Todd:Pictet-Spengler to PZQ: Difference between revisions
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==Abstract== | ==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[[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. | 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:PZQ PS Synthesis Intro.png|thumb|center|600px| '''Scheme: The general reaction scheme for the enantioselective Pictet-Spengler reaction to PZQ using chiral Lewis acid (CLA) catalysis'''.]] | ||
==Introduction== | ==Introduction== | ||
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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. | ||
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 | 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> | ||
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 | 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> | ||
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. | 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== | ||
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> | 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=== | ||
The peptide acetal precursors '''7a-d''' | 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> | ||
''' | 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''' ([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> | |||
''(need completion of summary of results here)''. | |||
'' | |||
''1b. ii) Ugi: Multicomponent Couplings'' | ''1b. ii) Ugi: Multicomponent Couplings'' | ||
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===2. Racemic Cyclizations=== | ===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 [[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 | 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]]. | ||
[[Image: | [[Image:MSA1.png|thumb|center|500px]] | ||
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]] | ||
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. | |||
[[Image:PS_mech.png|thumb|centre|700px]] | |||
'''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 ([http://www.ourexperiment.org/racemic_pzq/525 MW44])and phosphoramide ([http://www.ourexperiment.org/racemic_pzq/464 MW41]) catalysts did not yield any reaction. | |||
[[Image:MW44.png|thumb|center|500px]] | [[Image:MW44.png|thumb|center|500px]] | ||
[[Image:MW41.png|thumb|center|500px]] | [[Image:MW41.png|thumb|center|500px]] | ||
[http://www.ourexperiment.org/racemic_pzq/ | 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] | ||
) 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]] | ||
[http://www.ourexperiment.org/racemic_pzq/ | 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]). | ||
[ | [[Image:KAB_cats_TfOH.png|thumb|center|500px]] | ||
[[Image:Table02.PNG|thumb|center|600px]] | [[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.[ | 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]] | [[Image:Table03.PNG|thumb|center|700px]] | ||
==Experimental Protocols for Catalyst Screening== | ==Experimental Protocols for Catalyst Screening== | ||
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[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''') | ||
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[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. | [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 | ||
==Outlook== | ==Outlook== | ||
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==Supporting Information== | ==Supporting Information== | ||
'''Synthesis of cyclisation 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.]] | |||
Approaches:<br> | |||
Amine, NaOH, chloroform, benzyltriethylammonium chloride: [http://www.ourexperiment.org/racemic_pzq/309 MW34-1], [http://www.ourexperiment.org/racemic_pzq/5197 MNR 21-4], [http://www.ourexperiment.org/racemic_pzq/3909 KAB 4-2]<br> | |||
Synthesis/Acquisition of Candidate Catalysts | Synthesis/Acquisition of Candidate Catalysts | ||
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* 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]. | * 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]. | ||
==Reaction Tally== | |||
'''Grouping of Reactions''' | |||
Kat Badiola assembled an [http://www.ourexperiment.org/racemic_pzq/4248/KAB_ExperimentCompound_Index.html experiment/compound index] | |||
[http://www.ourexperiment.org/racemic_pzq/5670/MW_Compound_Index.html Woelfle Compound Index] | |||
[http://www.ourexperiment.org/racemic_pzq/6122/YbOTf3_Catalysed_AcylPS__Summary_of_Conditions.html Summary of Yb(OTf)3 catalysed acyl-PS reactions] | |||
'''1a data summary''' | |||
[http://www.ourexperiment.org/racres_pzq/1700/Analytical_data_of_Praziquantel.html data] | |||
[http://www.ourexperiment.org/racres_pzq/2202/Optical_Rotation_Measurement_of_stored_MW_compounds.html Optical rotation over time] | |||
[http://www.ourexperiment.org/racres_pzq/2378/NCyclohexanoylprotection_of_MNR23_to_give_SPZQ_MNR13.html Another check of stability of PZQ] | |||
[http://www.ourexperiment.org/racres_pzq/2382/NCyclohexanoylprotection_of_MNR32_to_give_RPZQ_MNR91.html Another check of stability] | |||
[http://www.ourexperiment.org/racres_pzq/2451/MNR_Compounds_in_SDF_format.html MNR Compounds in SDF Format] | |||
[http://www.ourexperiment.org/racres_pzq/4225/MNR_Compound_Index.html MNR Compound Index] | |||
'''1a to 5e''' (hydrolysis of PZQ to PZQamine) | |||
[http://www.ourexperiment.org/racres_pzq/693/Hydrolysis_of_RPZQ_MW211.html MW2-11] R | |||
[http://www.ourexperiment.org/racres_pzq/696/Hydrolysis_of_SPZQ_MW212.html MW2-12] S | |||
[http://www.ourexperiment.org/racres_pzq/1175/Hydrolysis_of_racPZQ_MW213.html MW2-13] rac | |||
[http://www.ourexperiment.org/racres_pzq/1521/Hydrolysis_of_racPZQ_MW214.html MW2-14] rac | |||
[http://www.ourexperiment.org/racres_pzq/2332/Hydrolysis_of_racPZQ__MNR71_MNR72_MNR73_MNR74.html MNR7-1 MNR7-2 MNR7-3 MNR7-4] arc data taken for paper | |||
