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Improved Methodology for the Preparation of Chiral Amines

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Improved Methodology for the Preparation of Chiral Amines (Important Chiral Building Blocks in Pharmaceutical Drugs and Natural Products Synthesis) Mohamed Mahmoud El-Shazly A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Organic Synthetic Chemistry Approved Thesis Committee Prof. Dr. Thomas Nugent Professor of Organic Chemistry Jacobs University Bremen Prof. Dr. Nikolai Kuhnert Professor of Organic Chemistry Jacobs University Bremen Dr. Pralhad Ganeshpure Indian Petrochemicals Corporation Limited, India Date of Defense: August 03, 2009 School of Engineering and Science, Jacobs University, Bremen, Germany. Declaration I herewith declare that this thesis is my own work and that I have used only the sources listed. No part of this thesis has been accepted or is currently being submitted for the conferral of any degree at this university or elsewhere. Mohamed El-Shazly Bremen This dissertation is dedicated to all those people who have always given me the love, trust, and support to come to this stage of my life -To My Family- Abstract The importance of α-chiral amines as building blocks in pharmaceutical drugs, natural products, fine chemicals and agrochemicals have encouraged scientists to develop different methodologies for their preparation. Their main goal was to develop a step wise efficient and low waste production methodology which utilizes inexpensive starting material for the synthesis of α-chiral amines in high yields and enantioselectivity. Different methodologies have been developed aiming to meet these criteria. These strategies are discussed and their importance and limitations are critically analyzed. Reductive amination is a powerful methodology for the synthesis of chiral amines in high yields and enantioselectivity. It is a two step strategy beginning from the prochiral carbonyl compound to the primary chiral amine. The historical development and the latest milestones in this field are discussed in chapter three. Different drugs and natural products which are prepared utilizing reductive amination as a key step in their synthesis are summarized in chapter four. Reductive amination utilizing chiral auxiliary/Lewis acid/ heterogeneous catalyst/ molecular hydrogen has been investigated in our group over the last five years. This combination allowed the preparation of alkyl-alkyl’ α-chiral amines in mediocre to good yields and enantioselectivities. This group of amines is known historically to be difficult synthetic task. We developed a new asymmetric reductive amination procedure using Yb(OAc)3 (50-110 mol %) that allows increased diastereoselectivity (6-15% units) for alkyl-alkyl’ α-chiral amines that previously only provided mediocre to good diastereoselectivity. Different Lewis acids were tested under different reaction conditions of temperature, pressure and solvents and the results of these experiments are discussed in chapter five. O (S,S)-2d HN Ph NH 1d Yb(OAc)3,MeOH-THF Pd-C (S)-3d 2 + H2N Ph Raney-Ni, H2 (120 psi) H2 (60 psi) (S)-α-MBA 86% de 85% ee The use of catalytic Lewis acids in reductive amination has never been reported in literatures. We demonstrated the beneficial use of 10-15 mol % of Yb(OAc)3 or Ce(OAc)3 or Y(OAc)3 in i suppressing alcohol formation and promoting reductive amination in good yield but without enhanced stereoselectivity. Despite the fact that the use of Brønsted acids in reductive amination is well established no literature reports are available. We have performed and extensive study on the use of commercially available Brønsted and mineral acids in reductive amination. The scope of the reaction and the substrate categories are summarized in chapter six. A mechanism for the reaction has been proposed and the basic mechanistic experiments have been performed. An in situ cis- to trans-ketimine isomerization mechanism, promoted by Yb(OAc)3, has been proposed to account for the observed increase in diastereoselectivity. The