[Doemling Chem.Eur.J. 2010] A large-scale route to (R)-PZQ is hence a viable possibility via a Pictet-Spengler sequence if a catalyst could be found to effect the required cyclization.

Unfortunately the key cyclization is beyond the current state of the art. There is a small number of reports in the literature of catalytic, asymmetric Pictet-Spengler reactions.[List, JACS, 2006, Hiemstra, Angew. Chem. Int. Ed, 2007] In all cases the aromatic ring involved in the cyclization is electron rich, usually by virtue of containing one or more methoxy substituents. To the best of our knowledge there are no reports of catalytic, asymmetric Pictet-Spengler reactions involving a simple phenyl ring as the reactive aromatic component. Besides the route described above, other racemic syntheses of PZQ have used the PS reaction.[Doemling Chem.Eur.J. 2010]

Besides the substrate (7a) required for the synthesis of PZQ by a PS approach, three other peptide acetal starting materials are worthy of investigation: the benzoyl analog (7c) and the dimethoxy-functionalised analogs of both these structures (7b and 7d). The change from cyclohexanoyl to benzoyl might influence the ease of initial acetal cyclisation to generate an acyliminium ion, and the final product of the reaction, the benzoyl analog of PZQ (1c), may be easier to crystallise/purify. It would also be possible to convert the benzoyl PZQ analog fairly easily to PZQ.[Todd, PLoS, 2011] The two methoxy analogs are clearly of interest as they are more likely to participate in PS cyclizations. In fact the 6,7-di(MeO) analog of PZQ (7b) is itself biologically active,[Rao, BMCL,2012] so again, the effective production of this molecule is an attractive possible alternative to enantiopure PZQ if the synthesis of (R)-PZQ itself proves intractable.


Scheme 1. Approaches to the Synthesis of Praziquantel and Close Analogs via a Pictet-Spengler (PS) Reaction, and Traditional vs. Ugi methods for Construction of the PS Cyclization Precursors
Scheme 1. Approaches to the Synthesis of Praziquantel and Close Analogs via a Pictet-Spengler (PS) Reaction, and Traditional vs. Ugi methods for Construction of the PS Cyclization Precursors


Question for consideration: PS reactions challenging on rings with no EDG's, but how important is the amide in the reaction?

Literature: Examples of Catalytic, Enantioselective Pictet-Spengler Reactions

There is only currently a brief account of PS reactions on Wikipedia, and no page for the asymmetric version of the reaction. A review on The Catalytic, Asymmetric Pictet-Spengler Reactionis currently being assembled.

Results

1. Preparation of Cyclization Precursors

The peptide acetal precursors to the PS reaction (7a-d) can be made using a traditional stepwise approach[Kim Tet, 1998, Min Arch. Pharm. Res., 1998] or an Ugi 3-component coupling [Doemling Chem. Eur. J. 2010] (Scheme 1).

The conventional stepwise synthesis successfully gave the cyclisation precursors (need method summary and description of yields) (See Supporting Information).

Synthesis of these materials via Ugi multicomponent coupling was also successful and more convenient. Synthesis of the isocyanides 6e (MW34-3) and 6f (MNR4-2) was achieved via the Ugi formamide route from the corresponding amines following Doemling's 2-step procedure.[Ugi, Angew Int, 1972,Doemling PCT Int, 2009] Attempts to use a Hoffman-type procedure did give the desired product (MW34-1)in one step using chloroform as the source of Cl, but this approach proved less efficient, especially on scale up (MW34-2). Details may be found in the Supporting Information.

(need completion of summary of results here).

1b. ii) Ugi: Multicomponent Couplings

The desired Ugi products were then produced using the pre-formed isocyanides (MW34-3 and MNR4-2) and two different carboxylic acids (benzoic and cyclohexane) to give the four cyclization precursors, KAB5-2, MNR8-5, MW51-1, MNR10-2 in excellent yields.

Scheme: Formation of UGI products KAB5-1, MNR8-5, MW51-1 and MNR10-2.
Scheme: Formation of UGI products KAB5-1, MNR8-5, MW51-1 and MNR10-2.

