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«Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der ...»

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Peptides as Catalysts

for Asymmetric 1,4-Addition Reactions

of Aldehydes to Nitroolefins

Inauguraldissertation

zur Erlangung der Würde eines Doktors der Philosophie

vorgelegt der

Philosophisch-Naturwissenschaftlichen Fakultät

der Universität Basel

von

Markus Wiesner

aus Bubendorf (BL)

Basel 2009

Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel

edoc.unibas.ch

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Die Commons Deed ist kein Lizenzvertrag. Sie ist lediglich ein Referenztext, der den zugrundeliegenden Lizenzvertrag übersichtlich und in allgemeinverständlicher Sprache wiedergibt. Die Deed selbst entfaltet keine juristische Wirkung und erscheint im eigentlichen Lizenzvertrag nicht. Creative Commons ist keine Rechtsanwaltsgesellschaft und leistet keine Rechtsberatung. Die Weitergabe und Verlinkung des Commons Deeds führt zu keinem Mandatsverhältnis.

Quelle: http://creativecommons.org/licenses/by-nc-nd/2.5/ch/ Datum: 3.4.2009 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel auf

Antrag von:

Prof. Dr. Helma Wennemers Prof. Dr. Andreas Pfaltz Basel, den 23. Juni 2009

–  –  –

Dekan Die vorliegende Arbeit wurde unter Anleitung von Prof. Helma Wennemers in der Zeit von April 2006 bis Juni 2009 am Departement Chemie der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel durchgeführt.

Teile dieser Arbeit wurden bereits publiziert:

M. Wiesner, G. Upert, G. Angelici, H. Wennemers, “Enamine Catalysis with Low Catalyst Loadings – High Efficiency via Kinetic Studies”, J. Am. Chem. Soc. 2009, in press.

M. Wiesner, M. Neuburger, H. Wennemers, “Tripeptides of the Type H-D-Pro-Pro-Xaa-NH2 as Catalysts for Asymmetric 1,4-Addition Reactions: Structural Requirements for High Catalytic Efficiency”, Chem. Eur. J. 2009, 15, 10103-10109.

M. Wiesner, J. D. Revell, S. Tonazzi, H. Wennemers, “Peptide Catalyzed Asymmetric Conjugate Addition Reactions of Aldehydes to Nitroethylene – A Convenient Entry into γ2Amino Acids”, J. Am. Chem. Soc. 2008, 130, 5610-5611.

M. Wiesner, J. D. Revell, H. Wennemers, “Tripeptides as Efficient Asymmetric Catalysts for 1,4-Addition Reactions of Aldehydes to Nitroolefins - A Rational Approach”, Angew. Chem.

Int. Ed. 2008, 47, 1871-1874.

P. Krattiger, J. D. Revell, M. Wiesner, H. Wennemers, “Peptides as asymmetric catalysts“, Peptide Science 2006, 43rd 333.

Für meine Eltern, auf deren Unterstützung ich immer zählen kann.

–  –  –

Ich möchte mich bei Prof. Helma Wennemers für die Förderung und Unterstützung während meiner Dissertation herzlich bedanken.

Prof. Andreas Pfaltz danke ich für die Übernahme des Co-Referates.

Bei Dr. Jefferson Revell bedanke ich mich für seine grosse Hilfe und für seine zahlreichen Ratschläge.

Folgende Personen haben am Gelingen dieser Arbeit direkt beigetragen:

Dr. Gregory Upert, Dr. Gaetano Angelici, Dr. Daniel Häussinger, Sandro Tonazzi, Markus Neuburger, Robert Kastl, Moritz Stoltz und Wei Liu. Für deren Einsatz bin ich sehr dankbar.

Der gesamten Arbeitsgruppe Wennemers danke ich für die Hilfe und für das angenehme Arbeitsklima.

Allen Mitarbeitern und Mitarbeiterinnen der Werkstatt, der Materialausgabe und des Sekretariats danke ich für ihre Hilfe.

Für die finanzielle Unterstützung danke ich dem Schweizerischen Nationalfonds, der Universität Basel, dem RTN RevCat der Europäischen Union und der Bachem AG.

Ein besonderer Dank geht an meine Familie, an meine Freundin Romina und an alle meine Freunde für ihre grosse Unterstützung.





