University of Wisconsin Milwaukee UWM Digital Commons Theses and Dissertations May 2015 Asymmetric Synthesis of Tryptophan Driviatives and Its Application to Streamlined Synthesis of Tryprosatain A and B Matthew uiH sman University of Wisconsin-Milwaukee Follow this and additional works at: https://dc.uwm.edu/etd Part of the Organic Chemistry Commons Recommended Citation Huisman, Matthew, "Asymmetric Synthesis of Tryptophan Driviatives and Its Application to Streamlined Synthesis of Tryprosatain A and B" (2015). Theses and Dissertations. 880. https://dc.uwm.edu/etd/880 This Dissertation is brought to you for free and open access by UWM Digital Commons. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of UWM Digital Commons. For more information, please contact [email protected]. ASYMMETRIC SYNTHESIS OF TRYPTOPHAN DRIVIATIVES AND ITS APPLICATION TO STREAMLINED SYNTHESIS OF TRYPROSATAIN A AND B. by Matthew Marcus Huisman A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy In Chemistry at The University of Wisconsin-Milwaukee May 2015 ii ABSRACT ASYMMETRIC SYNTHESIS OF TRYPTOPHAN DRIVIATIVES AND ITS APPLICATION TO STREAMLINED SYNTHESIS OF TRYPROSATAIN A AND B. BY Matthew Marcus Huisman The University of Wisconsin-Milwaukee, 2015 Under the Supervision of Professor Mahmun M. Hossain Tryprostatins have been shown to be potential antitumor antimitotic agents. Tryprostatins have been isolated from the fermentation broth of marine fungal strain Aspergillus fumigatus in trace amounts. Our lab has developed a phase-transfer-catalyzed asymmetric alkylation reaction to produce protected tryptophans (Trp) with high enantioselectivity (90-95% ee) as synthetic precursors to Tryprostatins. Studies of Tryprostatins indicate that manipulation of ring-A may cause enhanced activity. We propose a general synthetic route to several new tryprostatins that may be tolerant to ring-A analogues of gramine utilizing achiral reactants. The synthesis of Tryprostatin B has been completed with 20% overall yield in 7 steps. In the future our group will hopefully be able to utilize this chemistry to develop a large number of Tryprostatin analogs. We hope that one of these derivatives will be selective against cancer cells, with therapeutic concentrations in the nanomolar region. iii TABLE OF CONTENTS CHAPTER PAGE TABLE OF CONTENTS....................................................................................................................... iii LIST OF FIGURES ............................................................................................................................... v LIST OF TABLES ............................................................................................................................... vii LIST OF SCHEMES .......................................................................................................................... viii 1. INTRODUCTION ........................................................................................................................ 1 1.1. Tryprostatin A and B and their Biological Activity. ............................................................... 1 1.2. Development of this work by the Cook Group ..................................................................... 6 1.3. Fukuyama’s synthesis ......................................................................................................... 12 1.4. Cell Cycle and Anticancer Drugs.......................................................................................... 15 1.5. Inhibitors of Chromatin Function ........................................................................................ 18 1.6. Inhibitors of Breast Cancer Resistance Protein................................................................... 21 1.7. Benzophenone Imine Glycine Schiff Base ........................................................................... 21 1.8. Asymetric Phase-Transfer Catalysis Utilizing Chiral Quaternary Ammonium Salts: Asymmetric ................................................................................................................................ 25 1.9. Diketopiperizine rings and their significance ...................................................................... 28 2. BACKGROUND ............................................................................................................................ 31 2.1. Development of the Acrylates ............................................................................................ 31 2.2. Acrylates to 3-ethylesterindoles ......................................................................................... 33 2.3. 3-ethylesterindoles to gramines ......................................................................................... 35 3. OBJECTIVE .................................................................................................................................. 44 3.1. Optically active tryptophan derivatives .............................................................................. 44 3.2. Using optically active tryptophan to synthesize natural product tryprostatin A and B ..... 44 3.3. Utilizing enantio-enriched tryptophan and tryprostatin synthesis to make derivatives of tryprostatin ................................................................................................................................ 44 4. RESULTS...................................................................................................................................... 45 4.1. Synthesis of optically active tryptophan and three analogs ............................................... 45 4.2. Utilization of optically active tryptophan to synthesis natural product tryprostatin B ...... 46 4.3. Previous Tryprostatin syntheses ......................................................................................... 48 4.4. Our proposed synthesis ...................................................................................................... 51 iv 4.5. Alternative proposed synthesis .......................................................................................... 55 4.6. Monitoring the effectiveness of the C-2 isoprenyl quaternary ammonium bromide salt . 61 4.7. Attempts to synthesis Tryprostatin B ................................................................................. 64 4.8. DKP ring closure by microwave in water ............................................................................ 73 5. CONCLUSION .......................................................................................................................... 79 5.1. Importance of tryptophan and asymmetric synthesis in medicinal chemistry .................. 79 5.2. Our initial goals: .................................................................................................................. 80 5.3. Utilization asymmetric synthesis to make natural products tryprostatin A and B ............. 82 5.4. The future plans of this project: ......................................................................................... 83 6. EXPERIMENTAL SECTION ........................................................................................................... 84 7. DATA ........................................................................................................................................ 145 8. VITA .......................................................................................................................................... 259 9. REFERENCE ............................................................................................................................... 256 v LIST OF FIGURES Figure 1. Tryprostatin A and B ......................................................................................................... 1 Figure 2. Spirotryprostatins ............................................................................................................. 2 Figure 3. Cyclotryprostatins ............................................................................................................. 3 Figure 4. Fumitremorgins ................................................................................................................ 3 Figure 5. V-70 radical initiator ....................................................................................................... 13 Figure 6. The cell cycle ................................................................................................................... 15 Figure 7. Cell cycle representing G1, S, and G2 phases. ................................................................ 16 Figure 8. Cell cycle showing mitosis. ............................................................................................. 17 Figure 9. Microtubules roll in cell division ..................................................................................... 19 Figure 10. Chromosome division along microtubules ................................................................... 20 Figure 11. Comparison of Sörensen’s Glycine Anion and O’Donnell’s Glycine Anion ................... 22 Figure 12. Comparison of acidity of protons on alpha carbon when not alkylated and when mono alkylated. ............................................................................................................................. 22 Figure 13. First Generation Cinchona Alkaloids ............................................................................