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New Methods for the Synthesis of Vicinal Stereocenters: Palladium-Catalyzed Domino Reactions and Asymmetric Transfer Hydrogenation

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New Methods for the Synthesis of Vicinal Stereocenters: Palladium-Catalyzed Domino Reactions and Asymmetric Transfer Hydrogenation New Methods for the Synthesis of Vicinal Stereocenters: Palladium-Catalyzed Domino Reactions and Asymmetric Transfer Hydrogenation Brinton Seashore-Ludlow Doctoral Thesis Stockholm 2012 Akademisk avhandling som med tillstånd av Kungl Tekniska Högskolan i Stockholm framlägges till offentlig granskning för avläggande av doktorsexamen i kemi med inriktning mot organisk kemi fredagen den 17 augusti 2012 kl 10.00 i sal F3, KTH, Lindstedtsvägen 26, Stockholm. Avhandlingen försvaras på engelska. Opponent är Kevin Booker-Milburn, School of Chemistry, University of Bristol. ISBN 978-91-7501-374-9 ISSN 1654-1081 TRITA-CHE-Report 2012:27 © Brinton Seashore-Ludlow, 2012 Universitetsservice US AB, Stockholm Brinton Seashore-Ludlow 2012: “New Methods for the Synthesis of Vicinal Stereocenters: Palladium-Catalyzed Domino Reactions and Asymmetric Transfer Hydrogenation”, KTH Chemical Science and Engineering, Royal Institute of Technology, SE-100 44 Stockholm, Sweden. Abstract In this thesis the synthesis of vicinal stereocenters is investigated in two distinct contexts, namely the construction of 3,3-disubstituted oxindoles and the synthesis of β-hydroxy-α-amino acids. Both scaffolds are prevalent in a range of natural products and biologically relevant compounds and, therefore, methods for their synthesis are of great import. First, the construction of 3,3-disubstituted oxindoles using palladium-catalyzed domino reactions is described. This covers two stereospecific methods for the construction of the desired oxindoles based on domino carbopalladation sequences. The termination events for these domino reactions are carbonylation or cross- coupling. In the carbopalladation-carbonylation reaction, we studied the possibilty of suppressing β-hydride elimination for substrates possessing pendant β- hydrogens. In the carbopalladation-cross-coupling sequence, we examined the role of the boron source and substrate scaffold in the outcome of the reaction. In both of these methods, an intricate balance of rates needs to be attained in order to achieve the desired domino sequences. Thus, these investigations offer insight into the rates of the competing reactions, and the factors that influence these processes. Secondly, the stereoselective synthesis of β-hydroxy-α-amino acids is explored. This has lead to two separate methods for the construction of this scaffold. We first examined a 1,3-dipolar cycloaddition of azomethine ylides to aldehydes for the construction of syn-β-hydroxy-α-amino esters. It was found that one set of azomethine ylides reacted through a 1,3-dipolar cycloaddition, while the other set reacted via a direct aldol reaction. Finally, we studied an asymmetric transfer hydrogenation reaction to provide anti-β-hydroxy-α-amido esters from the corresponding α-amido-β-ketoesters. Two protocols were developed for the reduction of these substrates, one using triethylammonium formate and the other using sodium formate in an emulsion. The latter method gives high yields, diastereoselectivities and enantioselectivities for a broad range of substrates. Keywords: asymmetric synthesis, dynamic kinetic resolution, domino reactions, Pd-catalyzed reactions, 1,3-dipolar cycloadditions, amino alcohols, oxindoles Abbreviations AH - asymmetric hydrogenation ATH - asymmetric transfer hydrogenation DABCO -1,4-diazabicyclo[2.2.2]octane DKR- dynamic kinetic resolution DMAP - 4-Dimethylaminopyridine Dppf - 1,1′-Bis(diphenylphosphino)ferrocene Lg - leaving group LiHMDS – Lithium bis(trimethylsilyl)amide MeOBiPHEP - (S)-(−)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine) n.d. - not determined P(biphenyl)(t-Bu)2 - (2-Biphenyl)di-tert-butylphosphine Pg - protecting group PCy3 - tricyclohexylphosphine Pd2dba3⋅CHCl3 - Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct SIMes - 1,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazolium tetrafluoroborate TBDMS (TBS)- tert-butyl dimethyl silyl TBDPS - tert-butyl diphenyl silyl TS - transition state Xanthphos - 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene List of Publications This thesis is based on the following papers, referred to in the text by their Roman numerals I-VI: I. Addition of Azomethine Ylides to Aldehydes: Mechanistic Dichotomy of Differentially Substituted α-Imino Esters Brinton Seashore-Ludlow, Staffan Torssell, and Peter Somfai Eur. J. Org. Chem. 2010, 3927-3933. II. Domino Carbopalladation-Carbonylation: Generating Quaternary Stereocenters while Controlling β-Hydride Elimination Brinton Seashore-Ludlow and Peter Somfai Org. Lett. 2010, 12, 3732-3735. III. Enantioselective Synthesis of anti-β-Hydroxy-α-Amido Esters via Transfer Hydrogenation Brinton Seashore-Ludlow, Piret Villo, Christine Häcker and Peter Somfai Org. Lett. 2010, 12, 5274-5277. IV. Domino Carbopalladation-Carbonylation: Investigation of Substrate Scope Brinton Seashore-Ludlow, Jakob Danielsson and Peter Somfai Adv. Synth. Catal. 