Todd:Pictet-Spengler to PZQ

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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...)

(additional authors - add alphabetically. Please consider adding yourself and helping to write this paper, particularly if you have already helped out over at relevant The Synaptic Leap site)

(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.

Scheme: The general reaction scheme for the enantioselective Pictet-Spengler reaction to PZQ using chiral Lewis acid (CLA) catalysis.

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.

Scheme 1. Approaches to the Synthesis of Praziquantel and Close Analogs via a Pictet-Spengler (PS) Reaction, and Traditional vs. Ugi methods for Construction of the PS Cyclization Precursors

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 7a-d to the PS reaction could 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). These were then shown to undergo PS reactions in the presence of excess acid, to give PZQ and its three analogs as racemates. Investigations of chiral acids were then undertaken collaboratively in a search for an effective catalyst system for optimization.

1a. Conventional Stepwise Synthesis

Scheme: Formation of Pictet-Spengler starting materials

1b. Synthesis via Ugi Multicomponent Coupling

1b. i) Synthesis of the isocyanides
Isocyanides MW34-3 and MNR4-2 were prepared via the Ugi formamide route from the corresponding amines following Doemlings 2-step procedure.[Ugi, Angew Int, 1972,Doemling PCT Int, 2009] Attempts to use a Hoffman type procedure produced the desired product (MW34-1)in one step using chloroform as the source of Cl, but this proved less efficient especially on scale up (MW34-2).

• Care should be taken in the handling of the isocyanides as they have a strong odour with an unpleasant metallic taste
  

Scheme: Formation of isocyanides MW34-4 and MNR4-2.

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.

Scheme: Formation of UGI products KAB5-1, MNR8-5, MW51-1 and MNR10-2.

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].

2b Acid-catalised Pictet-Spengler cyclisation.

2b i)Screening of racemic catalysts

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?)

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)

Cleavage of the dimethoxy acetal of 2-((2,2-dimethoxyethyl)amino)-N-phenethylacetamide hydrochloride MW7 (MW42-1 to MW42-7)

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 and MNR10) was isolated in excellent yields of 91 and 96% respectively. Unfortunately, complete cyclisation was not observed for the other two examples and intermediate enediamide was isolated as the major product. Increasing catalyst loading did not help to push these reactions to completion.

Continuing on, metal triflates were then studied with the potential of employing bisoxazoline ligands (BOX ligands) to generate chiral catalysts.[REF] 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 and 87% yields 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.

Relevant Literature

• Youn 2006 JOC

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.

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.

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

HPLC trace of KAB8 using 25% EtOH in hexane + 0.2% TEA.

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

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

• 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/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

• 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.