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Page 1: DiVA portal1137254/...S N1 unimolecular nucleophilic substitution S N2 bimolecular nucleophilic substitution S N′ nucleophilic substitution with allylic rearrangement * Coghill,
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DIRECT CATALYTIC NUCLEOPHILIC SUBSTITUTION OF NON-DERIVATIZED ALCOHOLS

Anon Bunrit

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Direct Catalytic NucleophilicSubstitution of Non-DerivatizedAlcohols

Anon Bunrit

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©Anon Bunrit, Stockholm University 2017 ISBN print 978-91-7649-917-7ISBN PDF 978-91-7649-918-4 Cover Image: ‘ALCOHOLS’ by Anon Bunrit Printed in Sweden by Universitetsservice US-AB, Stockholm 2017Distributor: Department of Organic Chemistry, Stockholm University

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Life is a journey and full ofpossibility to make thingspossible.

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Abstract

This thesis focuses on the development of methods for the activation of the hydroxyl group in non-derivatized alcohols in substitution reactions. The thesis is divided into two parts, describing three different catalytic systems.

The first part of the thesis (Chapter 2) describes nucleophilic allylation of amines with allylic alcohols, using a palladium catalyst to generate un-symmetrical diallylated amines. The corresponding amines were further transformed by a one-pot ring-closing metathesis and aromatization reaction to afford β-substituted pyrroles with linear and branched alkyl, benzyl, and aryl groups in overall moderate to good yields.

The second part (Chapters 3 and 4) describes the direct intramolecular stereospecific nucleophilic substitution of the hydroxyl group in enantioen-riched alcohols by Lewis acid and Brønsted acid/base catalysis.

In Chapter 3, the direct intramolecular substitution of non-derivatized al-cohols has been developed using Fe(OTf)3 as catalyst. The hydroxyl groups of aryl, allyl, and alkyl alcohols were substituted by the attack of O- and N- centered nucleophiles, to provide five- and six-membered heterocycles in up to excellent yields with high enantiospecificities. Experimental studies showed that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile of the sub-strate. Competition and catalyst-substrate interaction experiments demon-strated that this transformation proceeds via an SN2-type reaction pathway.

In Chapter 4, a Brønsted acid/base catalyzed intramolecular substitution of non-derivatized alcohols was developed. The direct intramolecular and stereospecific substitution of different alcohols was successfully catalyzed by phosphinic acid (H3PO2). The hydroxyl groups of aryl, allyl, propargyl, and alkyl alcohols were substituted by O-, N-, and S-centered nucleophiles to generate five- and six-membered heterocycles in good to excellent yields with high enantiospecificities. Mechanistic studies (both experiments and density functional theory calculations) have been performed on the reaction forming five-membered heterocyclic compounds. Experimental studies showed that phosphinic acid does not promote SN1 reactivity. Rate-order determination indicated that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile. DFT calculations corroborated with a reaction pathway in which the phos-phinic acid has a dual activation mode and operates as a bifunctional Brønsted acid/Brønsted base to simultaneously activate both the nucleophile and nucleofuge, resulting in a unique bridging transition state in an SN2-type reaction mechanism.

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Populärvetenskaplig Sammanfattning

Råmaterialet som används inom den kemiska sektorn är olefiner som erhålls från raffinering av råolja och vidare ”krackning”. Dessa föreningar framställs i samband med produktionen av bensin och diesel som en relativt liten sidoström. Vårt samhälle är otroligt beroende av denna lilla sidoström i produktion av mat, material och läkemedel. När samhället blir varse om de negativa konsekvenserna av att använda fossila källor samtidigt som tekniska framsteg görs för att begränsa behovet av flytande drivmedel och de stora oljekällorna håller på att sina så är det viktigt att hitta en alternativ och förnybar källa av råmaterial för att täcka våra behov.

Alkoholer är kemiska föreningar som är naturligt förekommande i biomassa. I naturen så är de oftast optiskt rena. Inom kemin så nyttjas redan alkoholer som nukleofiler men om de ska användas som elektrofiler så behöver alkoholerna derivatiseras. Detta på grund av att den funktionella gruppen på alkoholer, hydroxylgruppen, är en dålig lämnande-grupp. Derivatiseringssteget gör inte bara syntesvägen längre utan leder till att det behövs extra reagens och att det bildas kemiskt avfall. Om hydroxylgruppen skulle kunna substitueras med en oladdad nukleofil så skulle endast vatten bildas som biprodukt.

I den här avhandlingen så har jag undersökt hur hydroxylgruppen utan derivatisering kan substitueras av olika nukleofiler med hjälp av katalysatorer. I den första delen av denna avhandling så används allyliska alkoholer som reagens ihop med en amin. Genom att använda tre katalysatorer, så kan vi generera pyrroler, en viktig substans inom kemiindustrin med bara eten och vatten som biprodukt. I den andra delen av avhandlingen så har vi utvecklat två olika katalytiska system för att stereospecifikt substituera hydroxylgruppen på stereogena alkoholer med olika nukleofiler. I ett arbete så använder vi en järnkatalysator och i ett annat arbete så använder vi en Brønsted syra/bas katalysator. Förutom att lyckas substituera hydroxylgruppen i allyliska alkoholer så har vi även lyckats att substituera hydroxylgruppen i bensyl-, propargyl- och alkylalkoholer för första gången.

