Research Collection Doctoral Thesis Chiral Tris(alkynyl)methanes building blocks for three-dimensional acetylenic scaffolding Author(s): Convertino, Vito Publication Date: 2007 Permanent Link: https://doi.org/10.3929/ethz-a-005548162 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH NO. 17464 Chiral Tris(alkynyl)Methanes: Building Blocks for Three-Dimensional Acetylenic Scaffolding A dissertation submitted to ETH ZURICH for the degree of Doctor of Sciences Presented by VITO CONVERTINO Dott. Chim. Ind. Université di Bologna born December 29, 1978 citizen of the Republic of Italy accepted on the recommendation of Prof. Dr. François Diederich, examiner Prof. Dr. Hans-Jürg Borschberg, co-examiner 2007 E'hello raccontare i guai passati Acknowledgments I would like to thank Professor Dr. François Diederich for giving me the opportunity to work on such an interesting and challenging project, and also for his guidance as well as for his encouragements during the course of this thesis. I greatly appreciated the enthusiasm he put into the scientific discussions, as well as the complete freedom that I had in the research project. My gratitude also goes to Professor Dr. Hans-Jürg Borschberg for accepting the co- examination of this thesis. I thank Dr. Peter Jarowki for proof-reading this manuscript and Dr. Carlo Thilgen for his help with the nomenclature and the stereochemistry, as well as for the many interesting discussions. I am grateful to all the staff members of the LOC for the valuable services they provided. In particular, I would like to thank Dr. Walter Amrein, Rolf Häßiger (great photos!), Louis Bertschi and Oswald Greter for the measuring of the mass spectra, as well as Dr. W. Bernd Schweizer for solving the X-ray crystal structure of my compounds. Many thanks go to Irma Näf for her kindness and for her fast and accurate help with all the administrative problems. Un grazie speciale va a Paolo Mombelli, che ha condotto con entusiasmo e tenacia (interista) il suo lavoro di master sotto la mia supervisione. Many thanks go to all the members of the (past and present) Diederich's group for their friendship and for having contributed enlarging my knowledge in chemistry. I particularly thanks to the lab G306: Dr. Peter Manini (bella gatta da pelare m'hai lasciato in eredità!), Dr. Nicolle Moonen (my first guide in Zürich), Dr. Simone Hörtner (ma quante sigarette avremo fumato insieme sul balcone?), Dr. Tsuyoshi Michinobu ("I don't care about the mechanismus"), Dr. Sara Eisler (without you and Christian I would not know Frank Zappa nor Sefior Coconut!), Dr. Tatsuya Yamaguchi (the best Japanese football player since Kazu Miura), Jens Hornung ("Rauch Haus Song"), Dr. Philippe Reutenauer ("Sarrabandaaaaa"), Dr. Lorenzo Alonso ("El tigre se fue"). Federica Marotti ("Aoooo"), Davide Bonifazi, Raffaella Faraoni, Severin Odermatt, Dr. Nikos Chronakis ("No,no,no! I'll show you how to roll a cigarette"), Dr. Fraser Hof Dr. Marine Guillot (and Captain Beefheart), Markus Frei, Milan Kivala and Dr. Matthijs ter Wiel (St. John's fellows), Henry Dube (Malaparte?), Corinne Baumgartner, Anna Hirsch, Cristophe Fäh ("genua über"), Thomas Gottschalk, Andrea Amantonico (uaglio', è tutto nelle tue mani adesso), Brian Frank, Leslie Fendt, Agnieszka Kraszewska, Fabio