[http://www.ourexperiment.org/racres_pzq/3615/Hydrolysis_of_racPZQ__MNR75.html MNR7-5] | |||
[http://www.ourexperiment.org/racres_pzq/6075/Hydrolysis_of_racPZQ__MNR76.html MNR7-1] | |||
'''1b to 5f''' | |||
[http://www.ourexperiment.org/racres_pzq/5438/Hydrolysis_of_racMNR1113_to_give_MNR262.html MNR26-2] rac no data | |||
[http://www.ourexperiment.org/racres_pzq/5901/Hydrolysis_of_MNR1116_to_MNR264.html MNR26-4] NMR data | |||
[http://www.ourexperiment.org/racres_pzq/5911/Hydrolysis_of_MNR1117_to_MNR265.html MNR26-5] no data | |||
'''1d HPLC methods development''' | |||
[http://www.ourexperiment.org/racres_pzq/4313/Chiral_HPLC_method_development_for_the_dimethoxy_analogues.html HPLC methods development on KAB8-1] | |||
'''1d to 5f''' | |||
[http://www.ourexperiment.org/racres_pzq/4224/Hydrolysis_of_racMNR125_to_give_MNR261.html MNR26-1] rac | |||
[http://www.ourexperiment.org/racres_pzq/6889/Hydrolysis_of_KAB817_to_give_KAB1191.html KAB119-1] NMR | |||
[http://www.ourexperiment.org/racres_pzq/6911/Hydrolysis_of_KAB818_to_give_KAB1192.html KAB119-2] | |||
'''2e to 3e''' | |||
[http://www.ourexperiment.org/racres_pzq/5830/Preparation_of_MNR361.html MNT36-1] | |||
'''2e to 6e''' | |||
[http://www.ourexperiment.org/racemic_pzq/309/Preparation_of_2Phenylethyl_isocyanide_MW341.html MW34-1] Hofmann | |||
[http://www.ourexperiment.org/racemic_pzq/338/Scaleup__Preparation_of_2Phenylethyl_isocyanide_MW342.html MW34-2] Hofmann | |||
[http://www.ourexperiment.org/racemic_pzq/1564/Preparation_of_2phenylethyl_isocyanide__alternative_route__MW343.html MW34-3] Formamide | |||
[http://www.ourexperiment.org/racemic_pzq/2657/Preparation_of_2isocyanoethylbenzene_MNR211.html MNR21-1] continued in [http://www.ourexperiment.org/racemic_pzq/2864/Test_reaction_to_try_and_drive_MNR211_to_complete_product.html MNR21-2] Formamide | |||
[http://www.ourexperiment.org/racemic_pzq/2736/Preparation_of_2isocyanoethylbenzene_KAB41.html KAB4-1] Hofmann | |||
[http://www.ourexperiment.org/racemic_pzq/3909/Preparation_of_2isocyanoethylbenzene_KAB42.html KAB4-2] Hofmann | |||
[http://www.ourexperiment.org/racemic_pzq/5134/Preparation_of_2isocyanoethylbenzene_MNR213.html MNR21-3] Hofmann | |||
[http://www.ourexperiment.org/racemic_pzq/5197/Preparation_of_2isocyanoethylbenzene_MNR214.html MNR21-4] Hofmann | |||
'''2f to 3f''' | |||
[http://www.ourexperiment.org/racres_pzq/5764/Preparation_of_MNR341__Step_1_in_the_alternative_route_to_MNR26.html MNR34-1] | |||
[http://www.ourexperiment.org/racres_pzq/5827/Preparation_of_MNR342.html MNR34-2] | |||
'''2f to 6f''' | |||
[http://www.ourexperiment.org/racemic_pzq/357/Preparation_of_234Dimethoxyphenylethyl_isocyanide_MW37.html MW37] Hofmann | |||
[http://www.ourexperiment.org/racemic_pzq/1587/Preparation_of_234Dimethoxyphenylethyl_isocyanide_MW372.html MW37-2] Formamide | |||
[http://www.ourexperiment.org/racemic_pzq/2275/Preparation_of_234Dimethoxyphenylethyl_isocyanide_MNR41.html MNR4-1] Formamide | |||
[http://www.ourexperiment.org/racemic_pzq/3915/Preparation_of_234Dimethoxyphenylethyl_isocyanide_MNR42.html MNR4-2] Formamide | |||
[http://www.ourexperiment.org/racemic_pzq/5440/Preparation_of_234Dimethoxyphenylethyl_isocyanide_MNR43.html MNR4-3] Formamide | |||
[http://www.ourexperiment.org/racemic_pzq/5526/Preparation_of_234Dimethoxyphenylethyl_isocyanide_MNR44_and_MNR45.html MNR4-4, MNR4-5] Formamide | |||
'''3f to 4f''' | |||
[http://www.ourexperiment.org/racemic_pzq/171/MeO2derivative_of_PZQ_preparation_of_starting_material_MW14379.html MW14-3-79] | |||
[http://www.ourexperiment.org/racres_pzq/5795/Preparation_of_MNR351__Step_2_in_the_alternative_route_to_MNR26.html MNR35-1] | |||
[http://www.ourexperiment.org/racres_pzq/5815/Repeat_Preparation_of_MNR352__Step_2_in_the_alternative_route_to_MNR26.html MNR35-2] | |||
[http://www.ourexperiment.org/racres_pzq/5882/Preparation_of_MNR353.html MNR35-3] | |||
'''4e to 4a''' | |||
[http://www.ourexperiment.org/racemic_pzq/228/NCyclohexanoylprotection_of_the_amine_intermediate_MW7227_of_PZQ_MW291_to_MW293.html MW29-1, MW29-2, MW29-3] | |||
[http://www.ourexperiment.org/racemic_pzq/241/NCyclohexanoylprotection_of_the_amine_intermediate_MW7227_of_PZQ_Upscale_MW294.html MW29-4] | |||
'''4e to 5e''' | |||
[http://www.ourexperiment.org/racemic_pzq/464/Attempts_to_the_Bronstedtacid_catalysed_PictetSpengler_cyclization_using_BINOLNtriflyl_phosphoramide_MW41.html MW41] | |||
[http://www.ourexperiment.org/racemic_pzq/470/Cleavage_of_the_dimethoxy_acetal_of_222dimethoxyethylaminoNphenethylacetamide_hydrochloride_MW7_MW421_to_MW427.html MW42] | |||
[http://www.ourexperiment.org/racemic_pzq/525/Attempts_to_the_Bronstedtacid_catalysed_PictetSpengler_cyclization_using_NNbis35bistrifluoromethylphenylthiourea_MW44.html MW44] | |||
'''4f to 5f''' | |||
[http://www.ourexperiment.org/racemic_pzq/206/Attempts_to_the_acidmediated_PictetSpengler_cyclization_of_MW14_MW28180.html MW28-1-80] | |||
[http://www.ourexperiment.org/racemic_pzq/464/Attempts_to_the_Bronstedtacid_catalysed_PictetSpengler_cyclization_using_BINOLNtriflyl_phosphoramide_MW41.html MW41] | |||
[http://www.ourexperiment.org/racemic_pzq/525/Attempts_to_the_Bronstedtacid_catalysed_PictetSpengler_cyclization_using_NNbis35bistrifluoromethylphenylthiourea_MW44.html MW44] | |||
[http://www.ourexperiment.org/racres_pzq/5835/Excess_MSA_PS_reaction_of_MNR352_to_give_MNR263.html MNR26-3] | |||
'''4f to 7b''' | |||
[http://www.ourexperiment.org/racemic_pzq/267/NCyclohexanoylprotection_of_the_amine_intermediate_MW14_of_MeO2PZQ_MW32.html MW32] | |||
[http://www.ourexperiment.org/racemic_pzq/297/Upscaling_of_NCyclohexanoylprotection_of_the_amine_intermediate_MW14_of_MeO2PZQ_MW323.html MW32-3] | |||
'''5e (PZQamine) resolution''' | |||
[http://www.ourexperiment.org/racres_pzq/641/Diastereomeric_salt_resolution_of_praziquanamine_with_dipanisoylDtartaric_acid_MW471.html MW47-1] | |||
