Inherently chiral calixarenes; methodology and applications by Dominic Christian Castell Submitted in partial fulfilment of the requirements for the degree Doctor of Philosophy at Stellenbosch University Department of Chemistry and Polymer Science Faculty of Science Supervisor: Dr. G. E. Arnott Date: August 2016 Stellenbosch University https://scholar.sun.ac.za DECLARATION By submitting this thesis electronically, I declare that the entirety of the work contained therein is my own, original work, that I am the owner of the copyright thereof (unless to the extent explicitly stated otherwise) and that I have not previously in its entirety or in part submitted it for obtaining any qualification. ______________________ Signature ______________________ Name in full ______/_____/__________ Date Copyright © 2016 Stellenbosch University All rights reserved i Stellenbosch University https://scholar.sun.ac.za Abstract The use of chiral directing groups has provided an efficient route to meta-functionalised inherently chiral calixarenes. Previously reported ortholithiation methods, incorporating chiral oxazolines have been reexamined, with the aim of revising the individual roles of the three major components of the reaction. The potential mechanistic ramifications of the solvent, additive and alkyllithium structure on the reaction outcomes were individually evaluated. The overarching complexity inherent in this chemistry, coupled with a wide scope of experimental results, point to a number of substrate, solvent and also reagent dependent reaction mechanisms. In addition to the oxazolines, the tert-butyl sulfoxide functional group has also been established as an effective chiral auxiliary for this ortholithiation strategy, yielding enriched diastereomeric mixtures of inherently chiral sulfoxide calixarenes. The absolute stereochemistry of these major and minor products were determined crystallographically. Despite restrictions in electrophile choice, an efficient desulfurization method afforded a route to a new class of meta-functionalised inherently chiral compounds. With the view to evaluating the potential of inherent chirality, oxazoline-directed ortholithiation methods were used to synthesize a new class of inherently chiral phosphine oxazoline ligands. The results from the application studies of these compounds, to both the Tsuji-Trost allylation and asymmetric Suzuki coupling reactions, suggested a definitive relationship between the configurations of the inherent chirality of the calixarene, and central chirality of the oxazoline auxiliary. A model of the -allyl palladium intermediate responsible for the enantioselection seen in the Tsuji-Trost reaction has been proposed for these calixarene ligands. The model was constructed using previously reported calixarene crystallographic data, in conjunction with numerous solid-state and computational studies of simpler Phox ligand systems. The experimental results obtained for this reaction were found to be in good correlation with the proposed model for the inherently chiral calixarene ligands. To confirm these observations, two additional inherently chiral Phox ligands, lacking a stereocenter on the oxazoline, were synthesized. Their preliminary application to the Tsuji-Trost allylation also yielded enantiomerically enriched product mixtures. These results point to a significant contribution made by the inherent chirality, toward the overall asymmetric induction observed in the reaction. These findings serve as a positive affirmation of the viability of inherently chiral calixarenes in the field of asymmetric catalysis, and create a platform for further development of new ligands containing this structural property. ii Stellenbosch University https://scholar.sun.ac.za Opsomming Die gebruik van chirale regie groepe verskaf ‘n doeltreffende roete tot meta-gefunksionaliseerde inherente chirale calixarene. Ortolitiëring metodes wat chirale oksasoliene inkorporeer, waarop daar voorheen verslag gelewer is, is weer ondersoek. Hierdie ondersoek is onderneem om die individuele rolle van die drie hoofkomponente van die reaksie te hersien. Die potensiële meganistiese effek van die oplosmiddel, ligande, en alkiellitiumstruktuur op die reaksie uitkomstes (not sure about uitkomstes, maybe produkte?), is individueel ondersoek. Die oorkoepelende inherente kompleksiteit van hierdie chemie, tesame met die breë omvang van die eksperimentele resultate, dui daarop dat daar ‘n hele paar substraat-, oplosmiddel-, en reagensafhanklike reaksiemeganismes teenwoordig is. Tersiêre-butielsulfoksied funksionele groepe is ook bevestig as ‘n effektiewe chirale hulpsgroep vir hierdie ortolitiasiestrategie, wat ‘n opbrengs van verrykde diastereomeriese mengsels van inherente chirale sulfoksied calixerene lewer. Die