Todd:Pictet-Spengler to PZQ: Difference between revisions
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===Preparation of the Ugi-intermediates=== | ===Preparation of the Ugi-intermediates=== | ||
See [http://www.thesynapticleap.org/node/317 Multistep synthesis of rac-PZQ (Ugi route)] | |||
[http://www.ourexperiment.org/racemic_pzq/1555 Preparation of the N-benzoyl-protected 'Ugi-intermediate' (MW51-1)] | |||
[http://www.ourexperiment.org/racemic_pzq/1587 Preparation of 2-(3,4-Dimethoxyphenyl)ethyl isocyanide (MW37-2)] | |||
[http://www.ourexperiment.org/racemic_pzq/1597 Preparation of the dimethoxybenzyl-N-benzoyl-derivative of the ‘Ugi-intermediate’ (MW52-1)] | |||
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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]. | ||
==Pictet-Spengler reactions - Cyclization== | |||
Acid-mediated and acid-catalysed Pictet-Spengler reactions & Screenings | |||
[http://www.ourexperiment.org/racemic_pzq/1658 Synthesis of the dimethoxy-N-benzoyl-derivative of PZQ via Pictet-Spengler reaction (MW54-3)] | |||
[http://www.ourexperiment.org/racemic_pzq/1654 Synthesis of the N-benzoyl-derivative of PZQ via Pictet-Spengler reaction (MW53-4)] | |||
==References== | ==References== |
Revision as of 01:09, 25 May 2011
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]
Preparation of the Ugi-intermediates
See Multistep synthesis of rac-PZQ (Ugi route)
Preparation of the N-benzoyl-protected 'Ugi-intermediate' (MW51-1)
Preparation of 2-(3,4-Dimethoxyphenyl)ethyl isocyanide (MW37-2)
Preparation of the dimethoxybenzyl-N-benzoyl-derivative of the ‘Ugi-intermediate’ (MW52-1)
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)
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.
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)
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)