An associated online discussion: Multistep synthesis of rac-PZQ (Ugi route)

2. Racemic Cyclizations

It has been shown in the literature that cyclisation of the peptide acetal intermediate via the Pictet-Spengler reaction occurs in the presence of very strong Bronsted acids. Previous examples include concentrated sulphuric acid [Kim, Tet, 1998] and methane sulfonic acid (MSA) [Doemling Chem.Eur.J. 2010].

The four Ugi products (KAB5-2, MNR8-5, MW51-1, MNR10-2) were subjected to varying loading levels of methanesulfonic acid to study its effect on the cyclisation. Initially the reactions were carried out in neat acid using 100 equivalents. The reaction to afford PZQ (MNR13-1) was the only one that did not give clean conversion to desired product at room temperature after 1 hour but all starting material was consumed. It was however found that increasing the reaction temperature to 60 °C resulted in conversion to PZQ in 70% yield (KAB3-8). The other analogues converted to desired product in similar yields (MNR14-1, MNR11-2 and MNR12-1). It should be noted that these yields are un-optimised. Reducing the level of methansulfonic acid to stoichiometric levels produced interesting results (KAB3-3, KAB7-1, KAB1-2 and KAB8-1). Following all four reactions by TLC it was clear to see consumption of starting material within 90 minutes however product spots were not observed for KAB3-3 and KAB7-1. Instead, isolated from these reactions were the corresponding enediamides KAB13 and UNK01. A similar result was found when carrying out the reactions using a catalytic 10 mol% of methanesulfonic acid.

The formation and isolation of the enediamide can be explained by looking at the proposed mechanism of the cyclisation. After formation of the first ring the iminium is formed by the loss of ethanol. This iminium can then tautomerise to the stable enediamide. Examples of when the phenyl ring is un-substituted don’t yield any of the desired product however examples where the ring is substituted with electron donation groups give exclusively the desired product with no enediamide being isolated.


2b Acid-catalysed Pictet-Spengler cyclisation.

2b i)Screening of racemic catalysts

Previously in the lab we’d tried several racemic Brønsted Acid and Thiourea Organocatalysts in an attempt to cyclise the Ugi intermediates. NMR studies using the thiourea (MW44)and phosphoramide (MW41) catalysts did not yield any reaction.

The BINAP-disulfonic acid (MW56-4and MNR11-8 ) however gave what looked like promising results based on LCMS analysis but at this stage the reaction requires further investigation on a larger scale.

Moving on triflic acid (TfOH) was screened as a catalyst for the Pictet-Spengler reaction using the four Ugi products from above. At a catalyst loading of 5 mol %, the desired product for the two electron rich systems (MNR8-5, MNR10-2) was isolated in excellent yields of 91 for KAB1-5and 96% for KAB8-14. Unfortunately, as with the previous examples, complete cyclisation was not observed for the other two examples (KAB3-2 and KAB7-3)and intermediate enediamide was isolated as the major product. Increasing catalyst loading did not help to push these reactions to completion (KAB3-12).

Continuing on, metal triflates were then studied with the potential of employing bisoxazoline ligands (BOX ligands) to generate chiral catalysts.[Nishiyama, Organometallics, 1989] Copper and silver triflate were investigated with the silver triflate being more extensively screened. Again as for the previous examples, electron rich systems (MNR8 and MNR10) cyclised and the desired products were isolated in 78 % of KAB1-6 and 87% for KAB8-15 with a catalyst loading of 10%. No further attempts at this stage were taken to reduce the catalyst loading any further. Also, as before, increasing the catalyst loading did not help to push KAB5-2 and MW51-1 to completion (see experiments KAB3-9 and KAB3-10). A negative control was also carried out using AgCl (table entry 6, KAB8-13). This confirmed that the metal alone was not catalysing the cyclisation.

