SYNTHESIS OF SMALL MOLECULE ANTAGONISTS AT THE ANDROGEN RECEPTOR FOR PROSTATE CANCER TREATMENT AND EFFORTS TOWARD AN ENANTIOSELECTIVE CO(II)-CATALYZED CYCLOPROPANATION by Serene Tai B.S. Chemistry, Tennessee Technological University, 2015 Submitted to the Graduate Faculty of the Kenneth P. Dietrich School of Arts and Sciences in partial fulfillment of the requirements for the degree of Master of Science University of Pittsburgh 2018 UNIVERSITY OF PITTSBURGH DIETRICH SCHOOL OF ARTS AND SCIENCES This thesis was presented by Serene Tai It was defended on November 14th, 2017 and approved by Dr. Paul Floreancig, Professor, Department of Chemistry Dr. Peng Liu, Assistant Professor, Department of Chemistry Thesis Advisor: Dr. Peter Wipf, Distinguished University Professor, Department of Chemistry ii Copyright © by Serene Tai 2018 iii SYNTHESIS OF SMALL MOLECULE INHIBITORS OF ANDROGEN RECEPTOR FOR PROSTATE CANCER TREATMENT Serene Tai, MS University of Pittsburgh, 2018 This thesis describes the synthesis of fluorinated cyclopropane analogues to enhance the metabolic stability of a previously published lead candidate for prostate cancer treatment. A structural unique motif such as the bicyclo[1.1.0]pentane was also incorporated to investigate its potential as cyclopropane bioisostere. Preliminary results from liver microsome and luciferase assays suggested that fluorinations on the cyclopropane carbon atoms have little impact on the metabolic stability. However, fluorination on other labile sites showed enhanced metabolic stability while retaining compound potency. An enantioselective route to improve the original racemic synthesis of these analogues was also investigated. The key step was a Co(II)-salen catalyzed enantioselective cis-cyclopropanation of an olefin with ethyl diazoacetate to provide the cyclopropyl amide in 98% ee over three high-yielding steps. iv TABLE OF CONTENTS 1.0 SYNTHESIS OF SMALL MOLECULE ANTAGONISTS AT THE NUCLEAR ANDROGEN RECEPTOR FOR PROSTATE CANCER TREATMENT ............................. 1 1.1 INTRODUCTION ............................................................................................... 1 1.1.1 Prostate cancer ................................................................................................. 1 1.1.2 Androgen receptor (AR) and androgen ......................................................... 2 1.1.3 Androgen deprivation therapy (ADT) ........................................................... 6 1.1.4 High-throughput screening (HTS) ................................................................. 9 1.1.5 Development of lead compound JJ-450 ....................................................... 10 1.1.6 Metabolic stability of JJ-450 ......................................................................... 12 1.1.7 Fluorine improves metabolic stability in small molecule drugs ................ 13 1.2 RESULTS AND DISCUSSION ........................................................................ 15 1.2.1 Synthesis of fluorinated cyclopropane analogues of JJ-450 ...................... 15 1.2.1.1 Fluorination and trifluoromethylation at the benzylic position ..... 15 1.2.1.2 Fluorination and trifluoromethylation at the α-carbonyl position . 16 1.2.1.3 Synthesis of gem-difluorocyclopropa(e)ne analogues ...................... 18 1.2.2 Bicyclo[1.1.1]pentane (BCP) as a bioisostere in medicinal chemistry ...... 23 1.2.2.1 Design and synthesis of BCP analogues ............................................ 25 v 1.2.3 Configuration determination of cyclopropane analogues .......................... 28 1.2.3.1 Determination of relative configuration ........................................... 28 1.2.3.2 Determination of absolute configuration .......................................... 30 1.2.4 Biological data ................................................................................................ 34 1.2.5 Conclusion ...................................................................................................... 40 2.0 EFFORTS TOWARD AN ENANTIOSELECTIVE CO(II)-CATALYZED CYCLOPROPANATION .......................................................................................................... 41 2.1 INTRODUCTION ............................................................................................. 41 2.1.1 Synthetic route toward JJ-450 and its analogues ....................................... 41 2.1.2 Enantioselective cis-cyclopropanation ......................................................... 42 2.2 RESULTS AND DISCUSSION ........................................................................ 45 2.2.1 Design and synthesis of Co(II)-salen complexes ......................................... 45 2.2.2 Gram-scale Co(II)-salen catalyzed asymmetric cyclopropanation ........... 48 2.2.3 Proposed mechanism for asymmetric induction......................................... 49 2.2.4 Conclusion ...................................................................................................... 51 3.0 EXPERIMENTAL SECTION .................................................................................. 52 3.1 GENERAL PROCEDURE ............................................................................... 52 3.2 EXPERIMENTAL PROCEDURES ................................................................ 53 APPENDIX A ............................................................................................................................ 112 APPENDIX B ............................................................................................................................ 169 APPENDIX C ............................................................................................................................ 177 BIBLIOGRAPHY ..................................................................................................................... 235 vi LIST OF TABLES Table 1. Attempted difluorocarbene additions to cis-alkene and alkyne ...................................... 19 Table 2. Screening for trans-to-cis isomerization conditions ....................................................... 20 Table 3. Condition screening for hydrogenation of difluorocyclopropene ................................... 22 Table 4. Tentative absolute configuration assignment of the analogues. ..................................... 32 Table 5. Half-life of analogues in mouse liver microsomes. ........................................................ 35 Table 6. Half-life of analogues with more stable side chains in mouse liver microsomes ........... 36 Table 7. Luciferase activity of selected analogues ....................................................................... 38 Table 8. Asymmetric cyclopropanation using Co(II)-salen complexes ........................................ 47 Table 9. Crystal Data for 3b. ...................................................................................................... 179 Table 10. Data collection and structure refinement for 3b. ........................................................ 179 Table 11. Atomic coordinates and equivalent isotropic atomic displacement parameters (Å2) for 3b. ............................................................................................................................................... 180 Table 12. Bond lengths (Å) for 3b. ............................................................................................. 180 Table 13. Bond angles (°) for 3b. ............................................................................................... 181 Table 14. Anisotropic atomic displacement parameters (Å2) for 3b. ......................................... 181 Table 15. Hydrogen atomic coordinates and isotropic atomic displacement parameters (Å2) for 3b. ............................................................................................................................................... 182 vii Table 16. Crystal data for 6a. ...................................................................................................... 184 Table 17. Data collection and structure refinement for 6a. ......................................................... 184 Table 18. Atomic coordinates and equivalent isotropic atomic displacement parameters (Å2) for 6a................................................................................................................................................. 185 Table 19. Bond lengths (Å) for 6a. ............................................................................................. 186 Table 20. Bond angles (°) for 6a. ................................................................................................ 187 Table 21. Anisotropic atomic displacement parameters (Å2) for 6a. ......................................... 188 Table 22. Hydrogen atomic coordinates and isotropic atomic displacement parameters (Å2) for 6a................................................................................................................................................. 189 Table 23. Crystal data for 11a. .................................................................................................... 192 Table 24. Data collection and structure refinement for 11a. ...................................................... 192 Table 25. Atomic coordinates and equivalent isotropic atomic displacement parameters (Å2) for 11a............................................................................................................................................... 193 Table 26.