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The Metalation of Terminal Alkynes by Zn" and Their Addition to Nitrones and Aldehydes

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The Metalation of Terminal Alkynes by Zn Research Collection Doctoral Thesis The metalation of terminal alkynes by Zn" and their addition to nitrones and aldehydes Author(s): Fässler, Roger Publication Date: 2003 Permanent Link: https://doi.org/10.3929/ethz-a-004503165 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library Diss. ETH No. 14936 The Metalation of Terminal Alkynes by ZnII and Their Addition to Nitrones and Aldehydes A dissertation submitted to the SWISS FEDERAL INSTITUTE OF TECHNOLOGY ETH ZÜRICH for the degree of Doctor of Natural Sciences Presented by Roger Fässler Dipl. Chem. ETH Born April 7, 1968 Citizen of Zürich (ZH) and Unteriberg (SZ) Accepted on the recommendation of Prof. Dr. Erick M. Carreira, examiner Prof. Dr. Peter Chen, co-examiner Zürich 2003 Meiner lieben Familie in Dankbarkeit gewidmet Meinem Doktorvater Professor Dr. Erick M. Carreira danke ich herzlich für die interessante Aufgabenstellung und die mir gewährte Freiheit bei der Durchführung dieser Arbeit, für das mir entgegengebrachte Vertrauen, die grosszügige materielle Unterstützung, sowie für die lehr- und abwechslungsreiche Zeit, die ich in seiner Arbeitsgruppe verbringen durfte. Danksagung Bei Dr. Doug E. Frantz bedanke ich mich ganz herzlich, dass er mich in einer sehr frühen Phase in dieses Projekt eingeführt hat. Die erfolgreiche gemeinsame Zeit, die wir sowohl im Rahmen unserer Zusammenarbeit, aber auch privat miteinander verbringen durften, wird mir stets in bester Erinnerung bleiben. Meinem Kollegen Patrick Aschwanden danke ich für die freundschaftliche Art und Weise der Zusammenarbeit im Kampf gegen zahlreiche Probleme im Zusammenhang mit dem Acetylen-Projekt und für seinen beispiellosen Einsatz als Gruppenverantwortlicher für unsere Computersysteme und ’alles sonst, was einen Stecker hat’. Auch dafür, dass er dieses Manuskript mehrmals kritisch durchgesehen hat, bin ich ihm zu Dank verpflichtet. Danken möchte ich auch Jürg Oetiker, der mir während seiner Chemielaborantenlehre anvertraut wurde und mir mit seinem wachsenden experimentellen Geschick über die Zeit ein vertrauter und unentbehrlicher Mitarbeiter wurde. Für das gute Arbeitsklima, das sich auf dem Hönggerberg im HCI G338 recht bald eingestellt hat, danke ich auch meinen übrigen Laborkolleginnen und –kollegen Christiane Meyers, Alec Fettes und Stephan Schnidrig. Dr. Nicolas Wurtz, dem die englische Sprache dank seiner Herkunft wesentlich geläufiger ist als mir, danke ich herzlich für die Geduld beim Korrekturlesen des Manuskripts. Bei Dr. Craig S. Tomooka bedanke ich mich für die erfolgreiche Zusammenarbeit am ReactIR-Spektrometer. Herzlicher Dank gebührt Claudia Dörfler und Franziska Peyer, die mich in organisatorischen und administrativen Belangen immer bereitwillig unterstützt haben. Prof. Dr. Peter Chen danke ich für die Übernahme des Korreferats. Besonderer Dank gebührt Prof. Dr. Volker Gramlich für die Anfertigung aller in dieser Arbeit präsentierten Röntgenstrukturanalysen. Danken möchte ich auch Dr. Harold Baumann für die geleistete