University of the Pacific Scholarly Commons University of the Pacific Theses and Dissertations Graduate School 2020 EXPLORATION OF CIS-1,2-DIAMINOCYCLOHEXANE-BASED CONFORMATIONALLY LOCKED CHIRAL LIGANDS IN ASYMMETRIC SYNTHESIS Carim van Beek University of the Pacific, [email protected] Follow this and additional works at: https://scholarlycommons.pacific.edu/uop_etds Part of the Organic Chemistry Commons Recommended Citation van Beek, Carim. (2020). EXPLORATION OF CIS-1,2-DIAMINOCYCLOHEXANE-BASED CONFORMATIONALLY LOCKED CHIRAL LIGANDS IN ASYMMETRIC SYNTHESIS. University of the Pacific, Dissertation. https://scholarlycommons.pacific.edu/uop_etds/3680 This Dissertation is brought to you for free and open access by the Graduate School at Scholarly Commons. It has been accepted for inclusion in University of the Pacific Theses and Dissertations by an authorized administrator of Scholarly Commons. For more information, please contact [email protected]. 1 EXPLORATION OF CIS-1,2-DIAMINOCYCLOHEXANE-BASED CONFORMATIONALLY LOCKED CHIRAL LIGANDS IN ASYMMETRIC SYNTHESIS By Carim van Beek A Dissertation Submitted to the Graduate School In Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Thomas J. Long School of Pharmacy and Health Sciences Pharmaceutical and Chemical Sciences University of the Pacific Stockton, California 2020 2 EXPLORATION OF CIS-1,2-DIAMINOCYCLOHEXANE-BASED CONFORMATIONALLY LOCKED CHIRAL LIGANDS IN ASYMMETRIC SYNTHESIS By Carim van Beek APPROVED BY: Dissertation Advisor: Vyacheslav V. Samoshin, Ph.D. Committee Member: Liang Xue, Ph.D. Committee Member: Jianhua Ren, Ph.D. Committee Member: Andreas Franz, Ph.D. Committee Member: Mamoun Alhamadsheh, Ph.D. Department Co-Chair: Jianhua Ren, Ph.D. Department Co-Chair: Jerry Tsai, Ph.D. 3 EXPLORATION OF CIS-1,2-DIAMINOCYCLOHEXANE-BASED CONFORMATIONALLY LOCKED CHIRAL LIGANDS IN ASYMMETRIC SYNTHESIS Copyright 2020 By Carim van Beek 4 DEDICATION We can get better, because we’re not dead yet. 5 ACKNOWLEDGMENTS First of all, I would like to sincerely thank my advisor Dr. Vyacheslav Samoshin for giving me the opportunity to pursue my PhD degree in his lab. Through the experience I gained under his supervision I greatly improved my experience in tackling complex scientific problems, something I deeply appreciate. I would also like to thank Dr. Nataliya Samoshina for teaching me how to construct liposomes, and I am sad that she is not with us anymore today. I would like to express my sincere gratitude to my dissertation committee, consisting of Dr. Andreas Franz, Dr. Jianhua Ren, Dr. Liang Xue, and Dr. Mamoun Alhamadsheh, for their willingness to share their expertise and provide valuable feedback on my dissertation. I would like to acknowledge Dr. Vincent Catalano and Dr. Kin Zhao for providing me with X-ray crystallography data and aiding me in visualizing proper crystal structures. On an official note, I would like to acknowledge Amano Enzyme, and Agilent Technologies, for their support in my research through the provision of materials. In financially supporting my research, I would like to express my gratitude for the PCSP Graduate Series Seminarian of the Year Awards (2019, 2018), the ACS Division of Organic Chemistry Travel Award (2019), the PCSP College of the Pacific Dean’s Travel Award (2019), the John H. Shinkai Endowed Graduate Student Scholarship (2018), the College Research Fund (2018), and the PCSP Graduate Series Award of Merit (2017). Without the help of the undergraduates I mentored throughout my time at UOP, I could never have realized as much work as I have. I would therefore like to thank Kelsey Wong, Vinh 6 Truong, Kara Smolinksi, Isaak Mercado, Zoë Ingram, Olivia Laprade, Chiron Tran, and Gabi Sonderegger. Additionally, I would like to thank Dr. Jerry Tsai and Dr. Jianhua Ren for their support in dealing with any difficulties I encountered during my time in the PCSP Program, and I would like to thank Prof. David Sparkman for recruiting me into the MS facility, granting me access to all MS instrumentation, providing me with a great course in mass spectrometry, and making Spring ’17 the most horrific semester in the history of mankind. I would like thank my former and current lab mates, Dr. Ronnie, Master Marcos, and Oscar, for their collaborations, discussions, support, having a good time in the lab (and insulting me in my own language, Marcos). My time at University of the Pacific wouldn’t have been the same without some of the new friends I made, whom I all deeply appreciate. Refraining from any particular ranking order, I am particularly grateful for my friends Mandeep, Taylor, and Marcos. Even though we have been separated for most of the time, I am incredibly grateful for my family supporting me from a distance. Pa en Ma, ook al begrijpen jullie