2012, 354, 205-216. V. Enantioselective Synthesis of anti-β-Hydroxy-α-Amido Esters by Asymmetric Transfer Hydrogenation in Emulsions Brinton Seashore-Ludlow, Piret Villo and Peter Somfai Chem. – Eur. J. accepted. VI. Domino Carbopalladation-Cross-Coupling for the Synthesis of 3,3- Disubstituted Oxindoles Brinton Seashore-Ludlow and Peter Somfai Submitted. Papers not included in this thesis: VII. 1,3-bis(silyl)propenes Brinton Seashore-Ludlow and Peter Somfai e-EROS, Encyclopedia of Organic Reagents [Online], John Wiley & Sons, Ltd., 2011. VIII. Sigmatropic Rearrangements in Stereoselective Synthesis Brinton Seashore-Ludlow and Peter Somfai Stereoselective Synthesis of Drugs and Natural Products Andrushko, V.; Andrushko, N., Eds. Wiley-Blackwell: 2012, accepted. IX. Organosilicon Reagents: Vinyl-, Alkynyl- and Arylsilanes Brinton Seashore-Ludlow and Peter Somfai Comprehensive Organic Synthesis Molander, G.; Knochel, P. Eds. Elsevier: 2012; Vol. 1, submitted. Table of Contents Abstract Abbreviations List of publications Abstract .................................................................................................................. I 1. Introduction ................................................................................................... 1 1.1. Domino Reactions ................................................................................................ 3 1.1.1. Oxindoles ...................................................................................................................... 5 1.2. Synthesis of β-Hydroxy-α-Amino Acids and their Derivatives .......................... 7 1.3. The Aim of this Thesis ....................................................................................... 11 2. Palladium-Catalyzed Domino Reactions ..................................................... 13 2.1. Introduction ........................................................................................................ 13 2.2. Domino Carbopalladation-Carbonylation .......................................................... 15 2.2.1. α,β-Unsaturated Amides: Trisubstituted Olefins ........................................................ 20 2.2.2. α,β-Unsaturated Amides: Tetrasubstituted Olefins .................................................... 25 2.2.3. Allylic Amines ............................................................................................................ 28 2.2.4. Construction of Carbocycles ....................................................................................... 30 2.2.5. Conclusion .................................................................................................................. 31 2.3. Domino Carbopalladation-Cross-Coupling ....................................................... 31 2.3.1. Domino Carbopalladation-Cross-Coupling with Alkyl Organoboranes ..................... 36 2.3.2. Conclusion .................................................................................................................. 39 3. Addition of Azomethine Ylides to Aldehydes: Synthesis of β-Hydroxy-α- Amino Esters ....................................................................................................... 40 3.1. Introduction ........................................................................................................ 40 3.2. Investigation of 1,3-Dipolar Cycloadditions between Azomethine Ylides and Aldehydes ............................................................................................................... 44 3.3. Conclusion .......................................................................................................... 48 4. Asymmetric Transfer Hydrogenation Coupled with Dynamic Kinetic Resolution for the Synthesis of β-Hydroxy-α-Amino Esters .............................. 50 4.1. Introduction ........................................................................................................ 50 4.2. Asymmetric Hydrogenation and Asymmetric Transfer Hydrogenation ............ 51 4.3. Synthesis of anti-β-Hydroxy-α-Amido Esters ................................................... 53 4.3.1. ATH in Emulsions using Sodium Formate ................................................................. 55 4.3.2. Conclusion .................................................................................................................. 59 4.4. Applications to Natural Products ....................................................................... 59 4.4.1. Conclusion .................................................................................................................. 62 5. Concluding Remarks ..................................................................................
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