Author ENANTIOSELECTIVE Katharina Anna Röser, BSc SYNTHESIS OF ACYCLIC Submission COMPOUNDS BEARING AN Institute of Organic Chemistry ALL-CARBON QUATERNARY Thesis Supervisor STEREOCENTER VIA Univ.-Prof. Dr. Mario Waser PHASE-TRANSFER- September 2020 CATALYZED NUCLEOPHILIC SUBSTITUTION REACTIONS Master’s Thesis to confer the academic degree of Diplom-Ingenieurin in the Master’s Program Chemistry and Chemical Technology JOHANNES KEPLER UNIVERSITY LINZ Altenberger Straße 69 4040 Linz, Austria jku.at SWORN DECLARATION I hereby declare under oath that the submitted Master’s Thesis has been written solely by me without any third-party assistance, information other than provided sources or aids have not been used and those used have been fully documented. Sources for literal, paraphrased and cited quotes have been accurately credited. The submitted document here present is identical to the electronically submitted text document. Leonding, September 2020 2 ACKNOWLEDGEMENTS I would like to thank Univ.-Prof. Dr. Dr.h.c. Norbert Müller for giving me the opportunity to carry out my Master’s thesis at the Institute of Organic Chemistry at JKU Linz. Special thanks to Ao. Univ.-Prof. Dr. Michael Widhalm and Mag. Bettina Berger for offering me ideal starting conditions when letting me continue their research and for providing starting material and catalyst for carrying out part of my syntheses. I want to express my deep gratitude to Univ.-Prof. Dr. Mario Waser for your guidance and your unconditional support throughout my thesis. Thank you so much for your inspiration and your significant influence you have on me. Some time ago, consciously only having a vague idea of what I’ve been looking for though truly knowing deep within what I tried to find, I listened to my heart intuitively deciding which way I chose. What I’ve found was my deep interest, fascination and love for synthetic organic chemistry as the research topic which is closer to my heart than any other field in science I can imagine; and I also uncovered something else – my inner self. Having the fortune to work with you, Mario, made me spread my wings and let me grow also personally, encouraging me to stay true to my uniqueness and to have faith into myself. Thanks to DI Thomas Bögl from the Institute of Analytical Chemistry for carrying out all the HRMS measurements of my substances. Special thanks to Dr. Beate Hager, Viktoria Naderer and Christian Rückl for offering me the best conditions regarding organization, even in such a challenging situation as the containment measures of COVID-19 drastically impacted our every-day life. Warm thanks to all members of the Institute of Organic Chemistry for the pleasant working environment and for your support. Thank you all for this time full of happiness, that was over much too soon. The isolation we all experienced in spring 2020 let it be perceptible that everything comes to an end one day. But if you do what you do with all of your heart, if you give it a peace of your soul, it becomes part of you and it makes you change. So isn’t it forever then? A very special word of thanks to my parents Claudia and Peter for your love, your continuous support throughout my life and for giving me the chance to follow the way I wanna go. 3 CURRICULUM VITAE Personal Data Date of Birth 02/08/1995 Place of Birth Linz, Austria Nationality Austria Education Since 08/2018 Master’s Program Chemistry and Chemical Technology Johannes Kepler University Linz 10/2013 – 08/2018 Bachelor’s Program Technische Chemie Johannes Kepler University Linz Bachelor Thesis: “Enantioselektive Azidierung eines β - Ketoesters” 09/2005 – 06/2013 Bundesrealgymnasium Landwiedstraße, Linz 09/2001 – 07/2005 Volksschule, Leonding Doppl Practical Experience 08/2019 – 09/2019 Internship at Thermo Fisher Scientific, St.-Peter-Straße 25, Linz, Austria 4 TABLE OF CONTENTS ABSTRACT ..............................................................................................................................................8 1. INTRODUCTION ..............................................................................................................................9 1.1. Significance and utilization of compounds bearing all-carbon quaternary stereocenters ..................................................................................................................................... 9 1.2. Synthetic methods for preparation of compounds bearing all-carbon quaternary stereocenters ................................................................................................................................... 10 1.2.1. Radical reactions ........................................................................................................... 10 1.2.2. Enzymatic synthesis ...................................................................................................... 11 1.2.3. Enantioselective desymmetrization of quaternary carbon atoms .................................. 12 1.2.4. Chiral auxiliary approach ............................................................................................... 13 1.2.5. Diels-Alder reactions...................................................................................................... 14 1.2.6. Rearrangement reactions .............................................................................................. 16 1.2.7. Heck reaction ................................................................................................................. 17 1.2.8. C-H Functionalization .................................................................................................... 18 1.2.9. Allylic alkylation .............................................................................................................. 19 1.2.10. Aldol reactions ........................................................................................................... 20 1.2.11. Michael addition ......................................................................................................... 21 1.2.12. Phase-transfer catalysis ............................................................................................ 22 1.2.13. Phase-transfer catalyzed construction of quaternary stereocenters utilizing malonates as nucleophiles ............................................................................................................ 24 2. OBJECTIVES ................................................................................................................................ 28 3. RESULTS AND DISCUSSION ...................................................................................................... 29 3.1. Comparison of different synthetic approaches for preparation of tert-butyl 2-cyano- 3-(1,3-dioxolan-2-yl)propanoate (90) ............................................................................................. 29 3.1.1. α-Alkylation employing NaH as base ................................................................................. 29 3.1.2. α-Alkylation performed as a one-phase reaction without a catalyst .................................. 30 3.1.3. α-Alkylation utilizing aqueous bases under phase-transfer catalysis ................................ 30 3.1.4. Observations in connection with the synthesis of compound 90 ....................................... 36 3.1.5. Alternative preparation of compound 90 employing the mesylated derivative of electrophile 97 ................................................................................................................................... 39 3.2. Testing of reaction conditions in order to improve enantioselectivity for benzylation of tert-butyl 2-cyano-3-(1,3-dioxolan-2-yl)propanoate (90)..................................... 41 3.2.1. Screening of various phase-transfer catalysts .................................................................. 41 3.2.2. Screening of bases and solvents ....................................................................................... 43 3.2.3. Variation of reaction conditions ......................................................................................... 45 3.2.4. Results for modified procedures carrying out the synthesis of compound 92 ................... 47 3.2.5. Results for application of a binary catalyst system of chiral Maruoka phase-transfer catalyst and achiral crown ether ........................................................................................................ 48 3.3. Influence of starting material 90 quality on the enantioselectivity in construction of the quaternary stereocenter of product 92 and 117 .................................................................... 50 5 3.3.1. Dependency of the enantioselectivity of product 92 on the “color” of the starting material 90 ......................................................................................................................................... 50 3.3.2. Determination of the starting material 90 quality used for the asymmetric scope for construction of the quaternary stereocenter ...................................................................................... 51 3.3.3. Further studies on the influence of the starting material 90 quality assessed by comparison of the enantioselectivities of product 117 ...................................................................... 51 3.4. Alternative synthetic strategy for preparation of compound 92 via the monobenzylated cyanoacetate 118 ..............................................................................................