[http://www.ourexperiment.org/racres_pzq/683/Upscale_Diastereomeric_salt_resolution_of_praziquanamine_with_dipanisoylDtartaric_acid_MW472.html MW47-2] | |||
[http://www.ourexperiment.org/racres_pzq/1110/Diastereomeric_salt_resolution_of_praziquanamine_with_dipanisoylLtartaric_acid_obtainig_SPZQamine_MW473.html MW47-3] | |||
[http://www.ourexperiment.org/racres_pzq/1206/Racemic_resolution_of_praziquanamine_with_DibenzoylDtartaric_acid_MW491_to_MW494.html MW49-1 MW49-2 MW49-3 MW49-4] | |||
[http://www.ourexperiment.org/racres_pzq/1237/Racemic_resolution_of_praziquanamine_with_DibenzoylLtartaric_acid_MW495_to_MW4911.html MW49-5 MW49-6 MW49-7 MW49-8 MW49-9 MW49-10 MW49-11] | |||
[http://www.ourexperiment.org/racres_pzq/1265/Scaleup_Racemic_resolution_of_praziquanamine_with_DibenzoylLtartaric_acid_MW4912.html MW49-12] | |||
[http://www.ourexperiment.org/racres_pzq/1309/Multigramscale_racemic_resolution_of_praziquanamine_with_DibenzoylLtartaric_acid_MW4913.html MW49-13] | |||
[http://www.ourexperiment.org/racres_pzq/1523/Optimizing_the_racemic_resolution_of_praziquanamine_with_DibenzoylLtartaric_acid_MW4914.html MW49-14] | |||
[http://www.ourexperiment.org/racres_pzq/2228/Resolution_of_praziquanamine_with_dipanisoylLtartaric_acid_to_obtain_SPZQamine_MNR21.html MNR2-1] S | |||
[http://www.ourexperiment.org/racres_pzq/2240/Resolution_of_praziquanamine_with_dibenzoylDtartaric_acid_to_obtain_SPZQamine_MNR22.html MNR2-2] S | |||
[http://www.ourexperiment.org/racres_pzq/2351/Resolution_of_racPZQamine_with_dibenzoylLtartaric_acid_to_obtain_RPZQamine_MNR32.html MNR3-2] R optical measurement | |||
[http://www.ourexperiment.org/racres_pzq/2356/Resolution_of_racPZQamine_with_dibenzoylDtartaric_acid_to_obtain_SPZQamine_MNR23.html MNR2-3] S optical measurement | |||
[http://www.ourexperiment.org/racres_pzq/3749/Resolution_of_racPZQamine_with_dibenzoylDtartaric_acid_to_obtain_SPZQamine_MNR24.html MNR2] S mp | |||
[http://www.ourexperiment.org/racres_pzq/3750/Resolution_of_racPZQamine_with_dibenzoylLtartaric_acid_to_obtain_RPZQamine_MNR33.html MNR3-3] R no data | |||
'''5e purification''' | |||
[http://www.ourexperiment.org/racres_pzq/1530/Purifying_PZQamine_for_defining_a_phase_diagram.html Purification of PZQamine] | |||
[http://www.ourexperiment.org/racres_pzq/2202/Optical_Rotation_Measurement_of_stored_MW_compounds.html Optical rotation over time] | |||
'''5e to 1a''' | |||
[http://www.ourexperiment.org/racres_pzq/753/From_RPraziquanamine_to_RPraziquantel_MW481_NCyclohexanoylprotection_of_the_enantiopure_PZQamine.html MW48-1] R | |||
[http://www.ourexperiment.org/racres_pzq/758/From_SPraziquanamine_to_SPraziquantel_MW482_NCyclohexanoylprotection_of_the_enantiopure_PZQamine.html MW48-2] S | |||
[http://www.ourexperiment.org/racres_pzq/1298/NCyclohexanoylprotection_of_the_enantiopure_RPZQamine_MW483.html MW48-3] R | |||
[http://www.ourexperiment.org/racres_pzq/1468/NCyclohexanoylprotection_of_the_enantiopure_RPZQamine_in_a_multigram_scale_MW484.html MW48-4] | |||
[http://www.ourexperiment.org/racres_pzq/1536/NCyclohexanoylprotection_of_the_enantiopure_RPZQamine_to_PZQ_MW485.html MW48-5] | |||
[http://www.ourexperiment.org/racres_pzq/2178/Resynthesising_SPZQ_and_recrystallization.html MNR1-1] S | |||
[http://www.ourexperiment.org/racres_pzq/2241/NCyclohexanoylprotection_of_MNR22_to_give_SPZQ_MNR12.html MNR1-2] S | |||
[http://www.ourexperiment.org/racres_pzq/2378/NCyclohexanoylprotection_of_MNR23_to_give_SPZQ_MNR13.html MNR1-3] S | |||
[http://www.ourexperiment.org/racres_pzq/2382/NCyclohexanoylprotection_of_MNR32_to_give_RPZQ_MNR91.html MNR9-1] R VT-NMR and chiral HPLC | |||
'''5e to 1c''' | |||
[http://www.ourexperiment.org/enantio_hydgen/1949/Nbenzoylation_of_racPZQamine_MW581.html MW58-1] rac, lots of data | |||
[http://www.ourexperiment.org/racres_pzq/4111/Nbenzoyl_protection_of_MNR33_to_give_MNR241.html MNR24-1] R mp HPLC ee NMR | |||
[http://www.ourexperiment.org/racres_pzq/4112/Nbenzoyl_protection_of_MNR24_to_give_MNR251.html MNR25-1] S mp ee HPLC | |||
[http://www.ourexperiment.org/racres_pzq/6228/Nbenzoyl_protection_of_MNR76_to_give_MNR146.html MNR14-6] rac NMR IR | |||
'''5f resolution''' | |||
[http://www.ourexperiment.org/racres_pzq/4307/Resolution_of_MNR261with_dibenzoylLtartaric_acid_to_obtain_RdimethoxyPZQamine_MNR271.html MNR27-1] R HPLC traces | |||
[http://www.ourexperiment.org/racres_pzq/4528/Resolution_of_MNR261with_dibenzoylLtartaric_acid_to_obtain_RdimethoxyPZQamine_MNR272_MNR273_MNR274.html MNR27-2 MNR27-3 MNR27-4] R no data | |||
[http://www.ourexperiment.org/racres_pzq/4529/Screening_conditions_for_optimum_resolution_of_MNR261_to_MNR27X.html MNR27-2 MNR27-3 MNR27-4] R no data | |||
[http://www.ourexperiment.org/racres_pzq/4530/Screening_conditions_for_optimum_resolution_of_MNR261_to_MNR27X.html MNR27-2 MNR27-3 MNR27-4 MNR27-5 MNR27-6 MNR27-7 MNR27-8 MNR27-9 MNR27-10 MNR27-11] no data | |||
[http://www.ourexperiment.org/racres_pzq/4531/Screening_conditions_for_optimum_resolution_of_MNR261_to_MNR27X__continued.html MNR27-12 MNR27-13 MNR27-14 MNR27-15 MNR27-16 MNR27-17 MNR27-18 MNR27-19 MNR27-20 MNR27-21 MNR27-22 MNR27-23 MNR27-24 MNR27-25] various attempts | |||
[http://www.ourexperiment.org/racres_pzq/4886/Screening_conditions_for_optimum_resolution_of_MNR261_to_MNR27X__continued_II.html MNR27-26 MNR27-27 MNR27-28 MNR27-29] R no data | |||
[http://www.ourexperiment.org/racres_pzq/5082/Resolution_of_MNR261_with_dibenzoylDtartaric_acid_to_obtain_SdimethoxyPZQamine_MNR301.html MNR30-1] S no data | |||
[http://www.ourexperiment.org/racres_pzq/5378/Resolution_of_MNR261_with_dibenzoylDtartaric_acid_to_obtain_SdimethoxyPZQamine_MNR302.html MNR30-2] S 70% ee | |||
[http://www.ourexperiment.org/racres_pzq/5656/Resolution_of_MNR261_with_dibenzoylDtartaric_acid_to_obtain_SdimethoxyPZQamine_MNR303.html MNR30] S no data | |||