Jag hoppas att resultaten från denna avhandling kommer att inspirera andra kemister att utveckla fler och effektivare metoder att substituera hydroxylgruppen så att vi på ett säkert sätt kan övergå till ett mer hållbart samhälle.

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List of Publications

This thesis is based on the following publications and unpublished results, which are referred to in the text by their Roman numerals. The contribution by the author to each publication is clarified in Appendix A. Reprints were made with permission from the publishers, enumerated in Appendix B.

I. A General Route to β-Substituted Pyrroles by Transition-Metal Catalysis Anon Bunrit, Supaporn Sawadjoon, Svetlana Tšupova, Per J. R.

Sjöberg, Joseph S. M. Samec* J. Org. Chem., 2016, 81 (4), 1450–1460. (ChemInform, 2016, 47 (28))

II. Iron(III)-Catalyzed Intramolecular Stereospecific Substitution of the OH Group in Stereogenic Secondary and Tertiary Alcohols Rahul A. Watile, Anon Bunrit, Emi Lagerspets, Ingela Lanekoff, Srijit Biswas, Timo Repo,* Joseph S. M. Samec* Manuscript

III. Brønsted Acid-Catalyzed Intramolecular Nucleophilic Substitu-tion of the Hydroxyl Group in Stereogenic Alcohols with Chirality Transfer Anon Bunrit, Christian Dahlstrand, Sandra K. Olsson, Pemikar Srifa, Genping Huang, Andreas Orthaber, Per J. R. Sjöberg, Srijit Biswas,* Fahmi Himo,* Joseph S. M. Samec* J. Am. Chem. Soc., 2015, 137 (14), 4646–4649. (Synlett, 2016, 27 (02), 173–176)

IV. H3PO2-Catalyzed Intramolecular Stereospecific Substitution of the Hydroxyl Group in Stereogenic Secondary Alcohols by N-, O-, and S-Centered Nucleophiles to Generate Heterocycles Anon Bunrit, Pemikar Srifa, Christian Dahlstrand, Genping Huang, Srijit Biswas, Fahmi Himo, Rahul A. Watile,* Joseph S. M. Samec* Manuscript

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Parts of this thesis build upon

Palladium and H3PO2-Catalyzed Nucleophilic Substitution of Non-Activated Alcohols Anon Bunrit, Licentiate Thesis, Department of Chemistry – BMC, Synthetic Organic Chemistry, Uppsala University, 2015.

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Abbreviations

Abbreviations and acronyms are used in agreement with the standards of the subject.* Additional non-standard and unconventional abbreviations that appear in this thesis are listed below:

cat. catalyst CBS Corey-Bakshi-Shibata conv. conversion dba dibenzylideneacetone 1,2-DCE 1,2-dichloroethane DFT Density Functional Theory e.e. enantiomeric excess equiv. equivalent(s) er enantiomeric ratio e.s. enantiospecificity L ligand Nu nucleophile OH hydroxyl OTf trifluoromethanesulfonate PMP para-methoxyphenyl p-TSA, PTSA para-toluenesulfonic acid RCM Ring-Closing Metathesis rt room temperature TBAHS tetrabutylammonium hydrogensulfate TIPS triisopropylsilyl THP tetrahydropyranyl TS transition state SN1 unimolecular nucleophilic substitution SN2 bimolecular nucleophilic substitution SN′ nucleophilic substitution with allylic rearrangement

* Coghill, A. M.; Garson, L. R. The ACS Style Guide: 3rd ed. American Chemical Society, 2006.

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Table of Contents

Abstract .................................................................................................................................... ix Populärvetenskaplig Sammanfattning ...................................................................................... xi List of Publications ................................................................................................................ xiii Abbreviations .......................................................................................................................... xv 1. Introduction ........................................................................................................................... 1 1.1. Alcohols ............................................................................................................................. 1 1.1.1. Availability and Classification of Alcohols ..................................................................... 1 1.1.2. Reactivity of the OH Group in Alcohols ......................................................................... 2 1.2. Catalysis ............................................................................................................................. 2 1.2.1. General Principles of Catalysis ........................................................................................ 2 1.2.2. Classification of Catalysis ............................................................................................... 3 1.3. The Catalytic C─O Bond Activation of the OH Group in Alcohols for Substitution Reac-tion ............................................................................................................................................ 5 1.3.1. Borrowing Hydrogen ....................................................................................................... 5 1.3.2. Direct Catalytic Substitution ........................................................................................... 6 1.4. Asymmetric Synthesis ........................................................................................................ 7 1.4.1. General Principles of Asymmetric Synthesis .................................................................. 7 1.4.2. Strategies of Asymmetric Synthesis ................................................................................ 8 1.5. Aims of the Thesis ............................................................................................................ 11 2. Palladium-Catalyzed Direct Aminaton of Allylic Alcohols and Its Application to Synthesis of β-Substituted Pyrroles (Paper I) .......................................................................................... 13 2.1. Background ...................................................................................................................... 13 2.1.1. Tsuji-Trost Reaction using Non-Derivatized Allylic Alcohols ...................................... 13 2.1.2. Synthesis of β-Substituted Pyrroles ............................................................................... 15 2.2. Results and Discussion ..................................................................................................... 17 2.2.1. Substrate Scope and Synthesis....................................................................................... 17 2.2.2. Monoallylation of Amines By Allyl Alcohols ............................................................... 18 2.2.3. Allylation of Amines With Allyl Alcohols .................................................................... 19 2.2.4. Ring-Closing Metathesis of Diallylated Amines ........................................................... 21 2.2.5. One-Pot Two Steps Synthesis of β -Substituted Pyrroles .............................................. 22 2.3. Conclusion ........................................................................................................................ 23 3. Lewis Acid-Catalyzed Intramolecular Stereospecific Substitution of Non-Derivatized Al-cohols (Paper II) ...................................................................................................................... 25 3.1. Background ...................................................................................................................... 25 3.1.1. Catalytic Activation of the Hydroxy Group in Alcohols in Substitution Reaction By Lewis Acids ............................................................................................................................. 25 3.2. Results and Discussion ..................................................................................................... 26 3.2.1. Substrate Scope and Synthesis....................................................................................... 26

