Sybrand Jonker Synthesis of Organoboronic Acids and Applications in Asymmetric Organocatalysis Synthesis of Organoboronic Acids and Applications in Asymmetric Organocatalysis in Applications Acids and Synthesis of Organoboronic Sybrand Jonker ISBN 978-91-7911-388-9 Department of Organic Chemistry Doctoral Thesis in Organic Chemistry at Stockholm University, Sweden 2021 Synthesis of Organoboronic Acids and Applications in Asymmetric Organocatalysis Sybrand Jonker Academic dissertation for the Degree of Doctor of Philosophy in Organic Chemistry at Stockholm University to be publicly defended on Friday 12 February 2021 at 14.00 in Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B. Abstract Allyl- and allenylboronic acids are valuable reagents in organic synthesis due to their configurational stability and high reactivity. Few allyl- and allenylboronates are commercially available. Therefore, both the preparation and synthetic application of these organoboronic acids are subjects of study. A copper-catalyzed method for the synthesis of tetrasubstituted allenylboronic acids is presented in this thesis. Several enantioselective applications of these allenylboronic acids are presented, including the synthesis of chiral α-amino acid derivatives. Applications of γ,γ-disubstituted allylboronic acids in asymmetric organocatalysis are also presented in this thesis. Varying the E-Z geometry of the allylboron reagents allowed for stereodivergent synthesis of products bearing up to three stereocenters. A common element in the asymmetric methodologies described in this thesis is the application of BINOL-type organocatalysts. The most notable example is the methodology developed for the preparation of α-chiral allylboronic acids via asymmetric homologation of olefinic boronic acids. The resulting chiral boronic acids are of high synthetic interest, which is demonstrated by the wide variety of synthetic applications including allylboration, oxidation, and a purification sequence leading to isolated α-chiral allylboronic acids. Keywords: Boronic acid, BINOL, allylboration, propargylation, homologation, stereoselective synthesis, asymmetric synthesis, organocatalysis, allylboronic acid, allenylboronic acid. Stockholm 2021 http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-187390 ISBN 978-91-7911-388-9 ISBN 978-91-7911-389-6 Department of Organic Chemistry Stockholm University, 106 91 Stockholm SYNTHESIS OF ORGANOBORONIC ACIDS AND APPLICATIONS IN ASYMMETRIC ORGANOCATALYSIS Sybrand Jonker Synthesis of Organoboronic Acids and Applications in Asymmetric Organocatalysis Sybrand Jonker ©Sybrand Jonker, Stockholm University 2021 ISBN print 978-91-7911-388-9 ISBN PDF 978-91-7911-389-6 Cover: Sørfjorden and its enantiomorph as seen from Odda (Norway) by Sybrand Jonker Printed in Sweden by Universitetsservice US-AB, Stockholm 2021 “Pain is inevitable. Suffering is optional.” Haruki Murakami What I Talk About When I Talk About Running Abstract Allyl- and allenylboronic acids are valuable reagents in organic syn- thesis due to their configurational stability and high reactivity. Few allyl- and allenylboronates are commercially available. Therefore, both the preparation and synthetic application of these organoboronic acids are subjects of study. A copper-catalyzed method for the synthesis of tetrasubstituted allenylboronic acids is presented in this thesis. Several enantioselective applications of these allenylboronic acids are presented, including the synthesis of chiral α-amino acid derivatives. Applications of γ,γ-disubstituted allylboronic acids in asymmetric organocatalysis are also presented in this thesis. Varying the E-Z geometry of the al- lylboron reagents allowed for stereodivergent synthesis of products bearing up to three stereocenters. A common element in the asymmetric methodologies described in this thesis is the application of BINOL-type organocatalysts. The most notable example is the methodology devel- oped for the preparation of α-chiral allylboronic acids via asymmetric homologation of olefinic boronic acids. The resulting chiral boronic ac- ids are of high synthetic interest, which is demonstrated by the wide variety of synthetic applications including allylboration, oxidation, and a purification sequence leading to isolated α-chiral allylboronic acids. i Populärvetenskaplig sammanfattning I världen omkring oss finns det många objekt som kan kallas ‘väns- terhänta’ eller ‘högerhänta’. Exempel inkluderar verktyg som en sax, en korkskruv, en golfklubba, men också naturligt förekommande ting som ett snäckskal och arrangemanget av en blommas kronblad. Alla dessa objekt har gemensamt att deras spegelbild inte kan passas över sig självt, likt en höger- och vänsterhand. Kemister kallar sådana objekt kirala. Många