K.,Ams, Victo and Isi, I thank for the good time we spent together in bars or clubs of Zürich, at restaurants or at home for delicious dinners, biking, running, at the lake, on the mountains.. .You all made living in Zürich much better than what I actually think. Un grazie di cuore ai miei genitori, continuo punto di riferimento, i primi a condividere con me le soddisfazioni e le delusioni di questi quattro lunghi anni. A loro dedico questo lavoro. Grazie alla Kupola, e a tutti i suoi adepti nel mondo, e grazie a Mao per le interminabili partite a scacchi scacciapensieri. Grazie a tutti i numerosissimi avventori dell'Ostello Convertino, fira cui mérita una speciale menzione Ado e il suo murales (sigh!). Infine grazie alia mia Carinide per la fondamentale correttura dell'Italiano présente in questa tesi. Publications and Presentations Publication: V. Convertino, P. Manini, W. B. Schweizer, F. Diedench, Org. Biomol. Chem. 2006, 4, 1206-1208, First Asymmetric Synthesis of a Differentially Silyl-Protected Tris(Alkynyl) Methyl Methyl Ether. Poster Presentations: V. Convertino, P. Manini, W. B. Schweizer, F. Diedench, Asymmetric Synthesis of Methyl Protected Tris(propargylic)alcohol, 11* International Symposium on Novel Aromatic Compound (ISNA-11), 14 - 18 August 2005, St. John's, Canada. V. Convertino, P. Manini, W. B. Schweizer, F. Diedench, Asymmetric Synthesis of a Differentially Silyl-protected Tris(alkynyl)methyl Methyl Ether, Swiss Chemical Society - Fall Meeting, 13 October 2006, Zürich, Switzerland. V. Convertino, B. Buschhaus, F. Diederich, Synthesis of an Optically Pure Differentially Silyl-protected Tris(alkynyl)phenyl Methane, 14* IUPAC Symposium on Organometallic Chemistry Directed Towards Organic Synthesis (OMCOS 14), 2-6 August 2007, Nara, Japan. Table of Contents Abbreviations I Summary V Riassunto VIII 1. Introduction 1 1.1 Polyethynylated Ethenes 3 1.2 Polyethynylated Aliènes 9 1.3 Polyethynylated Butatrienes 14 1.4 Polyethynylated Ethanes and Methanes 17 1.5 Aim of the project 24 2. Asymmetric Synthesis of a Differentially Silyl-Protected Tris(Alkynyl)Methyl Methyl Ether 25 2.1 Retrosynthetic Plan 25 2.2 Synthesis of the Optically Active Corner Module 26 2.2.1 Chelation-controlled addition 28 2.2.2 Protecting Group Replacement 29 2.2.3 Shapiro Reaction 32 2.2.4 First Success 33 2.2.5 An Unexpected Result 34 2.2.6 Improved Route 35 2.3 Separation of Diastereoisomers: the Way to Optical Purity 36 2.3.1 Resolution of the Ketone 3 7 2.3.2 Cyclic Ketal 39 2.3.3 Successful Strategy 41 2.4 Absolute Configuration 42 2.5 Conclusion 44 3 Synthetic Approach Toward Expanded Cubane and Expanded Tetrahedrane 47 3.1 Platonic Structures 47 Table of Contents 3.2 Expanded Cubane 49 3.2.1 Computational Studies 50 3.2.2 An Alternative Synthetic Strategy 51 3.2.3 Synthesis 53 3.2.4 Structural Assignment of the Diastereoisomers of82 57 3.3 Expanded Tetrahedrane 60 3.3.1 Computational Studies 61 3.3.2 Retrosynthetic Approach 62 3.3.3 Synthetic Route 63 3.4 Conclusion and Outlook 65 4 Synthesis of an Optically Pure Differentially Silyl-Protected Tris(alkynyl)Phenyl Methane 67 4.1 Retrosynthetic Analysis 67 4.2 Synthesis 69 4.2.1 Asymmetric Epoxidation 71 4.2.2 The Key Intermediate 74 4.2.3 Chiral Resolution 76 4.2.4 Optical Purity 77 4.2.5 Last Steps 79 4.3 Scaffolding 79 4.4 Conclusion and Outlook 82 5 Summary and Outlook 83 6 Experimental Part 89 6.1 General Methods and Instrumentation 89 6.2 Experimental Procedures 91 7 Literature 137 8 Appendlix 157 8.1 Crystal Structure Data of (+)-(i?)