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New Methods for Chiral Cyanohydrin Synthesis

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New Methods for Chiral Cyanohydrin Synthesis New Methods for Chiral Cyanohydrin Synthesis Erica Wingstrand Doctoral Thesis Stockholm 2009 Akademisk avhandling som med tillstånd av Kungl Tekniska Högskolan i Stockholm framlägges till offentlig granskning för avläggande av filosofie doktorsexamen i kemi med inriktning mot organisk kemi fredagen den 8 maj kl 10.00 i sal F3, KTH, Lindstedtsvägen 26, Stockholm. Avhandlingen försvaras på engelska. Opponent är Professor Benjamin List, Max-Planck-Institut für Kohlenforschung, Tyskland. ISBN 978-91-7415-263-0 ISSN 1654-1081 TRITA-CHE-Report 2009:12 © Erica Wingstrand, 2009 E-PRINT AB, Stockholm Erica Wingstrand, 2009: ”New Methods for Chiral Cyanohydrin Synthesis”, Organic Chemistry, KTH Chemical Science and Engineering, Royal Institute of Technology, SE-100 44 Stockholm, Sweden. Abstract This thesis deals with method development in asymmetric catalysis and specifically syntheses of enantioenriched O-functionalized cyanohydrins. The first part describes the development of a method for the synthesis of O-alkoxycarbonylated and O-acylated cyanohydrins. Ethyl cyanoformate and acyl cyanides were added to aldehydes in a reaction catalyzed by a chiral dimeric Ti-salen complex together with a tertiary amine. High yields and enantioselectivities were in most cases obtained. Mechanistic studies were performed and a reaction mechanism was proposed. The second part describes a method in which the undesired minor enantiomer in a Lewis acid–Lewis base-catalyzed acylcyanation is continuously recycled into prochiral starting material. Close to enantiopure O-acylated cyanohydrins were obtained in high yields. The third part deals with asymmetric acylcyanations of ketones. Acetyl cyanide was found to add to α-ketoesters in a reaction catalyzed by a chiral Lewis base. Yields up to 77% and 82% ee were obtained. The final part describes an enzymatic method for high-throughput analysis of O-acylated cyanohydrins. The enantiomeric excess and conversion were determined for products obtained from a number of aromatic and aliphatic aldehydes. Keywords: acyl cyanides, asymmetric catalysis, biocatalysis, cyanide, cyanohydrins, dual activation, enzymes, high-throughput screening, Lewis acid, Lewis base, metal catalysis, minor enantiomer recycling, salen, titanium. Abbreviations Abbreviations and acronyms used in agreement with the ACS standards1 are not listed here. BINOL 1,1-bi-2-naphthol (DHQD)2AQN hydroquinidine (anthraquinone-1,4-diyl) diether DIPEA N,N-diisopropylethylamine E electrophile ee enantiomeric excess EMDee enzymatic method for determining ee LA Lewis acid LB Lewis base M metal MER minor enantiomer recycling n.d. not determined PyBOX pyridine bis(oxazoline) r.d.s. rate determining step TMSCN trimethylsilyl cyanide List of Publications This thesis is based on the following papers, referred to in the text by their Roman numerals I-VI: I. Dual Lewis Acid–Lewis Base Activation in Enantioselective Cyanation of Aldehydes Using Acetyl Cyanide and Cyanoformate as Cyanide Sources Stina Lundgren, Erica Wingstrand, Maël Penhoat, and Christina Moberg J. Am. Chem. Soc. 2005, 127, 11592-11593 II. Lewis Acid–Lewis Base-Catalysed Enantioselective Addition of α- Ketonitriles to Aldehydes Stina Lundgren, Erica Wingstrand, and Christina Moberg Adv. Synth. Catal. 2007, 349, 364-372 III. O-Acylated Cyanohydrins: Versatile Intermediates and Products Erica Wingstrand, Fei Li, Stina Lundgren, Maël Penhoat, and Christina Moberg Chim. Oggi, 2007, 25 (Suppl.), 14-15 IV. Minor Enantiomer Recycling – Metal Catalyst and Biocatalyst Working in Concert Erica Wingstrand, Linda Fransson, Anna Laurell, Karl Hult, and Christina Moberg Manuscript V. Chiral Lewis Base-Catalyzed Enantioselective Acetylcyanation of α-Ketoesters Fei Li, Erica Wingstrand, Khalid Widyan and Christina Moberg Eur. J. Org. Chem. provisionally accepted VI. High-Throughput Synthesis and Analysis of Acylated Cyanohydrins Anders Hamberg, Stina Lundgren, Erica Wingstrand, Christina Moberg and Karl Hult Chem. Eur. J. 2007, 13, 4334-4341 Table of Contents Abstract Abbreviations List of publications 1. Introduction ............................................................................................... 1 1.1. Aim of the Thesis ............................................................................................. 2 1.2. Chiral Cyanohydrins ......................................................................................... 2 1.2.1. Cyanide Sources ........................................................................................................ 3 2. Enantioselective Cyanation of Aldehydes Using Acyl Cyanides and Cyanoformate as Cyanide Sources ........................................................................ 