University of Pennsylvania ScholarlyCommons Master of Chemical Sciences Capstone Projects Department of Chemistry 5-2017 Synthesis of Novel Tröger’s Base-Derived Helical Scaffolds Rahul Goel University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/mcs_capstones Part of the Chemistry Commons Goel, Rahul, "Synthesis of Novel Tröger’s Base-Derived Helical Scaffolds" (2017). Master of Chemical Sciences Capstone Projects. 5. https://repository.upenn.edu/mcs_capstones/5 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/mcs_capstones/5 For more information, please contact [email protected]. Synthesis of Novel Tröger’s Base-Derived Helical Scaffolds Abstract Tröger’s base (TB) is a chiral V-shaped molecule in which the aromatic rings are nearly perpendicular. The overarching goal of this project is to utilize the unique chirality and inherent shape of the Tröger’s base monomer to design, synthesize and study dimeric, tetrameric and octameric TB oligomers, which will form helical structures. We describe here the methodology for the synthesis of novel Tröger’s base diester monomer 13, which is highly soluble in most organic solvents compared to TB systems with methylene bridges. Chiral HPLC resolution of TB monomer 18, using a semiprep chiral AD-H column, gave access to pure enantiomers of the TB monomer. The (-)-enantiomer of 18 was used to synthesize the novel syn diester TB dimer 20, via double Buchwald-Hartwig coupling based phenazine formation. Energy minimization modeling of the syn dimer 20 using Web MO shows a potential binding cleft, which can ultimately be applied for the synthesis of desired tetrameric and octameric scaffolds. The chiral HPLC resolution of TB monomer 18 is expensive, time-consuming and has low scalability. This problem was solved by the synthesis of a menthone-based chiral auxiliary 27, which allows easy access to the enantiopure monomers of TB. The chirality of 27 was utilized to form the diastereomers of menthone TB 33, which were readily separable by column chromatography. These diastereomers were then hydrolyzed to give pure enantiomers of diol TB monomer 34. Keywords Tröger’s Base, TB, oligomers, Helical, Helical scaffolds, dimer, monomer, tetramer, octamer, menthone, chiral, auxiliary, Chiral resolution of Tröger’s Base Disciplines Chemistry Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License. This capstone report is available at ScholarlyCommons: https://repository.upenn.edu/mcs_capstones/5 AN ABSTRACT OF THE CAPSTONE REPORT OF Rahul Goel for the degree of Master of Chemical Sciences Title: Synthesis of Novel Tröger’s Base-Derived Helical Scaffolds Project conducted at: Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104, United States of America Supervisor: Jeffrey D. Winkler Dates of Project: May 6, 2016 to May 1, 2017 Abstract approved: Professor Jeffrey D. Winkler Tröger’s base (TB) is a chiral V-shaped molecule in which the aromatic rings are nearly perpendicular. The overarching goal of this project is to utilize the unique chirality and inherent shape of the Tröger’s base monomer to design, synthesize and study dimeric, tetrameric and octameric TB oligomers, which will form helical structures. We describe here the methodology for the synthesis of novel Tröger’s base diester monomer 13, which is highly soluble in most organic solvents compared to TB systems with methylene bridges. Chiral HPLC resolution of TB monomer 18, using a semiprep chiral AD-H column, gave access to pure enantiomers of the TB monomer. The (-)-enantiomer of 18 was used to synthesize the novel syn diester TB dimer 20, via double Buchwald-Hartwig coupling based phenazine formation. Energy minimization modeling of the syn dimer 20 using Web MO shows a potential binding cleft, which can ultimately be applied for the synthesis of desired tetrameric and octameric scaffolds. The chiral HPLC resolution of TB monomer 18 is expensive, time-consuming and has low scalability. This problem was solved by the synthesis of a menthone-based chiral auxiliary 27, which allows easy access to the enantiopure monomers of TB. The chirality of 27 was utilized to form the diastereomers of menthone TB 33, which were readily separable by column chromatography. These diastereomers were then hydrolyzed to give pure enantiomers of diol TB monomer 34. Synthesis of Novel Tröger’s Base-Derived Helical Scaffolds by Rahul Goel A CAPSTONE REPORT submitted to the University of Pennsylvania in partial fulfillment of the requirements for the degree of Master of Chemical Sciences Presented (May 1, 2017) Commencement (May 2017) ii Dedicated to my parents, Rajeev and Kavita Goel iv ACKNOWLEDGEMENTS I would first like to thank Professor