-70 157 8.2 Crystal Structure Data of 82b 177 8.3 Crystal Structure Data of 82c 183 Abbreviations â Angstrom (1 Â= l(T10m) anal. elemental analysis aq. aqueous bs broad signal BC Before Christ Bu4NF tetrabutylammonium fluoride «BuLi w-butyllithium °C degree centigrade (0 °C = 273.15 K) cal calorie (1 cal = 4.184 J) cal cd. calculated CAN cerium(IV) ammonium nitrate CDCI3 J-chloroform CHF Swiss francs cone. concentrated CSA camphorsulfonic acid CT charge transfer S chemical shift (NMR) d doublet (NMR) d day DCTB /ra«5-2-[3-(4-tert-butylphenyl)-2-methylprop-2- enylidene]malononitrile de diastereomeric excess DEE (£)-1,2-diethynylethene ((E)-hex-3-ene-1,5-diyne) DHB 2,5-dihydroxybenzoic acid DIBAL-H diisobutylaluminiumhydride DMAP jV,jV-dimethylaminopyridine DMF jV,jV-dimethylformamide Abbreviations DMP Dess-Martin periodinane dppp l,3-bis(diphenylphosphino)propane dr diastereomeric ratio EA elemental analysis ee enantiomeric excess er enantiomeric ratio Et ethyl Et20 diethyl ether EtOAc ethyl acetate FC flash chromatography Fe ferrocenyl FID flame ionization detector g gram GC gas chromatography GPC gel permeation chromatography h hour HMPA hexamethylphophoramide HPLC high performance liquid chromatography HR high resolution Hz Hertz (s"1) ICR ion-cyclotron-resonance i.e. that is IR infrared (spectroscopy) J Joule J coupling constant (NMR) k kilo (103) I wavelength L liter LDA lithium diisopropylamide LTMP lithium tetramethylpiperidine H micro (10"6) II Abbreviations m milli (10"3) m medium (IR), multiplet (NMR) M molarity [mol l"1] M metal MABR methyl aluminum bis-(4-bromo-2,6-di-tert-butyl-phenoxide) MALDI-FT fourier transform matrix assisted laser desorption-ionization MCPBA weto-chloroperbenzoic acid Me methyl MeCN acetonitrile MeOH methanol MHz megahertz min minute MO molecular orbital mol mole mp melting point MS mass spectrometry NaHDMS sodium hexamethyldisilazide NBS iV-bromosuccinimide nm nanometer NMR nuclear magnetic resonance (spectroscopy) PG protecting group PMB /»-methoxybenzyl chloride ppm parts per million zPr isopropyl PTA poly(triacetylene) q quartet (NMR) Rt retention factor s singlet (NMR) sat. saturated SiEt3 triethylsilyl SiMe3 trimethylsilyl III Abbreviations Si02 silica gel Si(/Pr)3 triisopropylsilyl t triplet (NMR) TDMPP tris(2,6-dimethoxyphenyl)phosphine TEE tetraethynylethene (3,4-diethynylhex-3-ene-l,5-diyne) TFA trifluoroacetic acid TfOH trifluoromethanesulfonic acid. THF tetrahydrofuran THP tetrahydopyran TLC thin layer chromatography TMEDA iV, iV, iV', Af'-tetramethylethylenediamine TOF matrix assisted laser desorption-ionization time-of-flight Tris 2,4,6 triisopropylbenzenesulfonyl /7-TsOH /»-toluenesulfonic acid UV ultra-violet Vis visible vs. versus IV Summary Oxidative acetylenic coupling, discovered by Glaser in 1869, and modified protocols such as the Hay variant for the homocoupling and the Cadiot-Chodkiewicz variant for heterocoupling provide powerful methodologies for the construction of exceptional molecular architectures and advanced materials based on acetylenic backbones.