absolute stereochemie van die hoof- en byprodukte is bepaal deur die gebruik van kristallografie. Ten spyte van beperkte keuse van elektrofiele, is ‘n doeltreffende ontswawelingsmetode gebruik om ‘n nuwe klas van meta-gefunksionaliseerde inherent chirale molekule te produseer. Oksasolien-gerigte ortolitiasie metodes is gebruik om ‘n reeks nuwe inherente chirale fosfiene ligande te sintetiseer, en om sodoende die potensiaal van inherente chiraliteit te evalueer. Die resultate van die toepassingstudies van hierdie molekules op beide die Tsuji-Trost allilering en die asimetriese Suzuki koppelingsreaksies, dui op ‘n definitiewe verhouding tussen die konfigurasie van die inherente chiraliteit van die calixareen en die sentrale chiraliteit van die oksasoliene hulpgroep. ‘n Hipotetiese model van die - alliel palladium intermediêr wat verantwoordelik is vir die enantiomeer seleksie wat tydens Tsuji-Trost reaksie waargeneem word, is vir die calixareen ligande voorgestel. Die model is gebou deur die gebruik van voorheen gerapporteerde kristallografiese data, talle vastetoestand studies en berekeningsstudies van eenvoudige fosfienoksasolienligandsisteme. Die eksperimentele resultate wat vir hierdie reaksie verkry is, het goed gekorreleer met die voorgestelde model vir die inherente chirale calixareen ligande. Twee addisionele inherent chirale fosfienoksasolienligande waar die stereosentrum op die oksasolien ontbreek, is gesintetiseer om hierdie waarnemings te bevestig. Hul voorlopige toepassing op die Tsuji-Trost allilasie het ook enantiomeriese verrykde produkmengsels opgelewer. Hierdie resultate dui op ‘n betekenisvolle bydrae deur die inherente chiraliteit tot die algehele asimetriese induksie wat in die reaksie waargeneem word. Hierdie bevindinge dien as ‘n positiewe bevestiging van die moontlike sukses van inherente chirale calixarene in die gebied van asimetriese katalise, en skep ‘n fondasie waarop verdere ontwikkeling gedoen kan word van nuwe ligande wat hierdie strukturele eienskap besit. iii Stellenbosch University https://scholar.sun.ac.za Acknowledgements First on my list of thanks are my parents, who have never let me down and given me more than I could ever return. My supervisor, Dr. Gareth Arnott, who has not only put up with me, but has provided the constant support and enthusiasm for this project. Thank you to my fellow students in the GOMOC research group for the support and chemistry related aid when it was needed. A big thank you to technical staff, Mary, Raymond and Debbie, whose efforts go a long way to keeping the cogs turning. Thank you to the NRF and STIAS organizations for providing me with generous financial support, without which none of this would have been possible. Thank you to Stellenbosch University for providing me with the opportunity and to Prof. Jonathan Williams at Bath University for hosting me during my time abroad. There are many people that have not been mentioned, who deserve so much more than a written thank you (You all know who you are). The three I am going to mention are Prof. Delia Haynes, Dr. Varvara Nikolayenko and Mr. Dylan Ranger. To Delia, your open door policy and positive spin on my never ending rants helped carry me through these many years of study. For Varia, besides being a terrifyingly competent chemist, you made integral contributions to the crystallography component of this dissertation. You have been a constant source of motivation and support throughout this whole process (even when I was grumpy). Finally, thank you to Dylan, who despite not being a scientist, read and edited the entire final draft. iv Stellenbosch University https://scholar.sun.ac.za Publications Herbert, S. A., Arnott, G. E., Clayden, J., Castell, D. C., “Manipulating the Diastereoselectivity of Ortholithiation in Planar Chiral Ferrocenes” Org. Lett., 2013, 15 (13), pp 3334-3337 Herbert, S. A., Arnott, G. E., Castell, D. C., van Laeren, L. J., “Inherently chiral calix[4]arenes via oxazoline directed ortholithiation: synthesis and probe of chiral space” Beilstein J. Org. Chem., 2014, 10, pp 2751-2755 Conferences Frank Warren, 2015, The Stellenbosch Institute for Advanced Study (STIAS), poster presentation. v Stellenbosch University https://scholar.sun.ac.za Abbreviations 1H Proton NMR 13C Carbon NMR 31P Phosphorus NMR de Diastereomeric excess ee Enantiomeric excess HPLC High performance liquid chromatography IR Infrared spectroscopy Mp Melting point MS Mass spectrometry MW Microwave reaction NMR Nuclear magnetic resonance Rf Retention factor Rt Retention time Δ Heat TLC Thin layer chromatography HMPA Hexamethylphosphoramide DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone PMDTA N′ ,N,N ,N′′,N′′-pentamethyldiethylenetriamine TMEDA N,N,N,N′ ′-Tetramethylethane-1,2-diamine vi Stellenbosch