Experimental Protocols for Catalyst Screening

Starting materials

N-(2,2-diethoxyethyl)-N-(2-((3,4-dimethoxyphenethyl)amino)-2-oxoethyl)cyclohexanecarboxamide (MNR8)

As a 50:50 mixture of rotamers

1H NMR (500 MHz, CDCl3): d= 6.80 (s, 0.5H), 6.79 (s, 0.5H), 6.74-6.70 (m, 2H), 4.73 (t, J = 5.1, 0.5H), 4.55 (t, J = 5.1 Hz, 0.5H), 4.04 (s, 1H), 3.99 (s, 1H), 3.88 (s, 1.5H), 3.88 (s, 1.5H), 3.85 (s, 3H), 3.77-3.65 (m, 2H), 3.55-3.41 (m, 6H), 2.79-2.65 (m, 2H), 2.31-2.23 (m, 1H), 1.81-1.71 (m, 2H), 1.71-1.58 (m, 3H), 1.53-1.36 (m, 2H), 1.31-1.13 (m, 9H). 13C NMR (125 MHz, CDCl3): d= 178.1, 177.7, 169.6, 169.3, 149.1, 149.0, 147.8, 147.6, 131.3, 131. 0, 129.0, 128.2, 120.6, 120.5, 111.9, 111.7, 111.4, 111.3, 101.3, 100.5, 64.1, 63.5, 55.9, 55.8, 54.0, 52.3, 52.1, 50.9, 41.0, 40.8, 40.6, 40.2, 40.1, 35.3, 35.2, 29.3, 29.2, 29.0, 25.7, 25.6, 25.6, 25.5, 15.3.

N-(2,2-diethoxyethyl)-N-(2-((3,4-dimethoxyphenethyl)amino)-2-oxoethyl)benzamide (MNR10)

As a 50:50 mixture of rotamers. Peaks not fully resolved at 300 K

1H NMR (500 MHz, CDCl3): d= 7.44-7.99 (m, 5H), 7.25 (br, NH), 6.84-6.66 (m, ,3H), 5.03 (br, 1H), 4.49 (br, 1H), 4.20 (br, 1H), 3.96 (br, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.66-3.15 (m, 8H), 2.85-2.72 (m, 2H), 1.23-1.03 (m, 6H). 13C NMR (125 MHz, CDCl3): d= 173.1, 168.9, 168.7, 149.1, 147.7, 135.4, 131.3, 130.3, 129.8, 128.5, 128.2, 127.0, 126.8, 120.7, 111.9, 111.4, 101.0, 100.5, 64.0, 63.4, 62.0, 55.9, 55.9, 55.4, 55.3, 53.4, 53.3, 51.4, 51.2, 40.7, 35.2, 15.4

General Procedure

Starting material (1 eq) and catalyst (0.05-0.5 eq) was dissolved in toluene (0.02 M). The reaction mixture was then taken quickly to 90 °C by placing in a pre-heated oil bath and monitored by TLC.

TLC stain: KMnO4. Product spot stains bright yellow.

2-(cyclohexanecarbonyl)-9,10-dimethoxy-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one (KAB1-2)

1H NMR (500 MHz, CDCl3): d= 6.73 (s, 1H), 6.64 (s, 1H), 5.11 (dd, J = 13.3, 2.6 Hz, 1H), 4.90-4.81 (m, 1H), 4.76-4.68 (m, 1H), 4.48 (s, 0.5H), 4.45 (s, 0.5H), 4.10 (s, 0.5), 4.06 (s, 0.5H), 3.87 (s, 3H), 2.98-2.75 (m, 3H), 2.70 (s, 0.5H), 2.67 (s, 0.5H), 2.53-2.43 (m, 1H), 1.91-1.67 (m, 5H), 1.62-1.48 (m, 2H), 1.36-1.22 (m, 3H). 13C NMR (125 MHz, CDCl3): d=174.9, 164.4, 148.3, 148.1, 126.9, 124.4, 111.7, 108.1, 56.1, 55.9, 54.8, 49.0, 45.4, 40.8, 39.2, 29.3, 29.0, 28.3, 25.7, 25.7, 25.7. Raw NMR data for KAB1-2 can be downloaded here

MNR8 reaction to KAB1-2 TLC (60% EtOAc:Hex) Starting material Rf = 0.2, Product Rf = 0.1, Enamide Rf = 0.33

Chiral HPLC trace of KAB1 using 25% EtOH in hexane + 0.2% TEA. using a CHIRALCEL OD-H column and a flow rate of 0.5 mL/min

2-benzoyl-9,10-dimethoxy-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one (KAB8-16)