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3.2.1.1. Synthesis of Starting Enantioenriched Alcohols with Nitrogen-Centered Nucleophiles................................................................................................................................................. 26 3.2.1.2. Synthesis of Starting Enantioenriched Alcohols with Oxygen-Centered Nucleophiles................................................................................................................................................. 28 3.2.2. Optimization of the Reaction Parameters for Intramolecular Stereospecific Substitution Reaction .................................................................................................................................. 29 3.2.3. Intramolecular Substitution to Generate Five-Membered Heterocycles From Benzylic Alcohols .................................................................................................................................. 31 3.2.4. Intramolecular Substitution to Generate Five-Membered Heterocycles From Non-Benzylic Alcohols ................................................................................................................... 32 3.2.5. Intramolecular Substitution to Generate Six-Membered Heterocycles From Benzylic Alcohols .................................................................................................................................. 33 3.2.6. Mechanistic Studies ....................................................................................................... 34 3.2.6.1. Rate-Order Determination .......................................................................................... 34 3.2.6.2. Competition Experiments ........................................................................................... 35 3.2.7. Plausible Mechanistic Pathways .................................................................................... 37 3.3. Conclusion ........................................................................................................................ 38 4. Brønsted Acid/Base-Catalyzed Intramolecular Stereospecific Substitution of Non-Derivatized Alcohols (Paper III And IV) ................................................................................ 41 4.1. Backgrounds ..................................................................................................................... 41 4.1.1. Catalytic Activation of the Hydroxyl Group in Alcohols in Substitution Reaction By Brønsted Acid/Base Pairs ........................................................................................................ 41 4.1.2. Bifunctional Catalysis ................................................................................................... 41 4.2. Results and Discussion ..................................................................................................... 43 4.2.1. Substrate Scope and Synthesis....................................................................................... 43 4.2.1.1. Synthesis of Starting Enantioenriched Alcohols with Nitrogen-Centered Nucleophile................................................................................................................................................. 43 4.2.1.2. Synthesis of Starting Enantioenriched Alcohols with Sulfur-Centered Nucleophile .. 43 4.2.2. Optimization of the Reaction Parameters for Intramolecular Stereospecific Substitution................................................................................................................................................. 44 4.2.3. Water Effect .................................................................................................................. 46 4.2.4. Intramolecular Substitution to Generate Five-Membered Heterocycles from Benzylic Alcohols .................................................................................................................................. 47 4.2.5. Intramolecular Substitution to Generate Five-Membered Heterocycles from Non-Benzylic Alcohols ................................................................................................................... 48 4.2.6. Intramolecular Substitution to Generate Six-Membered Heterocycles from Benzylic Alcohols .................................................................................................................................. 49 4.2.7. Mechanistic Studies ....................................................................................................... 50 4.2.7.1. Reaction Progress ....................................................................................................... 50 4.2.7.2. Interaction of H3PO2 Dimer with the Substrates ......................................................... 51 4.2.7.3. Rate-Order Determination: Catalyst ........................................................................... 52 4.2.7.4. Rate-Order Determination: Substrates ........................................................................ 52 4.2.7.5. Competition Experiments ........................................................................................... 53 4.2.7.6. Experiments to exclude the SN1 reaction .................................................................... 54

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4.2.7.7. Density Functional Theory Calculations .................................................................... 55 4.3. Conclusion ........................................................................................................................ 57 5. Concluding Remarks ........................................................................................................... 59 Appendix A: Contribution List ................................................................................................ 61 Appendix B: Reprint Permissions ........................................................................................... 63 Acknowledgements ................................................................................................................. 65 References ............................................................................................................................... 69

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1. Introduction

1.1. Alcohols

1.1.1. Availability and Classification of Alcohols

Alcohols are an important class of chemical compounds in nature. They are commonly found in beverages (ethanol), antifreeze (ethylene glycol),1 sweeteners (xylitol,2 glucose), household chemicals (2-phenylethanol,3 men-thol),4 and are abundant within biomass (carbohydrates, cellulose, lignin, DNA, RNA),5 see Figure 1.1. They find wide applications in the food, phar-maceutical, and chemical industries. Alcohols are characterized by their containing of at least one hydroxyl (OH) group attached to the carbon atom of a hydrocarbon.