Hilfestellung im Zusammenhang mit der Berechnung von Molekülorbitalen. Den Mitarbeiterinnen und Mitarbeiter der analytischen Abteilung des Laboratoriums für Organische Chemie bin ich zu Dank verpflichtet für Ihre Unterstützung: Prof. Dr. Berhard Jaun, Brigitte Brandenberg, Philipp Zumbrunnen (NMR); Dr. Walter Amrein, Rolf Häfliger, Oswald Greter (MS); Michael Schneider, Dieter Manser (EA). Zudem danke ich allen übrigen Angestellten des Instituts (Schalter, Werkstatt, Reinigungspersonal) für ihren Beitrag zu einer gut funktionierenden Infrastruktur. Schliesslich möchte ich mich bei allen nicht namentlich erwähnten Mitgliedern und Ehemaligen der Gruppe Carreira bedanken, die mich mit Ratschlägen und Diskussionen unterstützt und dazu beigetragen haben, meine Doktorandenzeit an der ETH so angenehm wie möglich zu gestalten. Der Roche Research Foundation danke ich für die grosszügige finanzielle Unterstützung während des zweiten Jahres meiner Forschungsarbeit. Parts of this thesis have been published: Doug E. Frantz, Roger Fässler, and Erick M. Carreira Catalytic in Situ Generation of Zn(II)-Alkynilides under Mild Conditions: A Novel C=N Addition Process Utilizing Terminal Acetylenes J. Am. Chem. Soc. 1999, 121, 11245. Doug E. Frantz, Roger Fässler, and Erick M. Carreira Facile Enantioselective Synthesis of Propargylic Alcohols by Direct Addition of Terminal Alkynes to Aldehydes J. Am. Chem. Soc. 2000, 122, 1806. Doug E. Frantz, Roger Fässler, Craig S. Tomooka, and Erick M. Carreira The Discovery of Novel Reactivity in the Development of C-C Bond-Forming II Reactions: In Situ Generation of Zinc Acetylides with Zn /R3N Acc. Chem. Res. 2000, 33, 373. Roger Fässler, Doug E. Frantz, Jürg Oetiker, and Erick M. Carreira First Synthesis of Optically Pure Propargylic N-Hydroxylamines by Direct, Highly Diastereoselective Addition of Terminal Alkynes to Nitrones Angew. Chem. Int. Ed. 2002, 41, 3054. Parts of this thesis have been presented as a lecture: Roger Fässler In Situ Generation of Zn(II)-Alkynilides under Mild Conditions: Novel C=O and C=N Addition Processes Utilizing Terminal Alkynes Directly Roche Symposium ’For Leading Chemists of the Next Decade’, October 2000, Basel, Switzerland. Roger Fässler In Situ Generation of Zn(II)-Alkynilides under Mild Conditions: Novel C=O and C=N Addition Processes Utilizing Terminal Alkynes Directly ESOC 12, The 12th European Symposium on Organic Chemistry, July 2001, Groningen, The Netherlands. Parts of this thesis have been presented as a poster: Roger Fässler In Situ Generation of Zn(II)-Alkynilides under Mild Conditions: Novel C=O and C=N Addition Processes Utilizing Terminal Alkynes Directly Pfizer Drug Discovery 2000 Symposium, September 2000, Pfizer Global Research & Development, Sandwich, UK. Table of Contents List of Abbreviations 1 1. Abstract 3 2. Zusammenfassung 7 3. Acetylides 13 3.1 Background 13 3.2 Scope and Limitations in the Application of Acetylides 15 3.3 The Activation of Terminal Alkynes with Zn(OTf)2, Results and Discussion 17 3.3.1 The Discovery of a New ZnII-Acetylide Species 17 3.3.2 ReactIR Studies 18 3.3.3 NMR Studies 20 3.4 Conclusions 27 4. Propargyl N-Hydroxylamines 29 4.1 Introduction 29 4.1.1 Background 29 4.2 General Addition