1H NMR (500 MHz, CDCl3): d=7.56-7.39 (m, 5H), 6.81 (br, 1H), 6.65 (s, 1H), 5.20 (br, 1H), 4.98-4.75 (m, 2H), 4.34 (br, 1H), 4.17-4.02 (m, 1H), 3.87 (br, 6H), 3.06 (br, 1H), 2.97-2.79 (m, 2H), 2.73-2.64 (m, 1H). 13C NMR (125 MHz, CDCl3): d=170.3, 164.2, 148.4, 148.1, 134.2, 130.7, 128.7, 127.4, 127.1, 124.4, 111.8, 108.2, 56.2, 55.9, 54.5, 51.4, 46.1, 39.1, 28.3. Raw NMR data for KAB8-16 can be downloaded here

MNR10 reaction to KAB8-16 TLC (60% EtOAc:Hex) Starting material Rf = 0.23, Product Rf = 0.15, Enamide Rf = 0.33

Chiral HPLC trace of KAB8 using 25% EtOH in hexane + 0.2% TEA. using a CHIRALCEL OD-H column and a flow rate of 0.5 mL/min

Outlook

What we plan to do: Short term: finish screening Longer term: More catalysts known – List [draw]?, and work with others

What we need: Ideas for catalysts we haven’t tried, conditions and others


References

The references for this page may also be found in the relevant Mendeley Group.

  • Synthesis of Praziquantel via N-Acyliminium Ion Cyclization of Amido Acetals Through Several Synthetic Routes, J. H. Kim, Y. S. Lee and C. S. Kim, Heterocycles 1998, 48, 2279-2285. Paper
  • Formation of Pyrazinoisoquinoline Ring System by the Tandem Amidoalkylation and N-Acyliminium Ion Cyclization: An Efficient Synthesis of Praziquantel, J. H. Kim, Y. S. Lee, H. Park and C. S. Rim, Tetrahedron , 1998, 54, 7395-7400. (DOI: doi:10.1016/S0040-4020(98)00401-3)
  • Africa is Desperate for Praziquantel, P. J. Hotez, D. Engels, A. Fenwick and L. Savioli, Lancet 2010, 376, 496-498. (DOI: 10.1016/S0140-6736(10)60879-3)
  • Drugs for the Control of Parasitic Diseases: Current Status and Development. Schistosomiasis, A. Fenwick, L. Savioli, D. Engels, R. Bergquist and M. H. Todd, Trends Parasitol. 2003, 19, 509-515. (DOI: 10.1016/j.pt.2003.09.005)
  • Chemotherapy of Schistosomiasis: Present and Future, C. R. Caffrey, Curr. Opin. Chem. Biol. 2007, 11, 433-439. (DOI: 10.1016/j.cbpa.2007.05.031)
  • C. R. Caffrey, D. L. Williams, M. H. Todd, D. L. Nelson, J. Keiser J. and Utzinger, Chemotherapeutic Development Strategies for Schistosomiasis, in Antiparasitic and Antibacterial Drug Discovery: From Molecular Targets to Drug Candidates (ed P. M. Selzer), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2009. (DOI: 10.1002/9783527626816.ch16)
  • Praziquantel, P. Andrews, H. Thomas, R. Pohlke and J. Seubert, Med. Res. Rev. 1983, 3, 147-200. (DOI: 10.1002/med.2610030204)
  • Praziquantel, D. Cioli and L. Pica-Mattoccia, Parasitol. Res. 2003, 90, S3-S9. (DOI: 10.1007/s00436-002-0751-z)
  • Comparison of the Therapeutic Efficacy and Side Effects of a Single Dose of Levo-Praziquantel with Mixed Isomer Praziquantel in 278 Cases of Schistosomiasis Japonica, M.-H. Wu, C.-C. Wei, Z.-Y. Xu, H.-C. Yuan, W.-N. Lian, Q.-J. Yang, M. Chen, Q.-W. Jiang, C.-Z. Wang, S.-J. Zhang, Z.-D. Liu, R.-M. Wei, S.-J. Yuan, L.-S. Hu and Z.-S. Wu, Am J Trop Med Hyg 1991, 45, 345 - 349. (http://www.ajtmh.org/cgi/content/abstract/45/3/345)
  • Taste, A New Incentive to Switch to (R)-Praziquantel in Schistosomiasis Treatment, T. Meyer, H. Sekljic, S. Fuchs, H. Bothe, D. Schollmeyer and C. Miculka, PLoS Negl. Trop. Dis. 2009, 3, e357. (DOI: 10.1371/journal.pntd.0000357)
  • Solid Phase Synthesis of Praziquantel, S. El-Fayyoumy, W. Mansour and M. H. Todd, Tetrahedron Lett. 2006, 47, 1287-1290. (DOI: 10.1016/j.tetlet.2005.12.073)
  • Efficient Multicomponent Reaction Synthesis of the Schistosomiasis Drug Praziquantel, H. Cao, H. Liu, and A. Domling, Chem. Eur. J.. 2010, 16, 12296-12298. (DOI: 10.1002/chem.201002046)
  • Open Science is a Research Accelerator, M. Woelfle, P. Olliaro and M. H. Todd, Nature Chemistry 2011, 3, 745-748. Paper
  • Resolution of Praziquantel, M. Woelfle, J.-P. Seerden, J. de Gooijer, K. Pouwer, P. Olliaro and M. H. Todd, PLoS Negl. Trop. Dis. 2011, 5(9): e1260. Paper