Figure 1.1. Examples of alcohols found in nature.

Alcohols can be classified, according to the position of the OH group in the molecule, as primary, secondary or tertiary (Figure 1.2.). A primary (1⁰)

alcohol has the OH group attached to a carbon substituted with at least two hydrogens. In secondary (2⁰) and tertiary (3⁰) alcohols, the OH group is at-tached to a carbon atom with two and three groups, e.g. alkyls, respectively. Furthermore, π-activated alcohols can be classified according to the func-tional groups on the carbon atom attached to the OH group. Allylic, ben-zylic, or propargylic alcohols are joined to an allylic carbon (─CH2CH=CH2), a benzylic carbon (─CH2C6H5), or a propargylic carbon (─CH2C≡CH), respectively (Figure 1.2.).

Figure 1.2. Structure and classification of alcohols.

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1.1.2. Reactivity of the OH Group in Alcohols

The OH group of an alcohol can either act as nucleophile or nucleofuge in a chemical reaction. Most commonly alcohols are used as nucleophiles, for example, in etherification reactions with alkyl halides. When the opposite reactivity is desired, the alcohol is used as electrophile. However, the OH group of alcohols has relatively poor leaving group ability. To increase the leaving group ability of the OH group, a pre-activation of alcohols is re-quired. The protonation of the alcohol is normally performed in substitution reactions to generate the leaving H2O group under strong acidic conditions. An alternative method is the derivatization of the OH group into a better leaving group, either performed in-situ,6 e.g. in the Mitsunobu reaction7 or in a separate reaction step, e.g. via tosylation (Scheme 1.1.).8 These procedures have drawbacks including; the use of stoichiometric and harmful reagents, multistep processes and purification issues, thus increasing the cost and envi-ronmental impact of the transformation.9 Already today, this is a big problem in the chemical industries and is a disadvantage for the use of these easily accessible classes of organic compounds. Therefore, the direct nucleophilic substitution of non-derivatized alcohols was recently voted as the second most desired reaction that pharmaceutical manufacturers wanted greener alternatives to.10 If we would like to evolve from a petroleum-based society to a bio-based society, this will be even more urgent.

Scheme 1.1. Examples of nucleophilic substitution via pre-activation of the hy-droxyl group of alcohols: (a) Mitsunobu reaction, (b) tosylation.

1.2. Catalysis

1.2.1. General Principles of Catalysis

A catalyst is a substance that increases the rate of a reaction without being consumed in the process. In general, a catalyst is used in a sub-stoichiometric amount. It accelerates a chemical reaction providing a reac-

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be efficiently tuned. One example of an organometallic catalyzed reaction is the asymmetric hydrogenation by (S)-BINAP-Ru(II) complex to produce the anti-inflammatory drug (S)-naproxen (Scheme 1.2.a.).11

Lewis acid catalysis is the use of a metal-based Lewis acid as a catalyst in organic reactions. The Lewis acid acts as an electron pair acceptor that inter-acts with the lone-pair of a substrate, such as oxygen, nitrogen, sulfur, or halogen, to increase the reactivity of the substrate. Lewis acid catalysts are usually easily available compounds such as TiCl4, BF3, SnCl4, and AlCl3. A drawback of Lewis acid catalysis is inefficient catalyst turnover and air- and moisture-sensitivity. An example of Lewis acid catalysis is the Friedel-Crafts acylation reaction (Scheme 1.2.b.).12

Brønsted acid catalysis (or so-called acid-base catalysis) is the most commonly used type of catalysis in chemical transformations. The acid is a proton donor and the base is a proton acceptor in the concept of Brønsted–

Lowry acid and base. Acid catalysis can be classified into two types with regards to their reaction mechanisms: specific acid catalysis and general acid catalysis. In specific acid catalysis, the protonated solvent is the actual catalyst and the rate depends on the specific acid (i.e. protonated solvent) and no other acids in the solution. On the other hand, general acid catalysis is the use of an acid catalyst which donates a proton to a substrate and this process occurs in the rate-limiting step. An example of acid catalysis is Fischer esterification reaction (Scheme 1.2.c.).13

Scheme 1.2. Examples of a) organometallic catalysis, b) Lewis acid catalysis, and c) Brønsted acid catalysis.

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1.3. The Catalytic C─O Bond Activation of the OH

Group in Alcohols for Substitution Reaction

From a green chemistry perspective, the OH group in alcohols would be an excellent nucleofuge for substitution reactions because water would be the only by-product formed in the overall reaction.14 However, alcohols are poor substrates for substitution reactions. This is due to the relatively poor leaving group ability of the OH group under normal reaction conditions. In 2007, the ACS Green Chemistry Institute Pharmaceutical Roundtable developed a list of key research areas where it encouraged the integration of green chemistry and green engineering into the pharmaceutical industry. As already men-tioned, the direct catalytic nucleophilic substitution of the OH group was considered as a top research priority.10 Since then, two catalytic approaches have gained attention: hydrogen borrowing and direct catalytic substitution (Scheme 1.3.).