Contents I. Introduction

1. Asymmetric Enamine Catalysis

1.1 Enamine Catalysed Conjugate Addition Reactions of Aldehydes and Nitroolefins 10

2. Peptides as Asymmetric Catalysts

2.1 Combinatorial Methods for the Development of Catalytically Active Peptides – The Catalyst Substrate Co-Immobilisation Method

2.2 Tripeptides as Catalysts for Asymmetric Aldol Reactions

II. Objective

3. Peptides as Catalysts for Conjugate Addition Reactions of Aldehydes to Nitroolefins?

III. Results & Discussions

4. Asymmetric 1,4-Addition Reaction of n-Butanal and Nitrostyrene as a Model Reaction

4.1 TFA H-Pro-Pro-Asp-NH2 1 as a Catalyst

4.1.1 Initial Studies

4.1.2 Influence of the Base

4.1.3 Solvent Screening

4.1.4 Conclusions

4.2 Screening of Various Catalysts Containing a N-Terminal Proline Residue and an Acidic Functionality

4.3 Diastereomeric Tri- and Tetrapeptides

5. TFA H-D-Pro-Pro-Asp-NH2 (21) as a Catalyst for Asymmetric 1,4-Addition Reactions of Aldehydes to Nitroolefins

6. Conformational Studies I

6.1 Lowest Energy Structures of Diastereoisomeric Catalysts and Transition State Model

6.2 X-Ray Crystal Structure Analysis of Peptidic Catalysts

6.3 Importance of the Turn-Structure and the N-terminal Proline Residue

7. Catalysts of the Type H-D-Pro-Pro-Xaa: Directed Modifications

7.1 Importance of the Carboxylic Acid in the Side Chain

7.2 Modifications at the C-Terminus

7.3 Importance of the Spacer Length in the Side-Chain of the C-terminal Amino Acid

7.4 H-D-Pro-Pro-Glu-NH2 56 and its Diastereoisomers

8. TFA H-D-Pro-Pro-Glu-NH2 (56) as a Catalyst for Asymmetric 1,4-Addition Reactions of Aldehydes to Nitroolefins

8.1 Substrate Scope

8.1.1 Addition of Aldehydes to Nitroolefins

8.1.2 Addition of Aldehydes to β-Nitroacrolein Dimethylacetal 69

8.2 Effect of Additives on the Catalytic Efficiency

Gram Scale Synthesis of γ-Nitroalcohol 73

8.3

9. Conformational Studies II

9.1 X-Ray Crystal Structure Analysis of H-D-Pro-Pro-Glu-NH2 56

9.2 NMR Studies

9.2.1 H-D-Pro-Pro-Glu-NH2 56

9.2.2 Enamine Formation between H-D-Pro-Pro-Glu-NH2 56 and Phenylacetaldeyde

10. Kinetic Studies of H-D-Pro-Pro-Glu-NH2 (56) Catalysed Conjugate Addition Reaction of Aldehydes to Nitrostyrenes using in situ FT-IR Spectroscopy.............. 65

10.1 Initial Investigations

10.1.1 Fraction Conversion versus In Situ Measurement

10.1.2 Investigation of Catalyst Instabilities

10.1.3 TFA Catalyst / NMM vs. Desalted Catalyst

10.1.4 Non-linear Effects?

10.2 Reaction Progress Kinetic Analysis

10.3 Determination of Reaction Orders: Log-Log Plots

10.3.1 Reaction Order with Respect to the Catalyst

10.3.2 Reaction Order with Respect to the Aldehyde

10.3.3 Reaction Order with Respect to the Nitrostyrene

10.3.4 Determination of Reaction Orders - Conclusions and Design of Further Experiments

10.3.5 Less Reactive Aldehyde: Addition of Isovaleraldehyde to Nitrostyrene......... 78 10.3.6 Less Reactive Nitrostyrenes: Addition of n-Butanal to 4-Methoxynitrostyrene and 2,4-Dimethoxinitrostyrene