Jeffrey D. Winkler for all the support and guidance that he has provided me over the last two years. His expert advice and encouragement has not only helped me evolve as a better chemist, but also as a better person. I will be forever grateful to Professor Winkler for giving me the opportunity to be a part of his research group, and learn the necessary skills that will help me during my entire career. I would also like to thank Dr. Ana-Rita Mayol for her continued support during my time at the University of Pennsylvania. From writing my capstone proposal to writing my final capstone report, Dr. Mayol has helped me during each step of the Master’s program. I would also like to thank Professor Donna Huryn for her valuable guidance, comments and feedback during the last two years. Next, I would like to thank the members of the Winkler group- Dr. Rosa Cookson. Dr. Michelle Estrada, Dr. Buddha Khatri, Dr. Sara Goldstein, Mike Nicastri, Katie Crocker and Tyler Higgins for being great mentors and friends. Without their patience and instruction, I would not have been able to come this far. I would also like to thank all my MCS friends, who made graduate school a memorable experience. Last but not the least, I would like to thank my parents, Rajeev and Kavita Goel, for their guidance, support, love and wisdom over the last 25 years. They have always been the constant source of my inspiration during everything that I have ever been a part of. None of this would have been possible without them being there to encourage and motivate me at every step of my journey. I would also like to thank my brother Sahil for always cheering me up during stressful times and being a constant pillar of support throughout. v TABLE OF CONTENTS Abstract…………………………...………………………………………………...........i Title page…………………………………………………………………...……………ii Approval page………………...………………………………………………………...iii Dedication……………………....…………………………………………………….…iv Acknowledgements……………....……………………..…………....………………..v Table of contents…………………...…………………………………………………..vi List of figures…………………….......…………………………………………………vii List of schemes……………...………………………………………………………...viii List of tables……………………...……………………………………………………..ix List of appendices……………………...…………………………………………….…x Introduction………………………………...…………………………………………....1 Materials and methods………………………...……………………………………....7 Results and Discussion……………………………...……………………………….17 Synthesis of TB helical scaffolds……………...…………………………..…17 Preliminary binding studies with Hydroquinone…………………………….23 Menthone-based chiral auxiliary for better separation of enantiomers……………………………………………………………….……25 Conclusion…………………………...………………………………………………...29 References……………...………………...…………………………………………...30 Appendices………………..……………..……...……………………………………..32 vi LIST OF FIGURES Figure 1. Tröger’s base………………………………………………………….….....1 Figure 2. Existing helical systems by Hamilton, Boger and Arora………………...2 Figure 3. TB monomer 1, extended pseudo-dimers syn 2 and 3, and anti 4…………..…………………………………………………………...…3 Figure 4. The ABA problem associated with conventional TB synthesis…………3 Figure 5. Double Buchwald- Hartwig coupling based synthesis of phenazine 5………………………..………………………………………...4 Figure 6. Energy minimized space-filling models (MM2) of the TB monomer 1.............................................................................................4 Figure 7. Energy minimized space-filling models of A) 6’, syn diastereomer of the TB dimer 6; C) 7’, anti diastereomer of the TB dimer 7……..………...……………………………………………...4 Figure 8. Energy minimized space filling models of A) 8’, side view of TB Tetramer 8; B) 8’’, top view of 8; C) 9’, side view of TB octamer 9; D) 9’’, top view of 9…....……………….……………………...5 Figure 9. TB monomer 10 and the syn TB phenazine dimer 6…………………....6 Figure 10. Energy minimized Web MO model of the TB dimer 14……..………..18 Figure 11. Energy minimized Web MO models of A) 15’, top view of diester TB tetramer 15; B) 15’’, side view of 15…………………........19 Figure 12. Energy minimized Web MO models of A) 16’, top view of diester TB octamer 16 and B) 16’’, side view of 16…………….….….20 Figure 13. 1H NMR peak shifts for syn dimer (graph 1,2,3 and 4) and hydroquinone (graph 5), with the increasing concentration of hydroquinone in 2:1 THF-d8/D2O………………………………………..24 vii LIST OF SCHEMES Scheme 1. Proposed synthesis showing the formation of more soluble monomer, which will be used to synthesize the syn TB oligomers…………….......................................................................…7 Scheme 2. Synthesis of methylene TB 11, diazocine 12 and Diester TB monomer 13..……………...…………………………………………18 Scheme 3. Synthesis of Diester TB monomer 17 and 18, and chiral resolution of diester