Scheme 1.3. Catalytic substitution reactions via different modes of activation of the OH group of alcohols: (a) hydrogen borrowing, and (b) direct catalytic substitution.

1.3.1. Borrowing Hydrogen

The borrowing hydrogen (also called hydrogen auto-transfer) methodology is a method for C─O bond activation in substitution reactions of alcohols.

The concept behind this methodology combines the dehydrogenation and rehydrogenation of a molecule. The reaction proceeds via the temporary oxidation of an alcohol into the corresponding carbonyl compound (aldehyde or ketone) by the metal-catalyzed removal of hydrogen. Carbonyl com-pounds are more reactive than alcohols towards nucleophilic addition and can undergo further transformations. The corresponding substituted com-pounds are then hydrogenated to generate the product. Water is the only by-product in this transformation. This methodology is environmentally friendly and efficient with respect to atom economy.15 One of the examples of the borrowing hydrogen methodology is the N-alkylation of aniline with [Cp*IrCl2]2 (Scheme 1.4.).

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Scheme 1.4. Activation of alcohol by borrowing hydrogen in N-Alkylation with an iridium catalyst.16

1.3.2. Direct Catalytic Substitution

The direct nucleophilic substitution reaction can be classified into three main types with regard to the fundamental mechanism: SN1-type, SN2′-type and SN2-type (Scheme 1.5.). SN1-type reaction is the substitution reaction where an OH group is acti-vated by a catalyst, such as a Brønsted or Lewis acid, to generate a cationic intermediate. The selectivity of an SN1-type reaction is governed by the ease to generate the corresponding carbocation rather than the electrophilicity of the generated cation.17 An example of an SN1-type reaction is the direct sub-stitution of a benzylic alcohol by an iron(III) catalyst (Scheme 1.5.a.).18, 20

SN2′-type is a reaction of allylic alcohols where the OH group is activat-ed by an allylic function, and the nucleophile attacks the double bond of the allyl, that is followed by a π-bond rearrangement to the next C─C bond and loss of the OH leaving group to generate the product. An example of such SN2′-type reaction is the gold-catalyzed intramolecular stereospecific allyla-tion of an alcohol to generate an enantioenriched ether (Scheme 1.5.b.).19 SN2-type reactions proceed through a nucleophilic attack at a sp3-hybridized electrophile. The departure of the OH leaving group occurs sim-ultaneously with a backside attack by the nucleophile, and two molecules are involved in the transition state in the intermolecular substitution reaction. The SN2 reaction thus leads to the formation of the product with an inversion of configuration at the stereocenter. Scheme 1.5.c. illustrates an example of SN2 type Fe(III)-catalyzed intramolecular Friedel-Crafts reaction.20

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Scheme 1.5. Examples of direct catalytic nucleophilic substitution via different mechanistic pathways: (a) Fe-catalyzed nucleophilic substitution, (b) Au-catalyzed

stereospecific allylation, (c) Fe-catalyzed Friedel-Crafts reaction.

1.4. Asymmetric Synthesis

1.4.1. General Principles of Asymmetric Synthesis

Asymmetric synthesis is a process that introduces one or more new stereo-genic centres during a chemical transformation. In asymmetric synthesis, a reaction can either be stereospecific or stereoselective depending on the re-action pathway. A stereospecific reaction is a reaction in which the stereo-chemistry of the reactant determines the stereochemistry of the product. In contrast, a stereoselective reaction is a chemical reaction in which a single reactant forms an unequal mixture of stereoisomeric products. A stereoselec-tive reaction can be further grouped into enantioselective or diastereoselec-tive, depending on whether an enantiomer or a diastereomer is being gener-ated. A stereoselective reaction has more than one possible reaction path-ways in which one reaction pathway is being more favourable than the other pathway.21

The term enantiomeric excess (e.e.) is used as one factor to determine the success of an asymmetric synthesis. Enantiomeric excess represents the ex-cess of one enantiomer in greater amount than the other in a mixture of enan-tiomers, where e.e. = (% of major enantiomer - % of minor enantiomer).21 A substance that is composed of a single enantiomer (100% e.e.) is called ho-mochiral or optically pure. In addition to stereospecific methods, the term of enantiospecificity (e.s.) is used to describe the conservation of enantiomeric purity over the course of the reaction where e.s.= (e.e. of product/e.e. of sub-strate)×100.17

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1.4.2. Strategies of Asymmetric Synthesis

The ability to synthesize a single enantiomer of chiral compounds has long been of interest because many biological active compounds are chiral. The properties of chiral molecules can be different in living organisms and may trigger different reactions. This is an important factor because different enan-tiomers often interact with biological receptors differently. For example, the different smells of the two enantiomers of limonene: (S)-(‒)-limonene is the most commonly found in nature and smells like orange while (R)-(+)-limonene smells like lemon (Figure 1.4.).22

Figure 1.4. Two enantiomers of Limonene.

To access enantiomerically pure compounds for organic synthesis, and in particular for biological applications, there is a need for efficient strategies for asymmetric synthesis which can be classified into five commonly used approaches: chiral catalysis, chiral auxiliary, chiral pool synthesis, organo-catalysis, and biocatalysis.