experiments and the proposed mechanism are summarized in chapter seven ii Acknowledgement All the work reported in this thesis have been carried out at the Department of Chemistry, School of Engineering and Science, Jacobs University, Bremen, Germany since joining here on August 2006 till August 2009. I would like to thank Jacobs University for the financial support and all the laboratory facilities during my stay here. In this regard I would like to thank Prof. Dr. h. c. Bernhard Kramer for approving my PhD scholarship. I would like to convey my kind regards to my supervisor Prof. Thomas C. Nugent and thank him for all his kind suggestions and deeply appreciate his skillful guidance throughout my research. It was due to his relentless efforts that I could master the various techniques and learn to solve the different scientific challenges that came by my way. Lastly, I would also acknowledge his patience and kind understanding. I would thank Prof. Nikolai Kuhnert for his kind consent to become the internal examiner of this thesis. I would also thank Dr. Pralhad Ganeshpure, Research Centre, Indian Petrochemicals Corporation Limited, 391 346 Vadodara, India (B-21, Kinnari Duplex Ellora Park, Vadodara, Gujarat 390023, India) for his kind consent to become the external examiner of this thesis. My sincere appreciation goes to all my lab mates, Dr. Rashmi R. Mohanty, Dr. Vijay N. Wakchaure, Dr. Abhijit Ghosh, Ahson J. Shaikh, Mohammad Naveed Umar, Mohammad Shoaib, A. Alvaradomendez, Abdul Sadiq, Dan Hu, Ahtaram Bibi, Satish Wakchaure, Andrei Dragan, Andrei Iosub and Daniela Negru for their constant help and encouragement in all respect. I would also thank Mrs. Müller for her continuous help. All my deepest veneration goes to my parents for everything that they have given to me. I would convey my regards to my sister and all my uncles and aunts for their constant support. I would also thank all professors and colleagues in Egypt. Especially I would like to thank iii Prof. Mohamed El-Azizi, Prof. Abdel-Nasser Singab and Prof. Nahla Ayoub for their support and help over the past years. I would like to thank all friends at Jacobs University, Iyad Tumar, Khaled Hassan, Dr. Raed Mesleh, Mohamed Noor, Hamdy El-Sheshtawy, Salahaldin Juba, Ahmed Moussa, Ahmed El- Moasry, Hany Elgala and all other friends in Germany and Egypt for their continuous support , , iv Abbreviations Ac Acetyl AcOH Acetic acid aq. Aqueous Ar Aryl bs Broad singlet (1H-NMR) BINOL 1,1'-Bi-2-naphthol BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl. BOC tert-Butyl carbamates iBu iso-Butyl nBu n-Butyl conv. Conversion cat. Catalyst CDCl3 Deuterated chloroform COD Cycloctadiene d Doublet (1H-NMR) dd Doublet of doublet (1H-NMR) DCM Dichloromethane de Diastereomeric excess DIBAL-H Diisobutyl aluminium hydride DME 1,2-Dimethoxyethane DMF N,N’-Dimethylfomamide DMSO Dimethylsulfoxide δ Chemical shift (1H-NMR) ee Enantiomeric excess equiv. Equivalent ESI Electron spray ionization (Mass spectroscopy) v Et Ethyl EtOH Ethanol EtOAc Ethylacetate GC Gas chromatography h Hours HPLC High performance liquid chromatography HRMS High resolution mass spectrometry Hz Hertz J Coupling constant (1H-NMR) KHMDS Potassium hexamethyldisilazide LDA Lithium diisopropylamide m Multiplate (1H-NMR) M Molar MBA Methyl Benzyl Amine Me Methyl min. Minutes MS Molecular sieves MS Mass spectroscopy MTBE Methyl-tert-butyl ether MW Molecular weight m/z Mass/charge m Meta NaOtBu Sodium tert-butoxide NBD N-Bornadiene NMR Nuclear Magentic Resonance o Ortho p Para Pd-C Palladium on carbon Ph Phenyl iPr iso-Propyl nPr n-Propyl Pt-C Platinum on carbon pyr Pyridine vi q Quartet (1H-NMR) Raney-Ni Raney-Nickel Ref. Reference Rh-C Rhodium on carbon s Singlet (1H-NMR) t Triplet (1H-NMR) t-Bu tert-Butyl tert Tertiary temp Temperature TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TMS Trimethylsilane Ts Tosyl TsOH p-Toluenesulfonic acid tBuLi tert-Butyllithium i Ti(O Pr)4 Titanium(IV) isopropoxide vii Table of Contents Abstract. i Acknowledgment. ii List of Abbreviations. v 1. Introduction to Chirality 1.1. Chiral Drugs 