[http://www.ourexperiment.org/racres_pzq/5925/Resolution_of_MNR265_with_dibenzoylDtartaric_acid_to_obtain_SdimethoxyPZQamine_MNR307.html MNR30-7] S HPLC data, NMR | |||
[http://www.ourexperiment.org/racres_pzq/5935/Resolution_of_MNR265_with_dibenzoylDtartaric_acid_to_obtain_SdimethoxyPZQamine_MNR305.html MNR30-5] S no data | |||
[http://www.ourexperiment.org/racres_pzq/5936/Resolution_of_MNR265_with_dibenzoylDtartaric_acid_to_obtain_SdimethoxyPZQamine_MNR306.html MNR30-6] S 75% ee no data | |||
[http://www.ourexperiment.org/racres_pzq/6867/Resolution_of_MNR267_with_dibenzoylLtartaric_acid_to_obtain_MNR2726.html MNR27-26] no data | |||
[http://www.ourexperiment.org/racres_pzq/6870/Resolution_of_MNR267_with_dibenzoylLtartaric_acid_to_obtain_MNR2727_to_MNR2729.html MNR27-27 MNR27-28 MNR27-29] R no data | |||
[http://www.ourexperiment.org/racres_pzq/6890/Resolution_of_KAB1191_using_MNR61_KAB1201.html KAB120-1] R | |||
[http://www.ourexperiment.org/racres_pzq/6922/Resolution_of_KAB1192_using_MNR61_KAB1202.html KAB120-2] | |||
'''5f to 1b''' | |||
KAB130-1: S: DOI 10.6070/H4WS8R68 | |||
[http://www.ourexperiment.org/racres_pzq/4745/NCyclohexanoylprotection_of_MNR27_to_give_MNR28.html MNR28-1] R ee 12% | |||
[http://www.ourexperiment.org/racres_pzq/5064/NCyclohexanoylprotection_of_MNR27_to_give_MNR283.html MNR28-3] R chiral HPLC of KAB1-2 | |||
[http://www.ourexperiment.org/racres_pzq/5938/NCyclohexanoylprotection_of_MNR307_to_give_MNR381.html MNR38-1] S HPLC NMR | |||
'''5f to 1d''' | |||
KAB127-1: R: DOI 10.6070/H4T151MM | |||
KAB129-1: S: DOI 10.6070/H41J97PJ | |||
[http://www.ourexperiment.org/racres_pzq/5067/NCyclohexanoylprotection_of_MNR27_to_give_MNR311.html MNR31-1] R mp includes HPLC of arc, R and S | |||
[http://www.ourexperiment.org/racres_pzq/5942/Nbenzoyl_protection_of_MNR307_to_give_MNR391.html MNR39-1] S NMR HPLC mp | |||
'''6e to 7a''' | |||
[http://www.ourexperiment.org/racemic_pzq/321/Preparation_of_the_Ugiintermediate_via_Ugi_reaction_MW361.html MW36-1] methyl acetal | |||
[http://www.ourexperiment.org/racemic_pzq/404/Optimizing_conditions_for_the_Ugi_reaction_MW362_to_MW365.html MW36-2 to MW36-5] methyl acetal | |||
[http://www.ourexperiment.org/racemic_pzq/2801/Preparation_of_the_PZQ_analogue_Ugiintermediate_KAB51.html KAB5-1] | |||
[http://www.ourexperiment.org/racemic_pzq/4029/Preparation_of_the_PZQ_peptide_acetal_Ugiintermediate_KAB52.html KAB5-2] | |||
[http://www.ourexperiment.org/racemic_pzq/5190/Preparation_of_the_dimethoxy_Ugiintermediate_MNR321.html MNR32-1] | |||
'''6e to 7c''' | |||
[http://www.ourexperiment.org/racemic_pzq/1555/Preparation_of_the_Nbenzoylprotected_Ugiintermediate_MW511.html MW51-1] methyl acetal | |||
[http://www.ourexperiment.org/racemic_pzq/2667/Preparation_of_the_dimethoxy_Ugiintermediate_MNR221.html MNR22-1] | |||
[http://www.ourexperiment.org/racemic_pzq/2796/Preparation_of_the_Nbenzoyl_PZQ_analogue_Ugiintermediate_KAB61.html KAB6-1] | |||
[http://www.ourexperiment.org/racemic_pzq/5201/Preparation_of_the_Ugiintermediate_MNR222.html MNR22-2] | |||
'''6f to 7b''' | |||
[http://www.ourexperiment.org/racemic_pzq/386/Preparation_of_the_dimethoxy_Ugiintermediate_via_Ugi_reaction_MW40.html MW40] methyl acetal | |||
[http://www.ourexperiment.org/racemic_pzq/2339/Preparation_of_the_dimethoxy_Ugiintermediate_using_22Diethoxyethylamine.html MNR8-1] | |||
[http://www.ourexperiment.org/racemic_pzq/2392/Preparation_of_the_dimethoxy_Ugiintermediate_MNR82_using_22Diethoxyethylamine.html MNR8-2] | |||
[http://www.ourexperiment.org/racemic_pzq/4015/Preparation_of_the_dimethoxy_Ugiintermediate_MNR83.html MNR8-3] | |||
[http://www.ourexperiment.org/racemic_pzq/5525/Preparation_of_the_dimethoxy_Ugiintermediate_MNR84.html MNR8-4] | |||
[http://www.ourexperiment.org/racemic_pzq/5642/Preparation_of_the_dimethoxy_Ugiintermediate_MNR85.html MNR8-5] | |||
'''6f to 7d''' | |||
[http://www.ourexperiment.org/racemic_pzq/1597/Preparation_of_the_dimethoxybenzylNbenzoylderivative_of_the_Ugiintermediate_MW521.html MW52-1] methyl acetal | |||
[http://www.ourexperiment.org/racemic_pzq/2396/Preparation_of_the_dimethoxy_Ugiintermediate_MNR101_using_22Diethoxyethylamine.html MNR10-1] | |||
[http://www.ourexperiment.org/racemic_pzq/4011/Preparation_of_the_dimethoxy_Ugiintermediate_MNR102_and_MNR103.html MNR10-2 and MNR10-3] | |||
'''7a to 1a''' | |||
[http://www.ourexperiment.org/racemic_pzq/262/Attempts_to_the_acidmediated_PictetSpengler_cyclization_of_the_Ugi_intermediate_MW29_MW31.html MW31] | |||
[http://www.ourexperiment.org/racemic_pzq/464/Attempts_to_the_Bronstedtacid_catalysed_PictetSpengler_cyclization_using_BINOLNtriflyl_phosphoramide_MW41.html MW41] BINOL-N-triflyl phosphoramide catalyst | |||
[http://www.ourexperiment.org/racemic_pzq/525/Attempts_to_the_Bronstedtacid_catalysed_PictetSpengler_cyclization_using_NNbis35bistrifluoromethylphenylthiourea_MW44.html MW44] N,N’-bis[3,5-bis(trifluoromethyl)phenyl]thiourea | |||
[http://www.ourexperiment.org/racemic_pzq/1755/Acidcatalyzed_PictetSpengler_reaction_with_binaphthalenedisulfonic_acid_MW561_to_MW564.html MW56-1 to MW56-4] 1,1’-binaphthalene-2,2’-disulfonic acid catalyst | |||
[http://www.ourexperiment.org/racemic_pzq/1765/Acidcatalyzed_PictetSpengler_reaction_with_methanesulfonic_acid_MW565_to_MW568.html MW56-5 to MW56-8] | |||
[http://www.ourexperiment.org/racemic_pzq/1799/Continuation_Acidcatalyzed_PictetSpengler_reaction_with_methanesulfonic_acid_MW569_to_MW5614.html MW56-9 to MW56-14] | |||
[http://www.ourexperiment.org/racemic_pzq/2443/Acidmediated_PictetSpengler_of_MW29_to_give_racPZQ_MNR131.html MNR13-1] Excess MeSO3H, 0% yield | |||
[http://www.ourexperiment.org/racemic_pzq/2696/Stoichiometric_acidmediated_PictetSpengler_of_MW294_to_give_racemic_PZQ_KAB31_and_KAB32.html KAB3-1 and KAB3-2] | |||
[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, KAB8-1, KAB1-2 and KAB7-1] | |||
