Todd:Pictet-Spengler to PZQ

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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

Here we summarise the results we have achieved so far from the Open Lablog: Pictet-Spengler route to Praziquantel.

The Pictet-Spengler approach is intended to find a method for an enantioselective cyclization of a precursor of PZQ to form selectively the (R)-enantiomer. We showed a 1-step synthesis of 4 intermediates, so-called Ugi-intermediates using a novel method... and determined the conditions for a (Bronsted-)acid-mediated (acid-catalysed) Pictet-Spengler cyclization of the open-chain compound.

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)

• Novel Synthesis of Praziquantel, A. Dömling, Patent Application 2009, WO 2009/11533(A1), Language: German.

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:

• PZQ
• Dimethoxy-PZQ
• N-benzoyl-protected PZQ
• Dimethoxy-N-benzoyl-PZQ

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.

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

• Design of Chiral N-Triflyl Phosphoramide as a Strong Chiral Brønsted Acid and Its Application to Asymmetric Diels-Alder Reaction, D. Nakashima and H. Yamamoto, J. Am. Chem. Soc. 2006, 128, 30, 9626–9627.

1,1-Binaphthyl-2,2-disulfonate

Strong acidic achiral BINOL catalyst wearing two sulfonic acid groups

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

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)

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)

• Novel Synthesis of Praziquantel, A. Dömling, Patent Application 2009, WO 2009/11533(A1), Language: German.