Methods 30 4.3 The Stereoselective Addition of Acetylides to Nitrones 32 4.3.1 Additions of Metalated Alkynes to Chiral N-Benzyl Nitrones 32 4.3.2 Nitrones Bearing Chiral Auxiliaries on Nitrogen 35 4.3.2.1 N-Benzyl Derivatives as Chiral Auxiliaries 35 4.3.2.2 Carbohydrate-Derived Chiral Auxiliaries 37 4.4 The Synthetic Versatility of Propargylic N-Hydroxylamines 45 4.5 The Catalytic Addition of In Situ Generated ZnII-Acetylides to N-Benzyl Nitrones 47 4.5.1 Objectives 47 4.5.2 Results and Discussion 47 4.5.2.1 The Preparation of N-Benzyl Nitrones 47 4.5.2.2 Addition of ZnII-Acetylides to N-Benzyl Nitrones 49 4.5.2.3 The Preparation of Propargyl Amines 53 4.5.2.4 A Working Model for the Catalytic Reaction Mechanism 53 4.5.3 Conclusions 55 4.6 Optically Pure Propargyl N-Hydroxylamines 55 4.6.1 Objectives 55 4.6.2 Chiral, α-Branched N-Benzyl Auxiliaries 56 4.6.2.1 The Preparation of α-Branched N-Benzyl Nitrones 56 4.6.2.2 Results and Discussion 58 4.6.2.3 Conclusions 59 4.6.3 N-Glycosyl Nitrones 60 4.6.3.1 Introduction 60 4.6.3.2 The Formation of D-(+)-Mannofuranosyl Nitrones 61 4.6.3.3 The Diastereoselective Addition of In Situ Generated ZnII-Acetylides to D-(+)-Mannofuranosyl Nitrones 64 4.6.3.4 Mannofuranosyl Auxiliary Cleavage 69 4.6.3.5 Auxiliary Recovery 71 4.6.3.6 Determination of the Absolute Configuration of the Propargyl N-Hydroxylamines 71 4.6.3.7 Further Elaboration of the Propargyl N-Hydroxylamines 75 4.6.3.8 Pseudoenantiomeric N-Glycosyl Auxiliaries 75 4.6.3.9 Conclusions 81 5 Optically Active Propargyl Alcohols 83 5.1 Introduction 83 5.1.1 Background 83 5.2 The Enantioselective Reduction of α,β-Acetylenic Ketones 85 5.2.1 General 85 5.2.2 The LiAlH4-Darvon Alcohol Complex (Chirald-LiAlH4 Complex) 85 5.2.3 Binal-H 86 5.2.4 Alpine-Borane 88 5.2.5 B-Chlorodiisopinocampheylborane (Ipc2BCl, DIP-Chloride) 90 5.2.6 Asymmetric Oxazaborolidine Mediated Reductions of Ynones 92 5.2.7 Asymmetric Transfer Hydrogenation of α,β-Acetylenic Ketones with RuII-Complexes 95 5.2.8 Reductive Cleavage of Homochiral Acetals with Lewis Acid Hydrides 96 5.2.9 Enzymatic Reduction of Ynones 97 5.3 The Asymmetric Addition of Acetylides to Aldehydes 99 5.3.1 General 99 5.3.2 Racemic and Diastereoselective Methods 99 5.3.3 The Chronological Development of the Enantioselective Addition of Acetylides to Aldehydes 102 5.4 A Facile Enantioselective Synthesis of Propargylic Alcohols by Direct Addition of Terminal Alkynes to Aldehydes 113 5.4.1 Introduction 113 5.4.2 Results and Discussion 113 5.4.2.1 Ligand Screening 113 5.4.2.2 Substrate Scope under Optimized Conditions 115 5.4.2.3 Sensitivity of the Process to Reaction Conditions 119 5.4.2.4 Determination of the Absolute Configuration of the Adducts 122 5.4.3 Conclusions 123 5.5 The Catalytic Enantioselective Addition of In Situ Generated ZnII-Acetylides to Aldehydes 125 5.5.1 Introduction 125 5.5.2 Scale-Up Experiments, Results and Discussion 128 5.5.2.1 Preparation of the THP-Protected 2-Methyl-3-butyn-2-ol 128 5.5.2.2 Addition Reactions 129 5.5.3 Conclusions 132 6. Alternative Zinc Sources 133 6.1 Introduction 133 6.2 Zinc Difluoromethanesulfonate 133 6.3 Zinc Fluorosulfonate 134 6.4 Zinc Chloride
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