Chiral catalysis is the most commonly used approach in asymmetric synthesis which employs chiral coordination complexes as catalysts. Cataly-sis is applicable for a broad range of chemical transformations. In most cas-es, the central atom (often a transition metal) of a catalyst, interacts with substrates where a chiral ligand influences the outcome of the reaction with respect to enantiomeric excess of the products. An example of chiral cataly-sis is the asymmetric hydrogenation of tert-alkyl ketones using a BIN-AP/PICA(α-picolylamine)-Ru complex (Scheme 1.6.a.).23 A chiral auxiliary is a chiral molecule that can be temporarily incorpo-rated into the structure of an achiral substrate and selectively direct the for-mation of enantiomerically enriched products. A chiral auxiliary physically blocks one of two possible pathways by steric hindrance. The auxiliary should be easily removed, either immediately during the work-up process or in a separate step, and may be recycled. A drawback of the auxiliary method is that the auxiliary may not be readily available. Another drawback is that they are required in a stoichiometric amount and their removal lowers the efficiency of the synthesis. A commercially available chiral auxiliary, such

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as a chiral oxazolidinone, is used in the asymmetric alkylation of an oxazoli-dinone imide (Scheme 1.6.b.).24 Chiral pool synthesis is a process that employs enantiomerically pure compounds as starting materials to synthesize a target chiral molecule. Common starting materials are readily available compounds derived from nature such as amino acids, monosaccharides, and chiral carboxylic acids. The stereochemistry of a starting molecule is generally preserved during the chemical transformations to a target product. The stereoselective total syn-thesis of (−)-allonorsecurinine can be achieved from chiral pool L-proline (Scheme 1.6.c.).25

Organocatalysis consist of the use of an organic compound as a catalyst to perform reactions. Catalysts are generally available in enantiomerically pure form and easily handled. A drawback of this system is the requirement of high catalyst loadings.26 As shown in Scheme 1.6.d., L-proline, as a chiral catalyst, is used in an enantioselective aldol reaction.27

Biocatalysis can be used in organic synthesis, in which an enzyme, either isolated or in a whole cell, is used as a catalyst. This reaction is generally highly selective towards a specific type of compound and operated under mild reaction conditions. An example of biocatalysis is the kinetic resolution reaction of a racemic mixture of an amine in which one of the two enantio-mers is acylated at a higher rate than the other enantiomer (Scheme 1.6.e.).28

In this thesis, the development of methodologies to utilize alcohols as sources of easily available stereogenic compounds in substitution reactions has been performed.

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Scheme 1.6. Examples of asymmetric synthesis approaches via (a) chiral catalysis, (b) chiral auxiliary, (c) chiral pool synthesis,

(d) organocatalysis, and (e) biocatalysis.

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1.5. Aims of the Thesis

This thesis focuses on the development of efficient catalytic methodologies to utilize non-derivatized alcohols as substrates in organic synthesis. The fundamental nature of the reactions between alcohols, catalysts, and nucleo-philes is in focus. The direct catalytic nucleophilic substitution reaction of the hydroxyl group in alcohols is highlighted by employing three types of catalysts: transition metals, Lewis acids and Brønsted acids. Moreover, to widen the scope of substrates, common functional groups and nucleophiles of interest have been used.

More specific goals are to: � Elucidate whether C─O bond activation of alcohols can be achieved in

organic synthesis. � Activate the OH group in alcohols for enantiospecific substitution reac-

tion. � Control the C─O bond cleavage in order to promote enantiospecific

substitution reaction. � Increase the understanding of the catalytic activation of the OH group in

different alcohols.

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2. Palladium-Catalyzed Direct Aminaton of Allylic Alcohols and Its Application to Synthesis of β-Substituted Pyrroles (Paper I)

2.1. Background

2.1.1. Tsuji-Trost Reaction using Non-Derivatized Allylic Alcohols

Nitrogen containing compounds are an important class of molecules because of their abundance in nature as well as in active pharmaceutical ingredi-ents.29 Compounds of this class, especially allylic amines, are structural building blocks for various biologically active compounds and advanced intermediates in total synthesis of natural products.30,31 A common example of a C─N bond forming reaction is the Tsuji-Trost32 transformation. This extensively used process involves a palladium-catalyzed nucleophilic substitution of allylic compounds such as halides,33 esters,34 carbonates, 35 carbamates, 36 phosphates37 and related derivatives.38 The general mechanistic pathway follows: the alkene moiety of an allylic compound coordinates to a palladium(0)complex to form a η2-π-allyl-Pd(0) complex (Scheme 2.1). Oxidative addition forms an η

3-π-allyl-Pd(II) com-plex and the leaving group (X) departs. The nucleophile attacks the terminal positions of the π-allyl to generate a new η2-Pd(0) complex. In the final step, the Pd(0) and alkene dissociate to form the product and the active catalyst for the next catalytic cycle.

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Scheme 2.1. Catalytic cycle of Tsuji-Trost reaction.