[http://www.ourexperiment.org/racemic_pzq/3138/Acidmediated_PictetSpengler_reaction_to_give_PZQ_KAB34_and_the_Nbenzoyl_PZQ_analogue_KAB72.html KAB3-4 and KAB7-2] | |||
[http://www.ourexperiment.org/racemic_pzq/3182/Acidmediated_PictetSpengler_reaction_to_give_PZQ_KAB35.html KAB3-5] | |||
[http://www.ourexperiment.org/racemic_pzq/3334/Reattempt_acidmediated_PictetSpengler_reaction_to_give_PZQ_KAB36.html KAB3-6] | |||
[http://www.ourexperiment.org/racemic_pzq/3385/Reducing_decomposition_in_the_acid_mediated_PictetSpengler_to_give_PZQ_KAB37.html KAB3-7] | |||
[http://www.ourexperiment.org/racemic_pzq/3445/The_PictetSpengler_reaction_to_give_PZQ_KAB38_in_neat_acid.html KAB3-8] Excess MeSO3H, heat, longer time, 70% yield | |||
[http://www.ourexperiment.org/racemic_pzq/3757/The_metal_triflate_catalysed_PictetSpengler_to_give_racemic_PZQ_KAB39__KAB310.html KAB3-9 and KAB3-10] | |||
[http://www.ourexperiment.org/racemic_pzq/3955/Partial_PS_reaction_to_give_the_PZQ_enediamide_intermediate_KAB131.html KAB13-1] attempt at enediamide | |||
[http://www.ourexperiment.org/racemic_pzq/4087/TfOH_catalysed_PS_reaction_to_give_PZQ_KAB311.html KAB3-11] | |||
[http://www.ourexperiment.org/racemic_pzq/4127/TfOH_catalysed_PS_reaction_to_give_PZQ_KAB312_to_KAB316.html KAB3-12, KAB3-13, KAB3-14, KAB3-15, KAB3-16] | |||
[http://www.ourexperiment.org/racemic_pzq/4187/Isolation_of_the_TfOH_catalysed_PS_to_PZQ_reaction_intermediates_KAB141.html KAB14-1] isolation of intermediates | |||
[http://www.ourexperiment.org/racemic_pzq/4453/TfOH_catalysed_PS_reaction_to_give_PZQ_KAB317.html KAB3-17] | |||
[http://www.ourexperiment.org/racemic_pzq/4540/TfOH_catalysed_partial_PS_reactions_to_give_the_enediamide_intermediates_of_PZQ_and_the_Nbenzoyl_analogue_KAB132__KAB171.html KAB13-2 and KAB17-1] synth of enediamide, 5 mol% TfOH, 88% yield | |||
[http://www.ourexperiment.org/racemic_pzq/5037/AgOTf_catalysed_PS_reaction_to_give_the_PZQ_enamide_KAB133.html KAB13-3] enediamide | |||
[http://www.ourexperiment.org/racemic_pzq/5721/Stoichiometric_MSA_PS_reaction_of_KAB52_to_give_MNR132.html MNR13-2] | |||
'''7b to 1b''' | |||
[http://www.ourexperiment.org/racemic_pzq/464/Attempts_to_the_Bronstedtacid_catalysed_PictetSpengler_cyclization_using_BINOLNtriflyl_phosphoramide_MW41.html MW41] | |||
[http://www.ourexperiment.org/racemic_pzq/525/Attempts_to_the_Bronstedtacid_catalysed_PictetSpengler_cyclization_using_NNbis35bistrifluoromethylphenylthiourea_MW44.html MW44] | |||
[http://www.ourexperiment.org/racemic_pzq/1755/Acidcatalyzed_PictetSpengler_reaction_with_binaphthalenedisulfonic_acid_MW561_to_MW564.html MW56-1 to MW56-4] | |||
[http://www.ourexperiment.org/racemic_pzq/1765/Acidcatalyzed_PictetSpengler_reaction_with_methanesulfonic_acid_MW565_to_MW568.html MW56-5 to MW56-8] | |||
[http://www.ourexperiment.org/racemic_pzq/2403/Acidmediated_PictetSpengler_of_MNR81_to_give_dimethoxy_PZQ_analog_MNR111.html MNR11-1] ethyl acetal | |||
[http://www.ourexperiment.org/racemic_pzq/2419/Acidmediated_PictetSpengler_of_MNR82_to_give_dimethoxy_PZQ_analog_MNR112.html MNR11-2] excess MeSO3H, rt, 69% yield | |||
[http://www.ourexperiment.org/racemic_pzq/2420/Acidmediated_PictetSpengler_of_MNR82_to_give_dimethoxy_PZQ_analog_MNR113.html MNR11-3] ethyl acetal | |||
[http://www.ourexperiment.org/racemic_pzq/2499/Acidcatalyzed_PictetSpengler_0f_MNR82_using_binaphthalenedisulfonic_acid_to_give_MNR11.html MNR11] | |||
[http://www.ourexperiment.org/racemic_pzq/2507/Stoichiometric_acidmediated_PictetSpengler_of_MNR82_to_give_dimethoxy_PZQ_analog_MNR119.html MNR11-9] | |||
[http://www.ourexperiment.org/racemic_pzq/2511/Catalytic_acidmediated_PictetSpengler_of_MNR82_to_give_dimethoxy_PZQ_analog_MNR1110.html MNR11-10] | |||
[http://www.ourexperiment.org/racemic_pzq/2524/Continuation_of_Acidcatalyzed_PictetSpengler_0f_MNR82_using_binaphthalenedisulfonic_acid_to_give_MNR11.html MNR11] | |||
[http://www.ourexperiment.org/racemic_pzq/2537/Attempts_to_imrove_the_acidcatalyzed_PictetSpengler_of_MNR82_using_binaphthalenedisulfonic_acid_to_give_MNR11.html MNR11] | |||
[http://www.ourexperiment.org/racemic_pzq/2672/Acidcatalyzed_PictetSpengler_of_MNR81_using_binapthalenedisulfonic_acid_to_give_KAB11.html KAB1-1] | |||
[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, KAB8-1, KAB1-2 and KAB7-1] | |||
[http://www.ourexperiment.org/racemic_pzq/4344/TfOH_catalysed_PS_reaction_to_give_the_dimethoxy_PZQ_analogue_KAB13.html KAB1-3] | |||
[http://www.ourexperiment.org/racemic_pzq/4380/TfOH_catalysed_PS_reaction_to_give_the_dimethoxy_PZQ_analogue_KAB14.html KAB1-4] used heavily, in paper, 10 mol% TfOH 99% yield | |||
[http://www.ourexperiment.org/racemic_pzq/4520/TfOH_catalysed_PS_reactions_to_give_the_dimethoxy_PZQ_analogues_KAB814__KAB15.html KAB8-14 and KAB1-5] continued as [http://www.ourexperiment.org/racemic_pzq/6441/mnr12X__duplicate_post_of_KAB814.html KAB8-14, KAB1-5 continued] used extensively, in paper, 5 mol% TfOH, 91% yield | |||
[http://www.ourexperiment.org/racemic_pzq/4755/AgOTf_catalysed_PS_reaction_to_give_the_dimethoxy_PZQ_analogue_KAB16.html KAB1-6] 10 mol% silver triflate example 78% yield | |||
[http://www.ourexperiment.org/racemic_pzq/5407/TfOH_catalysed_PS_reaction_of_MNR83_to_give_MNR1113.html MNR11-13] | |||
[http://www.ourexperiment.org/racemic_pzq/5718/TfOH_catalysed_PS_reaction_of_MNR85_to_give_MNR1114.html MNR11-14] | |||
[http://www.ourexperiment.org/racemic_pzq/5719/Stoichiometric_MSA_PS_reaction_of_MNR85_to_give_MNR1115.html MNR11-15] | |||
[http://www.ourexperiment.org/racemic_pzq/5894/Synthesis_of_MNR1116.html MNR11-16] | |||
[http://www.ourexperiment.org/racemic_pzq/5898/Synthesis_of_MNR1117.html MNR11-17] | |||
[http://www.ourexperiment.org/racemic_pzq/6847/Synthesis_of_MNR1118.html MNR11-18] | |||
'''7c to 1c''' | |||