5 2.1. Introduction ...................................................................................................... 5 2.1.1. Catalysts for Asymmetric Cyanation of Aldehydes .................................................. 5 2.1.2. Salen-Based Catalysts ............................................................................................... 7 2.1.3. Dual Lewis Acid–Lewis Base Activation ................................................................. 8 2.1.4. Aim of the Study ....................................................................................................... 9 2.2. Synthesis of O-Alkoxycarbonyl functionalized Cyanohydrins ......................... 9 2.3. Synthesis of O-Acylated Cyanohydrins .......................................................... 12 2.4. Synthesis of a Herbicide Intermediate ............................................................ 16 2.5. Mechanistic Aspects ....................................................................................... 17 2.6. Conclusions .................................................................................................... 22 3. Minor Enantiomer Recycling in Enantioselective Cyanohydrin Synthesis ............................................................................................................. 23 3.1. Introduction .................................................................................................... 23 3.1.1. Methods for Transforming a Racemate into a Single Enantiomer ......................... 23 3.1.2. Aim of the Study ..................................................................................................... 25 3.2. Minor Enantiomer Recycling (MER) ............................................................. 26 3.2.1. Development of the MER System ........................................................................... 26 3.2.2. Use of MER in O-Acylated Cyanohydrin Synthesis .............................................. 28 3.2.3. Modifications and Improvements ............................................................................ 29 3.3. Conclusions and Outlook ................................................................................ 30 4. Enantioselective Addition of Acyl Cyanides to Ketones ......................... 31 4.1. Introduction .................................................................................................... 31 4.1.1. Catalysts for Asymmetric Cyanation of Ketones .................................................... 31 4.1.2. Aim of the Study ..................................................................................................... 33 4.2. Chiral Lewis Base-Catalyzed Addition of Acetyl Cyanide to α-Ketoesters .... 33 4.2.1. Mechanistic Aspects ................................................................................................ 35 4.3. Acylcyanations of Methyl Ketones ................................................................. 37 4.4. Conclusions .................................................................................................... 38 5. Enzymatic Method for High-Throughput Analysis of O-Acylated Cyanohydrins ...................................................................................................... 39 5.1. Introduction .................................................................................................... 39 5.1.1. High-Throughput Methods for Determination of Enantiomeric Excess ................ 39 5.1.2. Aim of the Study ..................................................................................................... 40 5.2. Determination of Enantiomeric Excess Using an Enzymatic Method with a pH Indicator ................................................................................................................. 40 5.3. Determination of Enantiomeric Excess and Conversion Using an Enzymatic Method with NADH .................................................................................................... 42 5.4. Conclusions .................................................................................................... 44 6. Summary and Concluding Remarks ........................................................ 45 7. Acknowledgements ................................................................................. 47 8. References ............................................................................................... 49 1. Introduction The demand for chiral compounds in enantiopure form has increased during the past decades. The pharmaceutical industry has been the main driving force, but also industries producing flavorings, agricultural chemicals, fragrances, fine chemicals, and materials.2 In nature, chiral compounds are synthesized in highly enantioenriched form in reactions often run in a catalytic
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