Supporting Information

Synthesis of cylisation precursors using conventional stepwise approach

Scheme: Stepwise Formation of Pictet-Spengler Starting Materials
Scheme: Stepwise Formation of Pictet-Spengler Starting Materials

Synthesis of 3e: MW??? Synthesis of 3f: MW9-3-79 Synthesis of 4e: MW7-2-27 Synthesis of 4f: MW14-3-79 (74%) Synthesis of 7a: MW29-4 (98%) Synthesis of 7b: MW32-3 (93%) (What about &c and d by this route?)

Synthesis of Ugi Isocyanides

Scheme X: Formation of Isocyanides 6e and 6f.
Scheme X: Formation of Isocyanides 6e and 6f.

Synthesis/Acquisition of Candidate Catalysts

N,N’-bis-3,5-bis[3,5-bis(trifluoromethyl)phenyl]-thiourea

This achiral version of a 'Jacobsens thiourea-catalyst' is a Bronsted-acid which is used for Screening pretests to evaluate if a reaction works under the choosen conditions without using expensive chiral versions of the catalyst.

Procedure: Synthesis of N,N’-bis[3,5-bis(trifluoromethyl)phenyl-thiourea

  • Synthetic Studies toward Aryl-(4-aryl-4H-[1,2,4]triazole-3-yl)-amine from 1,3-Diarylthiourea as Urea Mimetics, A. Natarajan, Y. Guo, H. Arthanari, G. Wagner, J. A. Halperin and M. Chorev, J. Org. Chem. 2005, 70, 16, 6362–6368; DOI: 10.1021/jo0508189.


(+/-)-BINOL-N-triflyl phosphoramide

Achiral version of a BINOL catalyst with an acidic NH-proton, commonly used for acid-catalysed asymmetric reaction

Procedure: Preparation of (+/-)-BINOL-N-triflyl phosphoramide


1,1-Binaphthyl-2,2-disulfonate

Strong acidic achiral BINOL catalyst wearing two sulfonic acid groups

Procedure:

1. Step: 1,1’-Binaphthalene-2,2’-diyl-O,O’-bis(N,N’-dimethylthiocarbamate)

2. Step: 1,1’-Binaphthalene-2,2’-diyl-S,S’-bis(N,N’-dimethylthiocarbamate)

3. Step: 1,1’-Binaphthalene-2,2’-disulfonic acid


  • Pyridinium 1,1′-Binaphthyl-2,2′-disulfonates as Highly Effective Chiral Brønsted Acid−Base Combined Salt Catalysts for Enantioselective Mannich-Type Reaction, M. Hatano, T. Maki, K. Moriyama, M. Arinobe and K. Ishihara, J. Am. Chem. Soc. 2008, 130, 16858–16860; DOI: 10.1021/ja806875c.
  • A Powerful Chiral Counteranion Motif for Asymmetric Catalysis, P. García-García, F. Lay, P. García-García, C. Rabalakos, B. List, Angew. Chem. Int. Ed. 2009, 48, 4363 –4366; DOI: 10.1002/anie.200901768.
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