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Organocatalytic Acylation for the Kinetic Resolution of Secondary Aryl Alcohols

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Organocatalytic Acylation for the Kinetic Resolution of Secondary Aryl Alcohols Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 1191 Organocatalytic Acylation for the Kinetic Resolution of Secondary Aryl Alcohols Synthetic Applications and Mechanistic Studies LAURA MESAS SÁNCHEZ ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6214 ISBN 978-91-554-9075-1 UPPSALA urn:nbn:se:uu:diva-233734 2014 Dissertation presented at Uppsala University to be publicly examined in A1:111a, BMC, Husargatan 3, Uppsala, Friday, 28 November 2014 at 09:00 for the degree of Doctor of Philosophy. The examination will be conducted in English. Faculty examiner: Pavel Kočovský. Abstract Mesas Sánchez, L. 2014. Organocatalytic Acylation for the Kinetic Resolution of Secondary Aryl Alcohols. Synthetic Applications and Mechanistic Studies. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 1191. 54 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9075-1. The research described in this thesis focuses on the catalytic acylative kinetic resolution (KR) of aromatic secondary alcohols, using a planar-chiral 4-(dimethylamino)pyridine (DMAP) organocatalyst. In the first part of this thesis, the substrate scope of the above mentioned process was expanded to aromatic secondary alcohols that contain an extra functional group in the alkyl moiety, such as 1,2-azido alcohols, 2-hydroxy-2-aryl-ethylphosphonates and 2-hydroxy-2-aryl esters. Thus, the preparation of highly functionalized compounds in their enantiomerically pure form with excellent enantiomeric excess (up to 99% ee) was achieved. Furthermore, the synthetic applicability of this methodology was illustrated through the synthesis of two high value compounds, (R)-Pronethalol and (S)-3-hydroxy-N-methyl-3-phenylpropanamide, which is an immediate precursor of bioactive molecules such as (S)-Fluoxetine. The second part of this thesis deals with the mechanistic study of the acylative KR catalyzed by the planar-chiral DMAP derivative. Reaction Progress Kinetic Analysis methodology was used in the investigation of the reaction mechanism, probing that no notable product inhibition or decomposition of the catalyst occurs in the studied system. The reaction rate showed fractional order dependence on the concentration of both reactants. Furthermore, NMR spectroscopy was utilized to study the equilibrium between the different catalyst states, which explains the measured kinetics of the reaction. Keywords: kinetic resolution, organocatalysis, secondary alcohols, reaction progress kinetic analysis Laura Mesas Sánchez, Department of Chemistry - BMC, Synthetical Organic Chemistry, Box 576, Uppsala University, SE-75123 Uppsala, Sweden. © Laura Mesas Sánchez 2014 ISSN 1651-6214 ISBN 978-91-554-9075-1 urn:nbn:se:uu:diva-233734 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-233734) A toda mi familia “La vida es simplemente una cuestión de química” James Watson Cover: 3D Plot of the in situ IR spectra corresponding to the acetylation of (R)-1-phenylethanol catalyzed by a planar-chiral DMAP catalyst. List of Publications This thesis is based on the following publications, which are referred to in the text by their Roman numerals I-IV. I Mesas-Sánchez, L., Díaz-Álvarez, A. E., Dinér, P. Non-enzymatic kinetic resolution of 1,2-azidoalcohols using a planar-chiral DMAP derivative catalyst. Tetrahedron 2013, 69, 753−757. II Mesas-Sánchez, L., Díaz-Álvarez, A. E., Koukal, P., Dinér, P. Kinet- ic resolution of 2-hydroxy-2-aryl-ethylphosphonates by a non- enzymatic acylation catalyst. Tetrahedron 2014, 70, 3807−3811. III Díaz-Álvarez, A. E.†, Mesas-Sánchez, L.†, Dinér, P. Access to opti- cally pure β-hydroxy esters via non-enzymatic kinetic resolution by a planar-chiral DMAP catalyst. Molecules 2014, 19, 14273-14291. IV Mesas-Sánchez, L., Dinér, P. A mechanistic investigation of the ki- netic resolution of secondary aromatic alcohols using a ferrocene- based planar chiral DMAP catalyst. Manuscript 2014. Reprints were made with permission from the respective publishers. Publications not included in this thesis: V Díaz-Álvarez, A. E., Mesas-Sánchez, L., Dinér, P. Non-enzymatic dynamic kinetic resolution of secondary aryl alcohols: planar chiral ferrocene and ruthenium catalyst in cooperation. Angew. Chem. Int. Ed. 2013, 52, 502−504. † Authors contributed equally to the publication and are presented in alpha- betical order. The author wishes to clarify her contribution to the papers I-IV in the the- sis. I Prepared most of the racemic substrates; planned and performed the kinetic resolutions and characterized all the final products. Partially involved in the preparation of the manuscript; dis- cussed the results and commented on the