The use of allylic alcohols as substrates in the palladium-catalyzed direct nucleophilic substitution reaction has attracted attention for its environmen-tal friendliness since this reaction only generates water as a by-product.9 To date, a few reports have showed usage of non-derivatized allylic alco-hols as substrates in palladium-catalyzed reactions in the presence of activa-tors such as Lewis acids.39 Recently, palladium complexes bearing strong π-acceptor ligands (triphenyl phosphite,40 phospholes,41 diphosphinidenecyclo-butene,42 and phosphoramidite43) have been reported to promote the catalytic amination using a non-derivatized allylic alcohol without the use of other activators (Scheme 2.2.). Previous reports on phosphite-based catalysts showed that the complexes are highly reactive towards the allylic amination reaction of anilines44 or hydrazines45 using a non-derivatized allylic alcohol (1) as substrate for amines (2) to yield monoallylated amines (3) (Scheme 2.2)

Scheme 2.2. Palladium-catalyzed allylic amination with allylic alcohol.

In allylic amination of anilines, symmetrical diallylated amines (4) can be obtained in one step or one-pot two-step procedures, respectively (Scheme 2.3.). However, there is only one example of the diallylation of amines by

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different allylic alcohols to generate unsymmetrical allylated amines by a palladium phosphite-based catalyst, prior to the present work.44

Scheme 2.3. Previous results on palladium-catalyzed diallylation of aniline with allylic alcohol.

The palladium phosphite catalyst (Pd[P(OPh)3]3) can either be prepared by reacting PdCl2 with P(OPh)3 in the presence of Et3N or by mixing Pd(dba)2 and P(OPh)3 in-situ. By X-ray crystallography, it was found that the palladium pre-catalyst has three ligands coordinated to the metal (Pd[P(OPh)3]3) at room temperature. However, when a solution of Pd(dba)2 and P(OPh)3 was cooled below -40 ⁰C, the tetracoordinated complex (Pd[P(OPh)3]4) was observed.46 This is different from that of the related phosphine-based complex (Pd[PPh3]4) in which tetracoordination dominate (Scheme 2.4.).47

Scheme 2.4. Equilibrium of palladium triphenylphosphite complexes at different temperatures.

2.1.2. Synthesis of β-Substituted Pyrroles

Pyrroles, substituted in the β-position are structural motifs in biologically active compounds48 and functional materials.49 Traditionally, β-substituted pyrroles can be prepared in a five-step procedure where a bulky silyl group is introduced on the nitrogen atom to direct the halogenation to the β–

position of the pyrrole ring (Scheme 2.5).50 A drawback of this methodology is selectivity issues, leading to product mixtures of α-substituted and β-substituted pyrroles. This method also produces massive amounts of waste in each reaction and purification step.

Scheme 2.5. Traditional route to β–substituted N–aryl pyrroles.

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To date, several efficient synthetic methodologies in terms of greener ap-proaches for the preparation of β-substituted pyrroles have been developed. As can be seen in Scheme 2.6., a [4+2]-cycloaddition/ring contraction cas-cade reaction of arylnitroso and 1-boronodienes was successfully performed to achieve β-substituted pyrroles (Scheme 2.6.a.).51 β–Alkylation of pyrroles was used to introduce branched alkyls using alkynes or ketones by Lewis and Brønsted acid catalysis (Scheme 2.6.b.).52 Very recently, a transition metal catalyzed β-selective C–H arylation of pyrroles, either through initial borylation or directly, has successfully been performed to construct β-substituted pyrroles (Scheme 2.6.c.).53 These reports encouraged us in the development of a general and efficient methodology to generate β-substituted pyrroles.

Scheme 2.6. Alternative methodologies to achieve β–substituted N–aryl pyrroles.

Our research group has previously reported an atom efficient two-step procedure to achieve symmetrical pyrrolines (5) using palladium- and ruthe-nium-catalysis (Scheme 2.7.).44,54 The first step was the Pd[P(OPh)3]3-catalyzed diallylation of aromatic amines (2) with 1 to generate symmetrical allylated amines (4). In a second step, Ru-catalyzed ring-closing metathesis yielded unsubstituted pyrrolines. Thereby, only water and ethylene were generated as by-products. However, the synthesis of unsymmetrical pyr-rolines was not successful.

Scheme 2.7. Previously reported synthesis of non-substituted pyrrolines by Pd-

and Ru-catalysis.

We envisioned a general methodology to synthesize β-substituted pyr-roles where the Pd-catalyzed mono- and diallylation of amines is followed by a two-step procedure where a Ru-catalyzed ring-closing metathesis

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(RCM) and a Fe-catalyzed aromatization afford β-substituted pyrroles with linear and branched alkyl, benzyl, and aryl groups (Scheme 2.8).

Scheme 2.8. Synthesis of β-substituted pyrroles by Pd-, Ru-, and Fe-catalysts.

One challenge of this work was to selectively perform the monoallylation of an amine while minimizing the formation of undesired diallylated prod-ucts. Another challenge was to control the second allylation step of the mono-allylated amine with a different allyl alcohol to obtain the unsymmet-rical diallylated product, where the reversible reaction can result in undesired mixtures of symmetrical allylated amines.

2.2. Results and Discussion

2.2.1. Substrate Scope and Synthesis

Synthesis of allylic alcohols with alkyl or benzyl groups in β-position

The Mannich reaction was used to introduce an ethylene moiety to the alde-hydes (10) under acidic condition. The allylic aldehydes (11) were then re-duced to obtain allylic alcohols (6) using sodium borohydride in methanol (Scheme 2.9.).

i: Me2NH·HCl, CH2O, 60 ⁰C, 4 h.; ii: NaBH4, MeOH, 0 ⁰C, 1 h. Scheme 2.9. General route to allylic alcohols with alkyl or benzyl groups in β-

position.