[http://www.ourexperiment.org/racemic_pzq/1617/Acidmediated_PictetSpengler_of_the_NbenzoylUgi_intermediate_MW531_to_MW533.html MW53-1 to MW53-3] | |||
[http://www.ourexperiment.org/racemic_pzq/1654/Synthesis_of_the_Nbenzoylderivative_of_PZQ__via_PictetSpengler_reaction_MW534.html MW53-4] | |||
[http://www.ourexperiment.org/racemic_pzq/1755/Acidcatalyzed_PictetSpengler_reaction_with_binaphthalenedisulfonic_acid_MW561_to_MW564.html MW56-1 to MW56-4] | |||
[http://www.ourexperiment.org/racemic_pzq/1765/Acidcatalyzed_PictetSpengler_reaction_with_methanesulfonic_acid_MW565_to_MW568.html MW56-5 to MW56-8] | |||
[http://www.ourexperiment.org/racemic_pzq/1799/Continuation_Acidcatalyzed_PictetSpengler_reaction_with_methanesulfonic_acid_MW569_to_MW5614.html MW56-9 to MW56-14] | |||
[http://www.ourexperiment.org/racemic_pzq/2447/Acidmediated_PictetSpengler_of_MW51_to_give_Nbenzoylderivative_of_PZQ_MNR141.html MNR14-1] continued as [http://www.ourexperiment.org/racemic_pzq/2689/Acidmediated_PictetSpengler_of_MW51_to_give_Nbenzoylderivative_of_PZQ_MNR141_cont.html MNR14-1] Excess MeSO3H, rt, 70% yield | |||
[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, KAB8-1, KAB1-2 and KAB7-1] | |||
[http://www.ourexperiment.org/racemic_pzq/3138/Acidmediated_PictetSpengler_reaction_to_give_PZQ_KAB34_and_the_Nbenzoyl_PZQ_analogue_KAB72.html KAB3-4 and KAB7-2] | |||
[http://www.ourexperiment.org/racemic_pzq/3330/Acidmediated_PictetSpengler_of_KAB61_to_give_Nbenzoylderivative_of_PZQ_MNR142.html MNR14-2] | |||
[http://www.ourexperiment.org/racemic_pzq/4441/TfOH_catalysed_PS_reaction_to_give_the_Nbenzoyl_PZQ_analogue_KAB73.html KAB7-3] 10 mol% TfOH, 93%, enediamide | |||
[http://www.ourexperiment.org/racemic_pzq/4540/TfOH_catalysed_partial_PS_reactions_to_give_the_enediamide_intermediates_of_PZQ_and_the_Nbenzoyl_analogue_KAB132__KAB171.html KAB13-2 and KAB17-1] synth of enediamide | |||
[http://www.ourexperiment.org/racemic_pzq/4805/AgOTf_catalysed_partial_PS_reaction_to_give_the_Nbenzoyl_PZQ_analogue_enamide_KAB172.html KAB17-2] enediamide | |||
[http://www.ourexperiment.org/racemic_pzq/5722/Stoichiometric_MSA_PS_reaction_of_KAB61_to_give_MNR143.html MNR14-3] | |||
[http://www.ourexperiment.org/racemic_pzq/5918/Excess_MSA_PS_reaction_of_MNR22__The_Synthesis_of_MNR144.html MNR14-4] | |||
[http://www.ourexperiment.org/racemic_pzq/5934/The_Synthesis_of_MNR145.html MNR14-5] | |||
'''7d to 1d''' | |||
[http://www.ourexperiment.org/racemic_pzq/1643/Acidmediated_PictetSpengler_of_the_dimethoxyNbenzoylUgi_intermediate_MW541_to_MW542.html MW54-1 to MW54-2] | |||
[http://www.ourexperiment.org/racemic_pzq/1658/Synthesis_of_the_dimethoxyNbenzoylderivative_of_PZQ_via_PictetSpengler_reaction_MW543.html MW54-3] | |||
[http://www.ourexperiment.org/racemic_pzq/1755/Acidcatalyzed_PictetSpengler_reaction_with_binaphthalenedisulfonic_acid_MW561_to_MW564.html MW56-1 to MW56-4] | |||
[http://www.ourexperiment.org/racemic_pzq/1765/Acidcatalyzed_PictetSpengler_reaction_with_methanesulfonic_acid_MW565_to_MW568.html MW56-5 to MW56-8] | |||
[http://www.ourexperiment.org/racemic_pzq/2421/Acidmediated_PictetSpengler_of_MNR82_to_give_dimethoxyNbenzoylderivative_of_PZQ_MNR121.html MNR12-1] ethyl acetal continued in [http://www.ourexperiment.org/racemic_pzq/3043/Acidmediated_PictetSpengler_of_MNR82_to_give_dimethoxyNbenzoylderivative_of_PZQ_MNR121__continued.html MNR12-1] Excess MeSO3H, rt, 93% yield | |||
[http://www.ourexperiment.org/racemic_pzq/2422/Acidmediated_PictetSpengler_of_MNR82_to_give_dimethoxyNbenzoylderivative_of_PZQ_MNR122.html MNR12-2] ethyl acetal continued in [http://www.ourexperiment.org/racemic_pzq/3047/Acidmediated_PictetSpengler_of_MNR82_to_give_dimethoxyNbenzoylderivative_of_PZQ_MNR122.html MNR12-2] | |||
[http://www.ourexperiment.org/racemic_pzq/2541/Attempts_to_imrove_the_acidcatalyzed_PictetSpengler_of_MNR101_using_binaphthalenedisulfonic_acid_to_give_MNR12.html MNR12] | |||
7d purification: [http://www.ourexperiment.org/racemic_pzq/2678/Purification_of_MNR121_and_MNR122_to_give_KAB21_the_dimethoxyNbenzoyl_PZQ_analogue.html KAB2-1] | |||
[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, KAB8-1, KAB1-2 and KAB7-1] | |||
[http://www.ourexperiment.org/racemic_pzq/3509/Acidcatalyzed_PS_reaction_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB82.html KAB8-2] | |||
[http://www.ourexperiment.org/racemic_pzq/3566/Lewis_acid_catalysed_preparation_of_the_dimethoxy_Nbenzoyl_PZQ_enediamide_KAB111.html KAB11-1] attempt at enediamide | |||
[http://www.ourexperiment.org/racemic_pzq/3598/SilverI_triflate_catalysed_preparation_of_the_dimethoxy_Nbenzoyl_PZQ_enediamide_KAB112.html KAB11-2] attempt at enediamide | |||
[http://www.ourexperiment.org/racemic_pzq/3607/CopperII_triflate_catalysed_preparation_of_the_dimethoxy_Nbenzoyl_PZQ_enediamide_KAB113.html KAB11-3] attempt at enediamide | |||
[http://www.ourexperiment.org/racemic_pzq/3659/The_copperII_triflate_catalysed_PS_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB83.html KAB8-3] | |||
[http://www.ourexperiment.org/racemic_pzq/3660/The_silverI_triflate_catalysed_PS_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB84.html KAB8-4] | |||
[http://www.ourexperiment.org/racemic_pzq/3850/Enediamide_intermediate_cyclisation_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB121.html KAB12-1] from intermediate enediamide | |||
[http://www.ourexperiment.org/racemic_pzq/3873/Controls_for_the_AgOTf_catalysed_PS_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB85__KAB86.html KAB8-5 and KAB8-6] | |||
[http://www.ourexperiment.org/racemic_pzq/3912/TfOH_catalysed_PS_reaction_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB87__KAB88.html KAB8-7 and KAB8-8] | |||
[http://www.ourexperiment.org/racemic_pzq/3936/TfOH_catalysed_PS_reaction_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB89.html KAB8-9] | |||