manuscript. II Formulated the research problem. Partially involved in the syn- thesis of racemic substrates; designed and carried out all the ki- netic resolutions and characterized all the final products. Wrote the entire manuscript. III Formulated the research problem. Partially involved in the syn- thesis of racemic substrates; performed the complete initial sub- strate screening for the determination of the selectivity factor; performed the experiments for the assignation of the optical configuration; synthesized the precursor of (S)-Fluoxetine. Wrote virtually the complete manuscript. IV Designed, performed and analyzed the experiments for the ki- netic studies and the 1H-NMR spectroscopy studies. Partially involved in the preparation of the manuscript; discussed the re- sults and commented on the manuscript. Contents 1. Introduction ................................................................................................. 9 1.1. Chirality ............................................................................................. 10 1.2. Preparation of optically pure compounds .......................................... 14 1.3. Kinetic resolution .............................................................................. 15 1.4. Organocatalysts for acylative kinetic resolutions of chiral secondary alcohols .................................................................................... 18 1.4.1. 4-Aminopyridine derivatives ..................................................... 19 1.5. The aim of this thesis ......................................................................... 22 2. Kinetic resolution of secondary aryl alcohols catalyzed by a planar- chiral DMAP derivative (Papers I-III) .......................................................... 23 2.1. The importance of chiral functionalized alcohols ............................. 23 2.2. Substrate scope .................................................................................. 24 2.2.1. Kinetic resolution of β-azido alcohols ....................................... 24 2.2.2. Kinetic resolution of β-hydroxy phosphonates .......................... 26 2.2.3. Kinetic resolution of β-hydroxy esters ...................................... 28 2.3. Synthetic applications ........................................................................ 30 2.4. Conclusions ....................................................................................... 31 2.4.1. Structure-selectivity trends ........................................................ 32 3. Mechanistic studies of the acetylation by a planar-chiral DMAP catalyst (Paper IV) ......................................................................................... 33 3.1. Introduction ....................................................................................... 33 3.1.1. Reaction progress kinetic analysis ............................................. 34 3.2. Results and discussion ....................................................................... 37 3.3. Conclusions ....................................................................................... 41 4. Concluding remarks and outlook .............................................................. 42 Populärvetenskaplig sammanfattning ........................................................... 43 Resumen divulgativo en español ................................................................... 46 Acknowledgements ....................................................................................... 49 References ..................................................................................................... 51 Abbreviations BOX Bis(oxazoline) BTM Benzotetramisole CALB Candida Antarctica lipase B Conv. Conversion DCM Dichloromethane DIPT Diisopropyl tartrate DKR Dynamic kinetic resolution DMAP 4-(Dimethylamino)pyridine DNA Deoxyribonucleic acid DOPA 3,4-Dihydroxyphenylalanine ee Enantiomeric excess EMA European Medicines Agency Equiv Equivalents FDA Food and Drug Administration of United States of America GABA Gamma-aminobutyric acid HBTM Homobenzotetramisole IR Infrared KR Kinetic resolution LDA Lithium diisopropylamide NMR Nuclear magnetic resonance rac Racemic RNA Ribonucleic acid RPKA Reaction progress kinetic analysis s Selectivity sec Secondary TBHP tert-Butyl hydroperoxide THF Tetrahydrofuran 1. Introduction This thesis deals with the synthesis of enantiopure functionalized aromatic secondary alcohols, via kinetic resolution promoted by a planar-chiral 4- (dimethylamino)pyridine (DMAP) organocatalyst. Furthermore, the mecha- nism of this reaction has been studied in order to get a better understanding of this process. This thesis is structured as follows: chapter 1 starts with a brief introduc- tion of the concept of chirality and its importance in life. In this chapter dif-
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