Synthesis and Utility of Organoboron Reagents for Enantioselective Synthesis Author: Christopher Henry Schuster Persistent link: http://hdl.handle.net/2345/bc-ir:103558 This work is posted on eScholarship@BC, Boston College University Libraries. Boston College Electronic Thesis or Dissertation, 2014 Copyright is held by the author, with all rights reserved, unless otherwise noted. Boston College The Graduate School of Arts and Sciences Department of Chemistry SYNTHESIS AND UTILITY OF ORGANOBORON REAGENTS FOR ENANTIOSELECTIVE SYNTHESIS A dissertation by CHRISTOPHER HENRY SCHUSTER submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy June 2014 © copyright by CHRISTOPHER HENRY SCHUSTER 2014 SYNTHESIS AND UTILITY OF ORGANOBORON REAGENTS FOR ENANTIOSELECTIVE SYNTHESIS by CHRISTOPHER HENRY SCHUSTER Dissertation Advisor: Professor James P. Morken ABSTRACT: Described herein are three distinct projects centered on the formation and use of carbon-boron bonds. In the first, the enantioselective platinum-catalyzed 1,4- diboration of trans-1,3-dienes is advanced in both selectivity and scope through the development of a novel class of electron rich chiral monodentate phosphines. Under the action of the new ligands, highly selective diboration is maintained at reduced loadings of catalyst. Secondly, enantioenriched 1,2-bis(pinacol boronates) are engaged in regioselective Suzuki-Miyaura cross-coupling with aryl and vinyl electrophiles. A tandem diboration cross-coupling sequence is successfully implemented to afford homobenzylic and homoallylic pinacol boronates directly from terminal olefins, which subsequently undergo oxidation, amination or homologation of the remaining carbon- boron bond to arrive at a range of enantioenriched products. Lastly, aryl electrophiles containing tethered allylboronate units undergo efficient intramolecular coupling in the presence of a chiral palladium catalyst to give enantioenriched carbocyclic products. Dedicated to: My parents, James H. Schuster and Susan R. Schuster, for their love and unconditional support as well as my father’s countless lessons in seeing the world as a collection of simple machines and my mother’s many brave attempts to teach spelling. i ACKNOWLEDGEMENTS First, I would like to give thanks to my advisor, Professor James P. Morken. Jim has not only served as an excellent advisor but also as an ideal scientific role model. Much of my growth as a chemist has been a result of attempts to emulate his mixture of enthusiasm and patience that is brought to every meeting and chalkboard conversation. Graduate school can be a series of moments were you realize how little you know and Jim has taught me to view these as exciting learning opportunities rather than discouraging set-backs. With this much improved outlook, I look forward to having many more of these little moments. During my stay in the Morken group, I have had the pleasure of working alongside nearly 50 chemists at various stages of their careers and without them graduate school would not have been the incredible experience that it was. In particular, I would like to thank Dr. Dan Custar, Ph.D. for his advice and guidance, both chemical and non- chemical. I enjoyed collaborating with Scott Mlynarski and Ryan Coombs and learned a great deal through the many ups, downs, and moments of head-scratching that accompanied our projects. I shared many great white board discussions with Mike Ardolino and always walked away with a little more knowledge about chemistry, beer, or food depending on which way the conversation drifted. I would also like to thank Tom Caya, Meredith Eno, Bo Potter, Dr. Bob Kyne, Dr. Rob Ely, and Dr. Laura Kliman. I am grateful to Bo Potter, Tom Blaisdell, and Ryan Coombs for taking the time to proof read this thesis and providing many helpful suggestions. Lastly, I would like to thank my family. Without their love and support, I could have never completed graduate school. It turns out hunting for frogs with my nephew Cody was a great way to clear the head and re-focus. Finally, I owe everything to Candice Joe. I thought I knew what working hard meant before I meet her, and then she lapped me 4x in notebooks and I changed my thinking. She has made my life better in so many ways, and I can’t wait for what comes next. ii List of Abbreviations Å: angstrom Cy: cyclohexyl Ac: acetyl dan: 1,8-diaminonaphthalene acac: acetylacetonyl DART: direct analysis in real time Ad: adamantyl dba: dibenzylideneacetone Aliquat 336: trioctylmethylammonium DCE: 1,2-dichloroethane chloride DCM: dichloromethane approx: approximately dcpe: 1,2-bis(dicyclohexylphosphino) AQN: anthraquinone ethane B2(cat)2: bis(catecholato)diboron DHQD: dihydroquinidine B2(pin)2: bis(pinacolato)diboron DI: deionized BARF: tetrakis[3,5- DIBAL: diisobutylaluminum hydride bis(trifluoromethyl)phenyl] borate dippf: 1,1’-bis(diisopropylphosphino) 9-BBN: 9-borabicyclo[3.3.1]nonane ferrocene BHT: 2,6-di-tbutyl-4-methylphenol DMAP: N,N-4-dimethylaminopyridine BINOL: 1,1’-bi-2,2’-naphthol DME: 1,2-dimethoxyethane Bn: benzyl DMF: N,N-dimethylformamide Boc: tbutoxycarbonyl DMSO: dimethylsulfoxide BSA: N,O-bis(trimethylsilyl)acetamide dppb: 1,4-bis(diphenylphosphino)butane Bz: benzoyl dppe: 1,2-bis(diphenylphosphino)ethane CAN: cerium(IV) ammonium nitrate dppf: 1,1’-bis(diphenylphosphino) ferrocene cat: catechol dppm: 1,1-bis(diphenylphosphino) Cbz: benzyloxycarbonyl methane cod: 1,5-cyclooctadiene dppp: 1,3-bis(diphenylphosphino) conv: conversion propane iii dr: diastereomeric ratio NCS: N-chlorosuccinimide elim: elimination NHC: N-heterocyclic carbene ent: enantiomer NMDPP: neomenthyldiphenylphosphine eq: equation NMO: N-methylmorpholine oxide equiv: equivalent(s) NMR: nuclear magnetic resonance er: enantiomeric ratio NR: no reaction ESI: electrospray ionization Ph-BPE: 1,2-bis(2,5- diphenylphospholano) ethane EtOAc: ethyl acetate PhH: benzene GLC: gas liquid chromatography pin: pinacol h: hours PMA: phosphomolybdic acid HKR: hydrolytic kinetic resolution PMP: 1,2,2,6,6-pentamethylpiperidine HPLC: high performance liquid chromatography ppm: parts per million HRMS: high resolution mass Quinap: 1-(2-diphenylphosphino-1- spectrometry naphthyl)isoquinoline Hz: Hertz rac: racemic imid: imidazole red: reductive IPA: isopropanol RT: room temperature IR: infrared spectroscopy salen: bis(salicylidine)ethylenediamine LAH: lithium aluminum hydride SFC: supercritical fluid chromatography M: molar solv: solvent mCPBA: meta chloroperbenzoic acid TADDOL: 2,2-dimethyl-α,α,α’,α’- tetraaryl-1,3-dioxolane-4,5-dimethanol MDPP: menthyldiphenylphosphine TBAF: tetrabutylammonium fluoride Men: menthyl TBDPS: tbutyldiphenylsilyl NBS: N-bromosuccinimide TBS: tbutyldimethylsilyl nbd: norbornadiene iv Temp: temperature TEMPO: 2,2,6,6-tetramethyl-1- piperidinyloxy free radical TES: triethylsilyl Tf: trifluoromethanesulfonyl THF: tetrahydrofuran TIPS: triisopropylsilyl TLC: thin layer chromatography TMEDA: N,N,N’,N’- tetramethylethylenediamine TMS: trimethylsilyl TOF: turnover frequency tol: toluene TON: turnover number Ts: p-toluenesulfonyl UV: ultraviolet xylyl: dimethylphenyl v TABLE OF CONTENTS CHAPTER 1: DEVELOPMENT OF A NEW CLASS OF TUNABLE MONODENTATE CHIRAL LIGANDS FOR ENANTIOSELECTIVE CATALYSIS; UTILITY IN HIGHLY EFFICIENT 1,4-DIBORATION OF TRANS-1,3-DIENES 1.1 INTRODUCTION --------------------------------------------------------------------------------------- 1 1.2 BACKGROUND ---------------------------------------------------------------------------------------- 8 1.2.1 Early Ligand Development and the Beginnings of Asymmetric Catalysis ------------ 8 1.2.2 The Rise of Bidentate Chiral Phosphorus Ligands for Asymmetric Catalysis ------- 12 1.2.3 Renaissance of Monodentate Phosphorus Ligands -------------------------------------- 17 1.2.4 Key Design Features of Highly Successful Ligand Scaffolds -------------------------- 21 1.2.4.1 MOP-Based Ligands for Enantioselective Catalysis ----------------------------- 23 1.2.4.2 Binol-Derived Phosphonite, Phosphites, and Phosphoramidites for Enantioselective Catalysis ------------------------------------------------------------ 25 1.2.4.3 Binepines as Monodentate Phosphines for Asymmetric Catalysis ------------- 28 1.2.4.4 TADDOL-based Phosphorus Compounds for Asymmetric Catalysis --------- 31 1.3 DEVELOPMENT OF A NEW CLASS OF OXAPHOSPHOLANE LIGANDS AND UTILITY IN THE EFFICIENT 1,4-DIBORATION OF TRANS-1,3-DIENES. ------------------------------------------- 34 1.3.1 Design Aspects of the Oxaphospholane Scaffold ---------------------------------------- 34 1.3.2 Synthetic Approches to the Oxaphospholane Scaffold ---------------------------------- 38 1.3.3 Evaluation of Oxaphospholane Ligands in Platinum Catalyzed Diboration -------- 45 1.3.4 Efforts to Remedy the Limitations of the Oxaphospholane Scaffold ------------------ 51 1.4 CONCLUSION ---------------------------------------------------------------------------------------- 56 1.5 EXPERIMENTAL SECTION -------------------------------------------------------------------------- 57 1.5.1 General Information ------------------------------------------------------------------------- 57 1.5.2 Experimental Procedures ------------------------------------------------------------------- 60 1.5.2.1 Preparation of Pt(dba)3. --------------------------------------------------------------- 60 1.5.2.2 Representative Procedure for Preparation of Phosphine Oxides ---------------- 61 1.5.2.3 Characterization of Phosphine Oxides ----------------------------------------------