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(2011) Synthesis of Unnatural Enone-Containing Α- Amino Acids: Precursors to Chiral N-Heterocycles

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(2011) Synthesis of Unnatural Enone-Containing Α- Amino Acids: Precursors to Chiral N-Heterocycles Fowler, Lindsay S.(2011) Synthesis of unnatural enone-containing α- amino acids: Precursors to chiral N-heterocycles. PhD thesis. http://theses.gla.ac.uk/2524/ Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] Synthesis of Unnatural Enone-Containing α-Amino Acids: Precursors to Chiral N-Heterocycles Lindsay S. Fowler, M. Sci. A thesis submitted in part fulfilment of the requirements for the degree of Doctor of Philosophy. School of Chemistry College of Science and Engineering University of Glasgow February 2011 P a g e | i Abstract A fast and efficient synthetic route was developed for the synthesis of a novel class of enone- containing α-amino acid. An amino acid-derived β-ketophosphonate ester was subjected to Horner-Wadsworth-Emmons conditions using a variety of aldehydes to produce a diverse library of α,β-unsaturated amino acids. E-Configured enone-containing amino acids were also deprotected using a two-stage approach to give the parent α-amino acids. A minor modification to the route enabled the synthesis of Z-configured enones via the Still-Gennari reaction. A small library of Z-enones was produced using various aldehydes. Enone-functionalised α-amino acids were employed as substrates for an intramolecular cyclisation reaction to generate 6-substituted-4-oxopipecolic acids. A diastereoselective one-pot reductive amination/cyclisation strategy was developed to gain access to the anti-diastereomer of the chiral N-heterocycles. A small selection of 6-substituted-4-oxopipecolic acids was synthesised. 6-Substituted-4-oxopipecolic acids were also reduced diastereoselectively to generate 4- hydroxypipecolic acid analogues. P a g e | ii Contents Abstract ......................................................................................................................................... i Contents ........................................................................................................................................ii Acknowledgement .........................................................................................................................v Author’s Declaration ..................................................................................................................... vi Abbreviations............................................................................................................................... vii 1 Saturated 6-Membered N-Heterocycles ................................................................................ 1 1.1 Introduction .................................................................................................................. 1 1.2 Piperidine ...................................................................................................................... 2 1.2.1 Piperidine Synthesis ............................................................................................... 6 1.2.1.1 Reduction of Pyridine ......................................................................................... 6 1.2.1.2 Heterocycle Construction ................................................................................... 8 1.2.1.3 Cycloaddition ................................................................................................... 12 1.2.1.4 Ring Expansion / Rearrangement...................................................................... 13 1.3 Pipecolic Acid............................................................................................................... 15 1.3.1 4-Oxopipecolic Acid Synthesis .............................................................................. 22 1.3.1.1 Heterocycle Construction ................................................................................. 22 1.3.1.2 Cycloaddition ................................................................................................... 31 1.3.2 4-Hydroxypipecolic Acid Synthesis........................................................................ 38 1.3.2.1 Heterocycle Construction ................................................................................. 38 1.3.2.2 Cycloaddition ................................................................................................... 47 1.3.2.3 Ring Expansion / Rearrangement...................................................................... 52 1.4 Summary ..................................................................................................................... 54 1.5 Proposed Methodology to Synthesise 4-Oxygenated Pipecolic Acid Derivatives ........... 55 2 Novel Enone-Containing α-Amino Acids............................................................................... 57 2.1 Introduction ................................................................................................................ 57 P a g e | iii 2.2 Previous Syntheses of Enone-Containing α-Amino Acids .............................................. 57 2.3 Potential of Novel Enone-Containing α-Amino Acids .................................................... 61 2.4 Synthesis of Novel Enone-Containing α-Amino Acids ................................................... 62 2.4.1 E-Configured Enone-Functionalised α-Amino Acids .............................................. 62 2.4.2 Z-Configured Enone-Functionalised α-Amino Acids .............................................. 67 2.5 Further Elaboration of Novel Enone-Functionalised α-Amino Acids .............................. 70 2.6 Deprotection to Parent α-Amino Acids......................................................................... 72 2.6.1 Deprotection of E-Configured Enones .................................................................. 73 2.6.2 Deprotection of Z-Configured Enones .................................................................. 76 2.7 Stereochemical Evaluation ........................................................................................... 78 2.8 Application of Enone-Functionalised α-Amino Acids .................................................... 79 2.8.1 Fluorescent Labelling ........................................................................................... 80 2.8.2 Synthesis of a Novel α-Amino Acid Fluorophore ................................................... 80 2.9 Summary ..................................................................................................................... 83 3 Chiral 6-Substituted-4-Oxygenated Pipecolic Acid Derivatives ............................................. 84 3.1 Introduction ................................................................................................................ 84 3.2 Synthesis of 4-Oxopipecolic Acid Derivatives via an Intramolecular Conjugate Addition 85 3.2.1 Model Substrate 1 – Phenyl Derivative ................................................................. 86 3.2.2 Model Substrate 2 – Phenethyl derivative ............................................................ 88 3.3 One-Pot Reductive Amination/Intramolecular Cyclisation for the Synthesis of 4- Oxopipecolic Acid Derivatives .................................................................................................. 89 3.3.1 Rationale for the Observed Stereochemical Outcome of the Intramolecular Cyclisation ........................................................................................................................... 95 3.4 Reduction of 4-Oxo- to 4-Hydroxypipecolic Acid Derivatives ........................................ 97 3.4.1 Rationale for the Observed Stereochemical Outcome of the Reduction................ 99 3.4.2 Relative Stereochemistry ................................................................................... 102 3.5 Deprotection of 4-Hydroxypipecolic Acid ................................................................... 105 3.5.1 X-Ray Crystal Structure of 6-Methyl-4-Hydroxypipecolic Acid ............................. 106 3.6 Alternative Approach to 4-Oxopipecolic Acid Derivatives ........................................... 107 3.7 Future Work .............................................................................................................. 111 3.8 Summary ................................................................................................................... 113 4 Conclusions ....................................................................................................................... 115 5 Experimental ..................................................................................................................... 117 5.1 General Considerations .............................................................................................. 117 5.2 General Experimental ................................................................................................ 117 P a g e | iv 5.3 Experimental Procedures ........................................................................................... 120 6 References .......................................................................................................................
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