over het algemeen geen zak van wat ik doe, ik waardeer jullie continue enthousiasme, liefde, en steun gedurende deze tijd ontzettend. Floor en Guus, ik waardeer het ontzettend dat jullie ons zijn komen bezoeken in de VS en vond het super om deel uit te maken van jullie verloving. Daarnaast ben ik natuurlijk supertrots op de kleine Morris! Jens en Jim, jullie zijn natuurlijk een stelletje luie eikels, maar ik waardeer het toch ontzettend dat jullie voor mijn verjaardag naar de VS zijn gekomen en af en toe wat hebben laten horen, kwaliteit boven kwantiteit. Verder wil ik mijn 7 oom en goede vriend Peter bedanken voor al onze gesprekken (deze waardeer ik enorm), en de goede tijd die we gehad hebben in Canada (Carla natuurlijk ook!). Vertrekken naar een ander land brengt veel onzekerheden met zich mee en de vraag of je oude vrienden je nog herkennen na 4.5 jaar is een spannende. Ik ben dankbaar voor alle vrienden waarmee ik nog steeds contact onderhoud ondanks de afstand, en specifiek erg dankbaar voor Joost, Marijn, Britta, Gaston, en Marleen. De laatste persoon die ik wil bedanken is Maike, samen zijn we naar de VS vertrokken om dit avontuur tegemoet te gaan. We hebben aardig wat te verduren gekregen als gevolg van het verhuizen naar een nieuw land, in combinatie met lange reistijden en ontzettend drukke schema’s. Deze vallen echter compleet in het niet bij alle mooie ervaringen die we hier hebben opgedaan. Zonder jou had ik deze PhD waarschijnlijk nooit gehaald, zonder jouw onvoorwaardelijke steun, enthousiasme, en liefde, was ik nooit gekomen waar ik nu ben, hiervoor ben ik je enorm dankbaar. 8 EXPLORATION OF CIS-1,2-DIAMINOCYCLOHEXANE-BASED CONFORMATIONALLY LOCKED CHIRAL LIGANDS IN ASYMMETRIC SYNTHESIS Abstract By Carim van Beek University of the Pacific 2020 Natural products have been demonstrated to be of great significance to the pharmaceutical industry in the development of new drugs and medicine. Unfortunately, synthetic approaches to obtain these natural products often prove increasingly challenging due to the complexity of synthesizing the target drug in the proper stereochemistry. The availability of enantioselective reactions can play a pivotal role in overcoming this challenge, yielding access to optically pure intermediates and products. Chiral ligands based on a trans-1,2- diaminocyclohexane motif are often employed for this purpose and their complexes with transition metals have been demonstrated to act as efficient chiral catalysts in asymmetric reactions. In contrast, studies involving cis-1,2-diaminocyclohexane derivatives as chiral catalysts are strongly underrepresented. We have designed and performed the synthesis of an axially chiral conformationally locked cis-1,2-diamine scaffold, conveniently designed for further derivatization into more complex structures. A key step in this synthesis was the chiral resolution of a racemic intermediate, realized through both chemical and enzymatic means in a comparative study. Utilizing the newly gained optically pure primary diamine scaffold, a library of chemically 9 diverse secondary diamine ligands has been synthesized and characterized through NMR spectroscopy, mass spectrometry, and chiral HPLC. Assignment of the absolute configuration within the cis-1,2-diamine scaffold was realized through single-crystal X-ray crystallography experiments on one of the synthetic intermediates. The synthesized ligands have been evaluated for their potential to function as chiral catalysts in the asymmetric Henry reaction and asymmetric transfer hydrogenation. As a function of both steric and electronic structural variation, a range of catalytic activities and enantioselectivities in the Henry reaction were observed. The ligands proved to be less suitable for asymmetric transfer hydrogenation with only a select number of ligands catalyzing the reaction, and a single example resulting in a decent enantioselectivity. We additionally explored the possibility of incorporating a chemical switch into the scaffold, responsible for switching the axial chirality of the molecule. As a consequence of inverting the axial chirality, the configuration of the potential reaction product in asymmetric synthesis would also be inverted. To this extent, we performed the synthesis of a novel specifically designed crown ether, dicyclohexeno-18-crown-6, furnished with two π-bonds in the cyclohexane rings, allowing for additional modification into more advanced functionalized structures. 10 TABLE OF CONTENTS List of Tables ................................................................................................................................. 12 List of Figures ...............................................................................................................................