Todd:Pictet-Spengler to PZQ
Pictet-Spengler route to Praziquantel
Michael Woelfle,1 and Matthew H. Todd1*
1. School of Chemistry, The University of Sydney, NSW 2006, Australia
- To whom correspondence should be addressed: Tel. +61 2 9351 2180, matthew.todd@sydney.edu.au
Abstract
This article is a continually-updated summary of the results to date from the Open Lablog: Pictet-Spengler Route to Praziquantel.
The Pictet-Spengler approach is a potential method 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, we report here the progress to date on the enantioselective synthesis of PZQ using a Pictet-Spengler reaction. The approach employs a known peptide acetal precursor in an acid-catalyzed cyclization.
Introduction
The anthelmintic drug PZQ was found in XXX by Merck using the Reissert reaction as the first step to synthesis the heterocyclic core but the 4-step reaction suffered from low yields in the initial steps. After the patent had expired the Korean company Shin Poong developed the Pictet-Spengler route to Praziquantel an inexpensive and more efficient synthesis of PZQ in 4 steps.
A promising improvement for this approach was reported/made by Doemling (in 20XX) which uses the Ugi-multicomponent reaction to synthesise a open-chain PZQ precoursor in only one step as a pateted procedure [paper - Doemling]. The so-called Ugi-intermediate can be converted to PZQ by an acid-mediated cyclization in one more step.
Literature – says that this reaction is not possible asymmetrically. Examples are always on e-rich rings, and it seems to be easier on rings containing amines rather than amides. Which is the real problem?
Reason: di-Meo help the PS, benzoyl as an alternative that may be easier to form or purify. Also may change enantioselectivity. Easier to work with? Interested in the benzoyl for other projects – resolution and the enamide. Evidence that the di-Meo or the benzoyl PZQ are bioactive? All 3 analogs are they active?
Results
We showed that the synthesis of various intermediates of PZQ analogs can be xxx
First we started with conventional approach via the Shin Poong route [link]
Racemic PS for all 4 works? Links. Conditions are bad. Di-Meo was catalytic, others not.
Chiral catalysts synthesised to date: Description of which made, with links. [figure of catalysts made]
We have been looking at 4 different substrates. Can make all the precursors [Links]
Preparation of the Ugi-intermediates
The Ugi-multicomponent reaction is ... 4 components (isocyanide, amine, carboxylic acid, formaldehyde) forming a open-chain XXX product in very high yields. [Scheme] The reaction is easy to perform and 3 of the starting materials are cheap and commercially available. However highly reactive isonitrile can't be stored for a long time and has to be synthesised by ourselfes [link synthsis isocyanides]
See: Multistep synthesis of rac-PZQ (Ugi route)
Synthesis of the isocyanides
For the synthesis of the isocyanides two procedures were used published in the Doemling patent [#]. Route A uses chloroform as a C1 source in a 1-step procedure but the work-up is more effort because of impurities due to side reactions. The 2-step procedure is easy to perform and the yield is slightly better.
Procedures 2-phenylethyl isocyanide: Route A and Route B
(Note: very smelly compound with a pungent odor)
Procedures 2-(3,4-Dimethoxyphenyl)ethyl isocyanide: Route A and Route B
(Note: Route B works better for this compound)
Synthesis of the Ugi-intermediates
The Ugi-reaction was variied with 2 isocyanides (R1 = H, MeO) and carboxylic acids (benzoic acid, cyclohexane carboxylic acid) obtaining 4 'Ugi-intermediates' in good to very good yields. The procedure was easy to perform - the components were mixed in a 1:1:1:1 stoichiometry and stirred for 24 h at r.t.
Procedures for the Ugi-intermediates of:
Synthesis of the 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.
phenyl-thiourea.png)
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.
Pictet-Spengler reactions - Cyclization
The Pictet-Spengler cyclization of the Ugi-intermediates can be cylclisized by strong very Bronsted-acids. The acids used for this cyclisation are conc. sulforic acid [ref. Kim et. al] and methane sulfonic acid [ref. Doemling] were the acids were also used as a solvent (excess of acid) at r.t. or heated at 60°C up to 2 days (?). To find a (chiral) acid which can catalyse this reaction we tested several precursors of chiral Bronsted catalysts and and also looked for the conditions which can be
Acid-mediated and acid-catalysed Pictet-Spengler reactions & Screenings
Synthesis of the dimethoxy-N-benzoyl-derivative of PZQ via Pictet-Spengler reaction (MW54-3)
Synthesis of the N-benzoyl-derivative of PZQ via Pictet-Spengler reaction (MW53-4)
Experiments to the acid-mediated Pictet-Spengler of the PZQ intermediate with various Bronsted-acids (phenyl phosphonic acid, p-toluenic acid, TFA) -> no reaction
Attempts to the acid-mediated Pictet-Spengler cyclization of the ‘Ugi intermediate’ MW29 (MW31)
Brosted-acid catalysed reactions:
Attempts to the Bronstedt-acid catalysed Pictet-Spengler cyclization using N,N’-bis[3,5-bis(trifluoromethyl)phenylthiourea (MW44)] -> no reaction
Attempts to the Bronstedt-acid catalysed Pictet-Spengler cyclization using BINOL-N-triflyl phosphoramide (MW41) -> no reaction
Acid-catalyzed Pictet-Spengler reaction with binaphthalenedisulfonic acid (MW56-1 to MW56-4)
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?)
Acid-catalyzed Pictet-Spengler reaction with methanesulfonic acid (MW56-5 to MW56-8) -> no reaction for unactivated comp, P-S cyclization for the dimethoxy-intermediates
Continuation: Acid-catalyzed Pictet-Spengler reaction with methanesulfonic acid (MW56-9 to MW56-14)
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.
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
- 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)