molekyler är kirala, så även molekyler som används i mediciner. Eftersom molekyler och enzymer som styr människokroppen är kirala har en molekyls spegelbildsform en stark inverkan på hur den interagerar med kroppen. Detta är precis som i den makroskopiska värl- den: en vänsterhand är inte lämplig för att klippa med en högerhänt sax. För att molekyler ska interagera förutsägbart med människokrop- pen är det nödvändigt för kemister att kunna styra valet av spegel- bildsform när de syntetiserar dem. I denna avhandling presenteras en ny metod för syntes av allenyliska borsyror genom kopparkatalyserad borylering, samt utveckling av en ny syntes av kirala allylborsyror via homologering av olefiniska borsy- ror. De allenyliska och allyliska borsyrorna som framställts kan sedan användas till propargylborering och allylborering av aldehyder, ketoner, iminer, indoler, och hydrazonestrar med en hög grad av kontroll över den resulterande stereokemin. I de fall som produkten har mer än ett stereocenter kan man genom att förändra reaktionsbetingelserna kon- trollera varje stereocenter separat: man säger att reaktionen är stereo- divergent. Som exempel kan icke-naturliga aminosyraderivat produce- ras med denna nya metodologi. Många av de asymmetriska metoderna som presenteras i denna av- handling involverar organiska katalysatorer av BINOL-typ vilka har visat sig vara mycket effektiva för asymmetriska transformationer av borsyror. ii Abbreviations B2nep2 Bis(neopentyl glycolato)diboron B2pin2 Bis(pinacolato)diboron BINOL 1,1′-Bi-2-naphthol Bdan 1,8-Diaminonaphtaleneboron Bpin Pinacolatoboron cod 1,5-Cyclooctadiene Cy Cyclohexyl danH2 1,8-Diaminonaphtalene d.r. Diastereomeric ratio dba Dibenzylideneacetone DCM Dichloromethane DFT Density Funtional Theory DIPEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DME Dimethoxyethane DMSO Dimethyl sulfoxide ee Enantiomeric excess equiv. Equivalents HBcat Catecholborane HBpin Pinacolborane HFIP Hexafluoroisopropanol LDA Lithium diisopropylamide [M] Metal MTPA α-Methoxy-α-trifluoromethylphenylacetyl NMR Nuclear Magnetic Resonance r.t. Room temperature TESOTf Triethylsilyl trifluoromethanesulfonate TMS Trimethylsilyl Δ�SR Difference in chemical shift between MTPA epimers iii List of publications This document is based on the following publications, referred to in the text by their Roman numerals I-IV. I. Copper-catalyzed Synthesis of Allenylboronic Acids. Ac- cess to Sterically Encumbered Homopropargylic Alcohols and Amines by Propargylboration Jian Zhao, Sybrand J. T. Jonker, Denise N. Meyer, Göran Schulz, C. Duc Tran, Lars Eriksson and Kálmán J. Szabó Chem. Sci., 2018, 9, 3305–3312. II. Catalytic Asymmetric Propargyl- and Allylboration of Hy- drazonoesters: A Metal-Free Approach to Sterically En- cumbered Chiral α-Amino Acid Derivatives Sybrand J. T. Jonker, Colin Diner, Göran Schulz, Hiroaki Iwamoto, Lars Eriksson and Kálmán J. Szabó Chem. Commun., 2018, 54, 12852–12855. III. Catalytic Asymmetric Allylboration of Indoles and Dihy- droisoquinolines with Allylboronic Acids: Stereodivergent Synthesis of up to Three Contiguous Stereocenters Rauful Alam, Colin Diner, Sybrand Jonker, Lars Eriksson and Kálmán J. Szabó Angew. Chem. Int. Ed. 2016, 55, 14417–14421. IV. Organocatalytic Synthesis of α-Trifluoromethyl Al- lylboronic Acids by Enantioselective 1,2-Borotropic Migra- tion Sybrand J. T. Jonker, Ramasamy Jayarajan, Tautvydas Kireilis, Marie Deliaval, Lars Eriksson and Kálmán J. Szabó J. Am. Chem. Soc. 2020, 142, 21254–21259. iv Reprint permissions Permissions to reprint the following publications were obtained from their respective publishers: I. J. Zhao, S. J. T. Jonker, D. N. Meyer, G. Schulz, C. D. Tran, L. Eriksson, K. J. Szabó, Chem. Sci., 2018, 9, 3305– 3312. Copyright © 2018 Royal Society of Chemistry. Open ac- cess article licensed under a Creative Commons Attribu- tion 3.0 Unported License. II. S. J. T. Jonker, C. Diner, G. Schulz, H. Iwamoto, L. Eriks- son, K. J. Szabó, Chem. Commun., 2018, 54, 12852–12855. Copyright © 2018 Royal Society of Chemistry. Open ac- cess article licensed under a Creative Commons Attribu- tion 3.0 Unported License. III. R. Alam, C. Diner, S. Jonker, L. Eriksson, K. J. Szabó, Angew. Chem. Int. Ed. 2016, 55, 14417–14421. Copyright © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. Open access article licensed under a Creative Commons Attribution-NonCommercial 4.0 International Licence. IV. S. J. T. Jonker, R. Jayarajan, T. Kireilis, M. Deliaval, L. Eriksson, K. J. Szabó, J. Am. Chem. Soc. 2020, 142, 21254–21259. Copyright © 2020 American Chemical Society. Open ac- cess article licensed under an ACS AuthorChoice Creative Commons Attribution 4.0 International Licence. v Previous document based on this work This thesis builds partly