10.3.7 Standard Reaction, Dry Conditions and Additional Water – Influence on Reaction Rates and Reaction Orders

10.4 Summary and Conclusions

11. H-D-Pro-Pro-Glu-NH2 (56) Catalysed Asymmetric 1,4-Additions Reactions:

Optimised Conditions Based on Kinetic Studies

11.1 Evaluation of Improved Reaction Conditions

11.2 Substrate Scope

12. Asymmetric 1,4-Addition Reaction of Aldehydes to Nitroethylene

12.1 Introduction and Initial Studies

12.2 Catalyst Screening for the Reaction of 3-Phenylpropionaldehyde and Nitroethylene

12.3 Reaction Optimisation

12.3.1 Evaluation of Conditions using TFA H-D-Pro-Pro-Glu-NH2 56

12.3.2 Reaction Optimisation at Low Concentrations

12.4 Substrate Scope

12.5 Derivatisation of γ-Nitroalcohol 82

Synthesis of γ-Butyrolactone 86

12.5.1 Synthesis of Monosubstituted γ2-Amino Acid 87

12.5.2

12.6 Conclusions

13. Summary and Outlook

IV. Experimental Section

14. General Aspects

15. General Protocols

15.1 General Protocols for Solid-Phase Peptide Synthesis

15.2 General Protocols for 1,4-Addition Reactions

15.3 General Protocol for Ion Exchange of Peptides

16. Peptides, Building Blocks and Substrates

16.1 Characterisation Index

16.2 Peptides Prepared by Solid-Phase Synthesis

16.3 Peptides Prepared by Solution-Phase Synthesis

16.4 Synthesis of Non-Commercial Available Building Blocks

16.5 Synthesis of Non-Commercial Available Substrates

17. 1,4-Addition Products and Derivatives

17.1 Characterisation Index

17.2 1,4-Addition Products of Aldehydes and Nitroolefins

17.3 1,4-Addition Products of Aldehydes and Nitroethylene

17.4 Derivatives of 1,4-Addition Products

18. Conformational Studies

18.1 Calculations

18.2 X-Ray Studies

18.3 CD-Spectroscopy

18.4 NMR Studies

18.4.1 H-D-Pro-Pro-Glu-NH2 56

18.4.2 Enamine Formation and Assignement

19. Kinetic Studies on 1,4-Addition Reactions

V. Appendix

20. References

21. Abbreviations

22. Kinetic Studies (Chapter 10): Detailed Information and Additional Experiments

23. NMR Data of H-D-Pro-Pro-Glu-NH2 (56)

–  –  –

Asymmetric Enamine Catalysis 1.

Organocatalysis is regarded as the application of small organic molecules as catalysts to a variety of organic processes and has recently become very popular for the synthesis of chiral molecules.[1-8] Of particular interest are the high product enantio- and/or diastereoselectivities and reaction yields which can frequently be obtained using organocatalysts. In comparison to other firmly established fields such as enzymatic catalysis and organometallic catalysis, organocatalysis offers several fundamental advantages: In general, organocatalysts can be used in a wider range of solvents and for a broader scope of substrate in comparison to enzymes. In addition, they are typically less toxic and less sensitive towards oxidation and moisture than most organometallic based reagents. However, a major drawback of organocatalysis is their typically low catalytic activity which often requires 10 mol% or more of catalyst for the reaction of interest. Based on a mechanistic classification, organocatalysis can generally be categorised as either Lewis base, Lewis acid, Brønsted base or Brønsted acid mediated.[4] An important class of Lewis base catalysis is asymmetric enamine catalysis which is regarded as the catalysis of electrophilic substitution reactions in the α-position of carbonyl compounds by primary and secondary amines proceeding via enamine intermediates.[9] The versatility of enamines in stochiometric reactions was demonstrated for α-functionalisation of carbonyl compounds by Stork et al. in 1963.[10,11] The first catalytic application of enamines was recorded by Hajos and Parrish[12] and Eder, Sauer and Wiechert[13] in the early 1970’s. L-Proline was used to catalyse the asymmetric Robinson annulation of an achiral triketone. The corresponding steroid precursor was obtained in quantitative yield (100 %) and high enantioselectivity (93 % ee, Scheme 1.1).

Scheme 1.1.

Proline catalysed Robinson annulation (Hajos-Parrish-EderSauer-Wiechert reaction).[12,13] In 2000, List, Lerner and Barbas introduced the proline catalysed intermolecular aldol reaction of ketones and aldehydes (Scheme 1.2a).[14] The use of proline as catalyst for intraand intermolecular aldolreactions revealed that a small ‘rigid’ organic molecule could catalyse the same chemical reactions as a much larger enzyme (typ I aldolase) via a similar enaminetype mechanism. Almost simultaneously MacMillan reported iminium-type catalysis of an asymmetric Diels-Alder reaction, catalysed by a chiral imidazolidinone (Scheme 1.2b).[15] These two publications initiated the launch of organocatalyis as a new important research field in asymmetric catalysis.

–  –  –

Scheme 1.2.

a) Proline catalysed asymmetric aldol reactions.[14] b) Imidazolidinone catalysed DielsAlder reactions.[15] In enamine catalysis an aldehyde or ketone reacts with the catalyst to form the nucleophilic enamine species with a HOMO of higher energy compared to the respective carbonyl (enol) compound. The enamine can attack an electrophile to form an iminum ion species.



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