1 1.2. Isomers and Isomerism 2 1.3. Nature is Chiral 3 1.4. Chirality and Drug-Receptor Interaction 8 1.5. Sources of Enantiopure Substances 8 1.5.1. Synthesis of Enantiomerically Pure Compounds 9 1.5.2. Resolution 9 1.5.2.1. Preferential Crystallization 9 1.5.2.1. Diastereomer Crystallization 10 1.5.2.2. Kinetic Resolution 11 1.5.3. Chiral Pool Approach 12 1.5.4. Stereoselective Conversion of Prochiral Substrates to Enantiopure Compounds (Asymmetric Synthesis) 15 1.5.5. Asymmetric Synthesis vs Kinetic Resolution vs Chiral Pool 18 1.6. α-Chiral Amines Defining Terms 19 1.7. α-Chiral Amines Importance 20 1.8. α-Chiral Amine Synthesis Different Methodologies 22 1.8.1. Imine and Enamide Synthesis 23 1.8.2. Enantioselective Reduction of Enamides 23 1.9. Conclusion 28 1.10. References 28 2. Imine Reduction 2.1. Historical View 34 2.2. Asymmetric Reduction of N-Phosphinoyl Imines 35 2.2.1. Synthesis of N-Phosphinoyl Imines 35 viii 2.2.2. Different Substrates Categories 36 2.2.3. Nguyen Special Substrates 39 2.3. Asymmetric Reduction of N-aryl imines 40 2.3.1. Synthesis of N-Aryl Imines 40 2.3.2. Different Substrates Categories 43 2.4. Reduction of Miscellaneous Imines 49 2.5 Conclusion 49 2.6. References 50 3. Reductive Amination 3.1. Historical View 53 3.1.1. Reductive Amination Utilizing Heterogeneous Catalyst 53 3.1.2. Reductive Amination Utilizing Homogenous Catalysis 55 3.2. Reductive Amination the Current State of Art 57 3.3. Asymmetric Reductive Amination 60 3.3.1. Asymmetric Reductive Amination Utilizing Chiral Catalysts 60 3.3.2. Reductive Amination Utilizing Chiral Auxiliary 64 3.3.3. Reductive Amination Utilizing Molecular Hydrogen 65 3.3.4. Asymmetric Reductive Amination Utilizing Transfer Hydrogenation Conditions 66 3.4.5. Organocatalytic Asymmetric Reductive Amination 67 3.4.
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  • Synthesis and Polymerizability of Atom-Bridged Bicyclic Monomers

    Synthesis and Polymerizability of Atom-Bridged Bicyclic Monomers

    Polymers 2012, 4, 1674-1686; doi:10.3390/polym4041674 OPEN ACCESS polymers ISSN 2073-4360 www.mdpi.com/journal/polymers Review Synthesis and Polymerizability of Atom-Bridged Bicyclic Monomers Henry K. Hall, Jr. Department of Chemistry and Biochemistry, University of Arizona, 1306 E University Blvd, Tucson, AZ 85721, USA; E-Mail: [email protected]; Tel.: +1-520-621-6326; Fax: +1-520-621-8407 Received: 11 September 2012; in revised form: 19 November 2012 / Accepted: 20 November 2012 / Published: 5 December 2012 Abstract: The synthesis and polymerizability of atom-bridged bicyclic monomers was surveyed. The monomers included lactams, ureas, urethanes, lactones, carbonates, ethers, acetals, orthoesters, and amines. Despite widely-varying structures, they almost all polymerized to give polymers with monocyclic rings in the chain. The polymerizations are grouped by mechanism: uncoordinated anionic, coordinated anionic, and cationic. Keywords: alicyclic ring-containing polymers; anti-Bredt monomers; atom-bridged bicyclic monomers; ring-opening polymerizations 1. Introduction Ring-opening polymerizations, which convert cyclic monomers into linear polymers, are a major type of polymerization. A recent authoritative treatise [1] covered ring-opening polymerization of monocyclic monomers; this Review covers ring-opening polymerization of atom-bridged bicyclic monomers. “Atom-bridged” means all three chains connecting the bridgehead atoms contain at least one atom. Bicyclic compounds with bridgehead atoms directly attached to one another will not be considered here because they usually polymerize like monocyclics. Alkene metathesis of bicyclic monomers has been well-reviewed elsewhere and will not be included here. The reactions are arranged below according to mechanism: UNCOORDINATED ANIONIC POLYMERIZATIONS of lactams, ureas, and urethanes COORDINATED ANIONIC POLYMERIZATIONS of lactones and carbonates CATIONIC POLYMERIZATIONS of ethers, acetals, orthoesters and amines Polymers 2012, 4 1675 Although these monomers may appear exotic, they are often synthesized rather easily.