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 summarize the outcome of the Open Lablog: Pictet-Spengler route to Praziquantel.

Introduction

The Pictet-Spengler route to PZQ was developed by the Korean Shin Poong Pharmaceutical Company obtaining PZQ in a four step synthesis.

A promising improvement for this approach is the Ugi-multicomponent reaction which allows to synthesise the PZQ precoursor in only one step [paper - Doemling] and the so-called Ugi-intermediate can be converted to PZQ by an acid-mediated cyclization in one more step.

We showed that the synthesis of various intermediates of PZQ analogs can be xxx

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?

Results

We have been looking at 4 different substrates. Can make all the precursors [Links]

Synthesis of the catalysts

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

Procedure: Repetition of the synthesis of N,N’-bis[3,5-bis(trifluoromethyl)phenylthiourea (MW43-2)]

• 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

Procedure: Repeating the preparation of (+/-)-BINOL-N-triflyl phosphoramide (MW39-2)

• 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

1. Step: Preparation of 1,1’-Binaphthalene-2,2’-diyl-O,O’-bis(N,N’-dimethylthiocarbamate) (MW45-1)

2. Step: Preparation of 1,1’-Binaphthalene-2,2’-diyl-S,S’-bis(N,N’-dimethylthiocarbamate) (MW45-2)

3. Step: Preparation of 1,1’-Binaphthalene-2,2’-disulfonic acid (MW45-3)

• 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.

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.