[http://www.ourexperiment.org/racemic_pzq/4080/AgOTf_catalysed_PS_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB810.html KAB8-10] | |||
[http://www.ourexperiment.org/racemic_pzq/4097/TfOH_catalysed_PS_reaction_of_MNR102_to_give_MNR125.html MNR12-5] | |||
[http://www.ourexperiment.org/racemic_pzq/4323/The_TfOH_catalysed_PS_reaction_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB811.html KAB8-11] | |||
[http://www.ourexperiment.org/racemic_pzq/4376/The_TfOH_catalysed_PS_reaction_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB812.html KAB8-12] in paper, 10 mol% TfOH, 92% yield | |||
[http://www.ourexperiment.org/racemic_pzq/4510/AgCl_catalysed_PS_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB813.html KAB8-13] Silver chloride control, no conversion. | |||
[http://www.ourexperiment.org/racemic_pzq/4520/TfOH_catalysed_PS_reactions_to_give_the_dimethoxy_PZQ_analogues_KAB814__KAB15.html KAB8-14 and KAB1-5] in paper, 5 mol% TfOH, 96% yield | |||
[http://www.ourexperiment.org/racemic_pzq/4684/AgOTf_catalysed_PS_reaction_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB815.html KAB8-15] Used in paper. 10 mol% silver triflate. Anhydrous, 87% yield. | |||
[http://www.ourexperiment.org/racemic_pzq/4856/AgOTf_catalysed_PS_reaction_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB816.html KAB8-16] | |||
[http://www.ourexperiment.org/racemic_pzq/5298/Preparation_of_the_dimethoxy_Nbenzoyl_PZQ_enediamide_MNR331.html MNR33-1] enediamide | |||
[http://www.ourexperiment.org/racemic_pzq/5720/Stoichiometric_MSA_PS_reaction_of_MNR101_to_give_MNR126_MNR127.html MNR12-6, MNR12-7] | |||
[http://www.ourexperiment.org/racres_pzq/6882/Preparation_of_dimethoxyPZQ_KAB817.html KAB8-17] | |||
[http://www.ourexperiment.org/racres_pzq/6910/Preparing_more_material_dimethoxyPZQ_KAB818.html KAB8-18] | |||
'''Catalyst/Ligand Preparations''' | |||
[http://www.ourexperiment.org/racemic_pzq/363/Preparation_of_trifluoromethane_sulfonamide_MW38.html MW38] | |||
[http://www.ourexperiment.org/racemic_pzq/372/Preparation_of_BINOLNtriflyl_phosphoramide_MW39.html MW39] | |||
[http://www.ourexperiment.org/racemic_pzq/454/Repeating_the_preparation_of_BINOLNtriflyl_phosphoramide_MW392.html MW39-2] | |||
[http://www.ourexperiment.org/racemic_pzq/496/Preparation_of_NNbis35bistrifluoromethylphenylthiourea_MW431.html MW43-1] | |||
[http://www.ourexperiment.org/racemic_pzq/547/Repetition_of_the_synthesis_of_NNbis35bistrifluoromethylphenylthiourea_MW432.html MW43-2] | |||
[http://www.ourexperiment.org/racemic_pzq/567/Preparation_of_11Binaphthalene22diylOObisNNdimethylthiocarbamate__MW451.html MW45-1] | |||
[http://www.ourexperiment.org/racemic_pzq/583/Preparation_of_11Binaphthalene22diylSSbisNNdimethylthiocarbamate_MW452.html MW45-2] | |||
[http://www.ourexperiment.org/racemic_pzq/587/Preparation_of_11Binaphthalene22disulfonic_acid_MW453.html MW45-3] | |||
[http://www.ourexperiment.org/racemic_pzq/2559/Preparation_of_ROO11binaphthyl22diyl_bisdimethylcarbamothioate_MNR151.html MNR15-1] | |||
[http://www.ourexperiment.org/racemic_pzq/2565/Preparation_of_SOO11binaphthyl22diyl_bisdimethylcarbamothioate_MNR161.html MNR16-1] | |||
[http://www.ourexperiment.org/racemic_pzq/2574/Preparation_of_RSS11binaphthyl22diyl_bisdimethylcarbamothioate_MNR171_from_MNR151.html MNR17-1] | |||
[http://www.ourexperiment.org/racemic_pzq/2580/Preparation_of_SSS11binaphthyl22diyl_bisdimethylcarbamothioate_MNR181_from_MNR161.html MNR 18-1] | |||
[http://www.ourexperiment.org/racemic_pzq/2588/Preparation_of_racOO11binaphthyl22diyl_bisdimethylcarbamothioate_MNR191.html MNR19-1] | |||
[http://www.ourexperiment.org/racemic_pzq/2592/Preparation_of_racSS11binaphthyl22diyl_bisdimethylcarbamothioate_MNR20_from_MNR191.html MNR20-1 through MNR20-6] | |||
[http://www.ourexperiment.org/racemic_pzq/2616/Repeat_of_MNR151_Preparation_of_ROO11binaphthyl22diyl_bisdimethylcarbamothioate_MNR152.html MNR15-2] | |||
[http://www.ourexperiment.org/racemic_pzq/2617/Repeat_of_MNR161_Preparation_of_SOO11binaphthyl22diyl_bisdimethylcarbamothioate_MNR162.html MNR16-2] | |||
[http://www.ourexperiment.org/racemic_pzq/2699/Preparation_of_racSS11binaphthyl22diyl_bisdimethylcarbamothioate_MNR20_from_MNR191.html MNR19-1] | |||
[http://www.ourexperiment.org/racemic_pzq/3056/Microwave_assisited_preparation_of_racSS11binaphthyl22diyl_bisdimethylcarbamothioate_MNR20_from_MNR191.html MNR20-9 and MNR20-10] | |||
[http://www.ourexperiment.org/racemic_pzq/3124/Attempts_to_improve_the_preparation_of_racOO11binaphthyl22diyl_bisdimethylcarbamothioate_MNR19.html MNR19-2, MNR19-3, MNR19-4] | |||
[http://www.ourexperiment.org/racemic_pzq/3178/Further_attempts_to_convert_MNR19_to_MNR20_efficiently_using_DMA_as_a_solvent.html MNR20-11, MNR20-12, MNR20-13, MNR20-14, MNR20-15] | |||
[http://www.ourexperiment.org/racemic_pzq/3514/Preparation_of_Imidobissulfuryl_chloride_MNR231.html MNR23-1] | |||
[http://www.ourexperiment.org/racemic_pzq/4276/Preparation_of_Imidobissulfuryl_chloride_KAB151.html KAB15-1] | |||
[http://www.ourexperiment.org/racemic_pzq/4539/Synthesis_of_11Binaphthyl22bissulfurylimide12Et2O_KAB161.html KAB16-1] | |||
'''Different Routes''' | |||
'''Cbz''' | |||
[http://www.ourexperiment.org/racemic_pzq/305/Cbzprotection_of_the_amine_intermediate_of_PZQ_MW7227_MW33.html MW33] | |||
Toluene reactions with acid | |||
[http://www.ourexperiment.org/racemic_pzq/3454/Observation_of_toluenemethanesulfonic_acid_mixture_KAB91.html KAB9-1] | |||
'''Praziquanamine from PZQ hydrolysis''' | |||
[http://www.ourexperiment.org/racemic_pzq/3530/Hydrolyis_of_racPraziquantel_to_give_PZQamine_KAB101.html KAB10-1] | |||
'''MeO-praziquanamine (5f) from hydrolysis of MeO-PZQ (1b)''' | |||
[http://www.ourexperiment.org/racemic_pzq/6848/Hydrolysis_of_MNR1118_to_give_MNR267.html MNR26-7] |
Latest revision as of 06:29, 24 August 2015
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...)
