The Generation and Reactivity of Functionalised Organozinc Carbenoids for Cyclopropane Synthesis A Thesis Presented by Laure Jerome In Partial Fulfilment of the Requirements for the Award of the Degree of DOCTOR OF PHILOSOPHY OF THE UNIVERSITY COLLEGE LONDON Christopher Ingold Laboratories Department of Chemistry University of London London WC1H 0AJ May 2009 1 Declaration Declaration I, Laure Jerome, confirm that the work presented in this thesis is, to the best of my knowledge, my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract Abstract This thesis describes the generation and reactivity of functionalised organozinc carbenoids for cyclopropane synthesis with alkenes. In the introductory chapter, a brief overview of the different methods for preparation of heteroatom-functionalised cyclopropanes is presented, including [2+1] cycloaddition reactions using a carbene or carbenoid as a cyclopropanating agent with an alkene, ionic stepwise methods, and chemical modifications from existing cyclopropanes. The remainder of this chapter then focuses on previous work within our own group in this area. The second chapter presents the results obtained from different areas of research in the present study, the first of these being a deeper understanding and extension of the research work undertaken by my predecessor for the development of the cyclopropanation reaction using an “amidoorganozinc” carbenoid derived from N,N diethoxymethyloxazolidinones derivatives in the presence of a source of zinc and chlorotrimethylsilane. Thus, the chemoselectivity and stereoselectivtity of the reaction were fully studied, and a quadrant model was constructed to rationalise the stereochemistry of the products obtained. The second part of this section outlines the generation of new enantiopure organozinc carbenoids precursors derived from substituted chiral precursors followed by the synthesis of novel enantiopure highly functionalised N-cyclopropyl oxazolidinones. The intramolecular version of this cyclopropanation reaction was then successfully studied using diethoxylactam derivatives as organozinc carbenoid precursors. The methodology was then applied to the preparation of novel aminocyclopropyl functionalised compounds selected as interesting building blocks which can lead to the synthesis of natural and biologically active compounds. The fifth part of this chapter describes subsequent studies towards the design of new carbenoid precursors containing additional functional groups of interest. Finally, a brief study on the potential of an organozinc carbenoid to participate in a novel [2,3] sigmatropic rearrangement was investigated. The thesis concludes with a summary of the results obtained, a detailed description of the experimental procedures used and the characterization and analysis of the compounds prepared, together with a full bibliography. 3 Contents Contents Declaration .................................................................................................... 2 Abstract ......................................................................................................... 3 Contents ......................................................................................................... 4 Acknowledgments ......................................................................................... 7 Abbreviations ................................................................................................ 9 Chapter 1: Introduction ............................................................................... 12 1.0. Introduction .......................................................................................... 13 1.0.1. Background ....................................................................................................... 13 1.0.2. Occurrence in nature and biosynthesis .............................................................. 13 1.0.3. Synthetic studies................................................................................................ 16 1.1. Carbenes and carbenoids ...................................................................... 17 1.1.1. Carbenes as cyclopropanating agents ................................................................ 17 1.1.2. Carbenoids as cyclopropanating agents ............................................................ 19 1.1.2.1. Simmons-Smith reaction ............................................................................ 20 1.1.2.2. Diazoalkanes as cyclopropanating agents .................................................. 24 1.1.2.3. Fischer carbenes as cyclopropanating agents ............................................. 26 1.1.3. Heteroatom-functionalised cyclopropane synthesis .......................................... 26 1.1.3.1. Reactions with heteroatom-functionalised alkenes .................................... 27 1.1.3.2. Cyclopropanation using heteroatom-functionalised carbenes or carbenoids ................................................................................................................................. 34 1.2. Ionic stepwise methods ........................................................................ 39 1.2.1. Ylide chemistry ................................................................................................. 39 1.2.1.1. Definition ................................................................................................... 39 1.2.1.2. Synthesis of heteroatom substituted cyclopropanes ................................... 40 1.2.2. Titanium-mediated cyclopropanation ............................................................... 41 1.2.3. 1,3-Ring-closure Reactions ............................................................................... 45 1.2.3.1. Cyclopropanes bearing nitrogen functionality ........................................... 46 1.2.3.2. Thiocyclopropanes ..................................................................................... 47 1.2.3.3. Alkoxycyclopropanes ................................................................................. 47 1.3. Functional group modifications leading to heteroatom substituted cyclopropanes from existing cyclopropanes ............................................... 48 1.3.1. Direct displacement ........................................................................................... 48 1.3.1.1. Cyclopropanes bearing a sulfur atom ......................................................... 48 1.3.1.2. Cyclopropanes bearing an oxygen atom .................................................... 49 1.3.1.3. Aminocyclopropanes ................................................................................. 49 4 Contents 1.3.2. Functional group interchange ............................................................................ 50 1.3.2.1. Sulfur substituted cyclopropanes ............................................................... 50 1.3.2.2. Aminocyclopropanes ................................................................................. 51 1.4. Previous research within our group ..................................................... 53 1.4.1. Carbonyl compounds as cyclopropanating agents: The Clemmensen reduction ..................................................................................................................................... 53 1.4.2. Carbonyl compounds as organozinc carbenoid precursors ............................... 54 1.4.3. Evolution of organozinc carbenoid chemistry as a cyclopropanating agent within our group .......................................................................................................... 55 1.4.4. Inter and intramolecular cyclopropanation ....................................................... 57 1.4.5. Synthesis of aminocyclopropanes ..................................................................... 59 Chapter 2: Results and Discussion .............................................................. 62 2.0. Introduction .......................................................................................... 63 2.1. Oxazolidin-2-one derivatives as carbenoid precursors ........................ 65 2.1.1. Synthesis of alkenes .......................................................................................... 65 2.1.2. A preamble on the assignment of stereochemistry ........................................... 66 2.1.3. Cyclopropanation studies .................................................................................. 67 2.1.4. Stereochemistry ................................................................................................. 72 2.2. Chiral oxazolidin-2-one derivatives as carbenoid precursors .............. 76 2.2.1. Synthesis of chiral carbenoid precursors ........................................................... 77 2.2.1.1. Optimisation of reaction conditions using the oxazolidinone derived from L-valine ................................................................................................................... 81 2.2.1.2. Optimisation of reaction conditions using the oxazolidinone derived from L-Leucine ................................................................................................................ 82 2.2.1.3. Optimisation of reaction conditions using the oxazolidinone derived from 2-amino-1-butanol ................................................................................................... 83 2.2.2. Synthesis of chiral N-cyclopropyloxazolidinones