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Towards the Total Synthesis of Anthracimycin

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Towards the Total Synthesis of Anthracimycin Towards the Total Synthesis of Anthracimycin Giacomo Lodovici Doctor of Philosophy University of York Chemistry January 2019 1. Abstract In 2013 W. Fenical et al. reported the isolation of a natural product from a marine microorganism of streptomyces species, which possessed significant activity against Gram-positive pathogens Bacillus anthracis, methicillin-resistant and vancomycin resistant Staphylococcus aureus (MRSA).15 The compound responsible for the antibiotic activity was found to be the 14-membered macrolide named anthracimycin. The research detailed in this thesis describes the efforts towards the total synthesis of this natural product and specifically the formation of the core of anthracimycin in 12-steps. Direct palladium catalysed oxidation formed the enone used as a dienophile in a stereo- and regio-selective Diels‒Alder/epimerisation sequence, which afforded the trans-decalin. A facial and stereoselective Hosomi‒Sakurai 1,4-addition reaction, followed by a selective borylation/dihydroxylation sequence on the exocyclic alkene, allowed the formation of the core of anthracimycin (Scheme 1). Scheme 1. The formation of the decalin core of anthracimcyin. 1 2. Contents 1. Abstract ............................................................................................................................................... 1 2. Contents .............................................................................................................................................. 2 3. List of Figures ...................................................................................................................................... 4 4. List of Schemes .................................................................................................................................... 5 5. List of Tables........................................................................................................................................ 8 6. Acknowledgements ............................................................................................................................. 9 7. Declaration ........................................................................................................................................ 10 8. Introduction ...................................................................................................................................... 11 8.1 Natural product synthesis ........................................................................................................... 11 8.2 The need for new antibiotics ...................................................................................................... 12 8.2.1 The mechanism of action of antibiotics ............................................................................... 15 8.3 Anthracimycin: a new molecule active against MRSA bacteria .................................................. 16 8.3.1 The biosynthesis of anthracimycin ...................................................................................... 18 8.3.2 The biological effect of anthracimycin ................................................................................. 20 8.4 Isolation of an anthracimycin analogue 14 ................................................................................. 23 8.5 A related polyketide: chlorotonil A 15 ........................................................................................ 24 8.5.1 The total synthesis of chlorotonil A 15 ................................................................................ 28 8.6 Computational investigations into IMDA synthesis of anthracimycin ........................................ 31 8.7 Synthesis of functionalised decalin scaffold ............................................................................... 33 9. Results and discussion ...................................................................................................................... 40 9.1 The Robinson annulation to form a functionalised trans-decalin .............................................. 40 9.1.1 Retrosynthetic analysis ........................................................................................................ 40 9.2 Diels‒Alder/epimerisation sequence to the trans-decalin ......................................................... 45 9.2.1 Retrosynthetic analysis ........................................................................................................ 45 9.3 Formation of the trans-decalin core of anthracimycin 114 ........................................................ 61 9.3.1 The synthetic plan ................................................................................................................ 61 9.4 Direct palladium catalysed oxidation studies ............................................................................. 65 9.4.1 Direct palladium catalysed oxidation studies: Stahl conditions .......................................... 65 9.4.2 Direct palladium catalysed oxidation studies: additives effect ........................................... 67 9.4.3 Direct palladium catalysed oxidation studies: the nitrate effect ......................................... 70 9.4.4 Direct palladium catalysed oxidation studies: substrate scope ........................................... 72 9.5 Enone 115 in the Diels-Alder reaction ........................................................................................ 74 9.6 Oxidation of trans-decalin 114 to enone trans-decalin 113 ....................................................... 80 9.6.1 The Ito‒Saegusa oxidation ................................................................................................... 80 9.6.2 The selenoxide elimination .................................................................................................. 84 2 9.6.3 The α-bromination/elimination sequence ........................................................................... 85 9.6.4 The Rubottom oxidation ...................................................................................................... 86 9.6.5 The oxidation in the presence of IBX ................................................................................... 88 9.7 Strategies to the core of anthracimycin 162. .............................................................................. 92 9.7.1 The Ireland‒Claisen rearrangement .................................................................................... 92 9.7.2 The Tsuji‒Trost transformation ......................................................................................... 103 9.7.3 The Mukaiyama‒Michael strategy ..................................................................................... 106 9.7.4 The Hosomi‒Sakurai strategy ............................................................................................ 109 9.7.5 The Hosomi‒Sakurai to the core of streptosetin A ............................................................ 110 9.7.6 The Hosomi‒Sakurai approach towards anthracimycin core 162 ..................................... 111 9.7.7 Functionalisation of the exocyclic double bond ................................................................ 124 9.7.8 The synthesis of the Still‒Gennari reagent 92 ................................................................... 131 10. Conclusions ................................................................................................................................... 136 11. Future work ................................................................................................................................... 138 12. Experimental ................................................................................................................................. 140 12.1 General experimental ............................................................................................................. 140 12.2 Methods and Characterisation of Compounds ....................................................................... 141 13. Abbreviations ................................................................................................................................ 222 14. References .................................................................................................................................... 226 3 3. List of Figures Figure 1. Generations of different antibiotics. ..................................................................................... 13 Figure 2. Mode of action of different antiobitoics. .............................................................................. 15 Figure 3. The chemical structure of anthracimycin 1. .......................................................................... 17 Figure 4. Concentration effect of anthracimycin 1. .............................................................................. 22 Figure 5. The chemical structure of anthracimycin BII-2619 14. .......................................................... 23 Figure 6. The chemical structure of chlorotonil A 15. .......................................................................... 24 Figure 7. Computational calculation to study the biomimetic cycloaddition to form the decalin scaffold of anthracimycin, by Dr. Ian George. ...................................................................................... 32 Figure 8. The transition of anthracimycin 11. ......................................................................................
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