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(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.
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.
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.
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.
- Reissert Approach to PZQ: Synaptic Leap Summary
- Shin Poong/Peptide Acetal approach to PZQ: Synaptic Leap Summary
- 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)
- Ugi route to peptide acetal precursor: Synaptic Leap Summary
- 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)
- Drug Development and Evaluation for Helminths and Other Neglected Tropical Diseases: Business Plan 2008-2013, WHO/TDR, May 2007. (http://apps.who.int/tdr/svc/publications/about-tdr/business-plans/bl6-business-plan-2008-2013)
- 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
- 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
Supporting Information
Synthesis of cyclisation precursors using conventional stepwise approach
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
Approaches:
Amine, NaOH, chloroform, benzyltriethylammonium chloride: MW34-1, MNR 21-4, KAB 4-2
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
- Acid-free, organocatalytic acetalization, M. Kotke and P. R. Schreiner, Tetrahedron 2006, 62, 2-3, 434-439; 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; 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.
Reaction Tally
Grouping of Reactions
Kat Badiola assembled an experiment/compound index
Summary of Yb(OTf)3 catalysed acyl-PS reactions
1a data summary
Another check of stability of PZQ
1a to 5e (hydrolysis of PZQ to PZQamine)
MW2-11 R
MW2-12 S
MW2-13 rac
MW2-14 rac
MNR7-1 MNR7-2 MNR7-3 MNR7-4 arc data taken for paper
1b to 5f
MNR26-2 rac no data
MNR26-4 NMR data
MNR26-5 no data
1d HPLC methods development
HPLC methods development on KAB8-1
1d to 5f
MNR26-1 rac
KAB119-1 NMR
2e to 3e
2e to 6e
MW34-1 Hofmann
MW34-2 Hofmann
MW34-3 Formamide
MNR21-1 continued in MNR21-2 Formamide
KAB4-1 Hofmann
KAB4-2 Hofmann
MNR21-3 Hofmann
MNR21-4 Hofmann
2f to 3f
2f to 6f
MW37 Hofmann
MW37-2 Formamide
MNR4-1 Formamide
MNR4-2 Formamide
MNR4-3 Formamide
MNR4-4, MNR4-5 Formamide
3f to 4f
4e to 4a
4e to 5e
4f to 5f
4f to 7b
5e (PZQamine) resolution
MW49-5 MW49-6 MW49-7 MW49-8 MW49-9 MW49-10 MW49-11
MNR2-1 S
MNR2-2 S
MNR3-2 R optical measurement
MNR2-3 S optical measurement
MNR2 S mp
MNR3-3 R no data
5e purification
5e to 1a
MW48-1 R
MW48-2 S
MW48-3 R
MNR1-1 S
MNR1-2 S
MNR1-3 S
MNR9-1 R VT-NMR and chiral HPLC
5e to 1c
MW58-1 rac, lots of data
MNR24-1 R mp HPLC ee NMR
MNR25-1 S mp ee HPLC
MNR14-6 rac NMR IR
5f resolution
MNR27-1 R HPLC traces
MNR27-2 MNR27-3 MNR27-4 R no data
MNR27-2 MNR27-3 MNR27-4 R no data
MNR27-2 MNR27-3 MNR27-4 MNR27-5 MNR27-6 MNR27-7 MNR27-8 MNR27-9 MNR27-10 MNR27-11 no data
MNR27-12 MNR27-13 MNR27-14 MNR27-15 MNR27-16 MNR27-17 MNR27-18 MNR27-19 MNR27-20 MNR27-21 MNR27-22 MNR27-23 MNR27-24 MNR27-25 various attempts
MNR27-26 MNR27-27 MNR27-28 MNR27-29 R no data
MNR30-1 S no data
MNR30-2 S 70% ee
MNR30 S no data
MNR30-7 S HPLC data, NMR
MNR30-5 S no data
MNR30-6 S 75% ee no data
MNR27-26 no data
MNR27-27 MNR27-28 MNR27-29 R no data
KAB120-1 R
5f to 1b
KAB130-1: S: DOI 10.6070/H4WS8R68
MNR28-1 R ee 12%
MNR28-3 R chiral HPLC of KAB1-2
MNR38-1 S HPLC NMR
5f to 1d
KAB127-1: R: DOI 10.6070/H4T151MM
KAB129-1: S: DOI 10.6070/H41J97PJ
MNR31-1 R mp includes HPLC of arc, R and S
MNR39-1 S NMR HPLC mp
6e to 7a
MW36-1 methyl acetal
MW36-2 to MW36-5 methyl acetal
6e to 7c
MW51-1 methyl acetal
6f to 7b
MW40 methyl acetal
6f to 7d
MW52-1 methyl acetal
7a to 1a
MW41 BINOL-N-triflyl phosphoramide catalyst
MW44 N,N’-bis[3,5-bis(trifluoromethyl)phenyl]thiourea
MW56-1 to MW56-4 1,1’-binaphthalene-2,2’-disulfonic acid catalyst
MNR13-1 Excess MeSO3H, 0% yield
KAB3-3, KAB8-1, KAB1-2 and KAB7-1
KAB3-8 Excess MeSO3H, heat, longer time, 70% yield
KAB13-1 attempt at enediamide
KAB3-12, KAB3-13, KAB3-14, KAB3-15, KAB3-16
KAB14-1 isolation of intermediates
KAB13-2 and KAB17-1 synth of enediamide, 5 mol% TfOH, 88% yield
KAB13-3 enediamide
7b to 1b
MNR11-1 ethyl acetal
MNR11-2 excess MeSO3H, rt, 69% yield
MNR11-3 ethyl acetal
KAB3-3, KAB8-1, KAB1-2 and KAB7-1
KAB1-4 used heavily, in paper, 10 mol% TfOH 99% yield
KAB8-14 and KAB1-5 continued as KAB8-14, KAB1-5 continued used extensively, in paper, 5 mol% TfOH, 91% yield
KAB1-6 10 mol% silver triflate example 78% yield
7c to 1c
MNR14-1 continued as MNR14-1 Excess MeSO3H, rt, 70% yield
KAB3-3, KAB8-1, KAB1-2 and KAB7-1
KAB7-3 10 mol% TfOH, 93%, enediamide
KAB13-2 and KAB17-1 synth of enediamide
KAB17-2 enediamide
7d to 1d
MNR12-1 ethyl acetal continued in MNR12-1 Excess MeSO3H, rt, 93% yield
MNR12-2 ethyl acetal continued in MNR12-2
7d purification: KAB2-1
KAB3-3, KAB8-1, KAB1-2 and KAB7-1
KAB11-1 attempt at enediamide
KAB11-2 attempt at enediamide
KAB11-3 attempt at enediamide
KAB12-1 from intermediate enediamide
KAB8-12 in paper, 10 mol% TfOH, 92% yield
KAB8-13 Silver chloride control, no conversion.
KAB8-14 and KAB1-5 in paper, 5 mol% TfOH, 96% yield
KAB8-15 Used in paper. 10 mol% silver triflate. Anhydrous, 87% yield.
MNR33-1 enediamide
Catalyst/Ligand Preparations
MNR20-11, MNR20-12, MNR20-13, MNR20-14, MNR20-15
Different Routes
Cbz
Toluene reactions with acid KAB9-1
Praziquanamine from PZQ hydrolysis
MeO-praziquanamine (5f) from hydrolysis of MeO-PZQ (1b)