Synthesis of allylic alcohols with an aryl group in β-position

Phenyl acetic acids (12) were esterified to obtain benzyl esters (13). A Man-nich-type reaction was used to prepare methyl 2-phenylacrylates (14) from the corresponding ester, followed by reduction using DIBAL-H to obtain allylic alcohols (6) (Scheme 2.10.).

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i: H2SO4, MeOH, reflux, 12 h.; ii: TBAHS, CH2O, K2CO3, toluene, 80 ⁰C, 3 h.; iii: DIBAL-H, CH2Cl2, -78 ⁰C, 2 h.

Scheme 2.10. General route to allyl alcohols with aryl groups in β-position.

2.2.2. Monoallylation of Amines by Allyl Alcohols

The catalyst precursor (Pd[P(OPh)3]3), was conveniently generated in-situ from Pd(dba)2 and P(OPh)3 prior to the reactions. Efficient and highly selec-tive monoallylation of aromatic amines was achieved within 12 hours by employing an excess of the aniline (Table 2.1.). The reactivity of allylic al-cohols with an aliphatic, benzylic, or aromatic group in the β-position was investigated. Allylic alcohols with linear or branched alkyl groups in the β-position were reacted with aniline to afford products 7a and 7b in very good yields (Entries 1 and 2). Allylic alcohol with a benzyl group in the β-position gave the corresponding allylated aniline in a good yield (Entry 3). Allylic alcohols bearing aryl groups, including aryl groups substituted in the para-position, were subjected to the reaction (Entries 4–7). The monoallylation of aniline with an allylic alcohol with a phenyl group in the β-position generat-ed product 7d in 85% yield (Entry 4). Substrates with different electronic properties were investigated. It was found that the reaction was tolerant to both electron-withdrawing and electron-donating groups on the aryl in the β-position of the allylic alcohol. The introduction of p-fluoro substituent on the aryl resulted in the formation of allylated product 7e in a very good yield (Entry 5). Monoallylation of aniline with an allylic alcohol with an electron-donating p-methoxy substituted aryl in the β-position generated product 7f in 78% yield (Entry 6). The allylic substrate containing the sterically bulky naphthyl group gave product 7g in very good yield (Entry 7). In addition to the electronic properties of allyl alcohols, the effect of anilines substituted in the para-position was investigated. To investigate this effect, allylic alcohol with the sterically demanding isopropyl group in the β-position was selected as the counterpart. The monoallyation of anilines was achieved to give prod-ucts 7h and 7i in very good to excellent yields (Entries 8 and 9). Thereby, the monoallylation of aromatic amines has a wide scope in respect to the aromatic amine as well as the allylic alcohol. Moreover, benzylic, and ali-

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phatic amines were investigated in the monoallylation reaction. The monoal-lylation of benzylic and aliphatic amines with benzyl allylic alcohol gave products 7j and 7k in very good and good yields respectively (Entries 10 and 11). However, for these two substrates, different reaction conditions using Pd(OAc)2, electron-rich PBu3 and BEt3 as Lewis acid were required.

Table 2.1. The scope of the monoallylation reaction of amines 2 with allylic alcohols 6 Reaction conditions: flame-dried Schlenk tube, 2 (1.5 mmol), 6 (1.0 mmol), toluene (1.5 mL), and Pd[P(OPh)3]3 (2 mol %) were stirred at 80 °C for 12 h. aIsolated yields. bReaction conditions: flame-dried Schlenk tube, 2 (2.0 mmol), 6 (1.0 mmol), and 5 mol % of Pd(OAc)2, 20 mol % of PnBu3, and 25 mol % of BEt3, in 2 mL of THF at 66 ⁰C for 12 h.

2.2.3. Allylation of Monoallylated Amines with Allylic Alcohols

Allylation of the monoallylated amines and allyl alcohol 1 can lead to un-symmetrical diallylated amines. By using the optimized reaction conditions found for the monoallyaltion reaction, vide supra, the second allylation reac-tion was sluggish. Generally in a palladium-catalyzed allylation, an equilib-rium between the three possible diallylated products occur. This was also observed in our previous studies (Scheme 2.11.).44

Scheme 2.11. Product mixture of diallylated amines.

By increasing the amount of allyl alcohol (4.0 equiv.) and lowering the reaction temperature (50 °C), this problem was circumvented and a selective reaction to generate the unsymmetrical diallylated amines in moderate to

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very good yields was achieved (Table 2.2.). The second allylation of mono-allylated amine 7a with allyl alcohol was chosen as a model reaction. This reaction was completed within 6 hours with full conversion to diallyated amine 8a which was isolated in 84% yield (Entry 1). With the optimized reaction conditions in hand, the scope of second allylation of monoallylated anilines 3 was investigated. The reaction has a wide substrate scope in which the steric influence in the vinylic position has negligible effect on the trans-formation. The second allyation of anilines 7b–7d with allyl alcohols was performed to obtain diallylated products 8b–8d in good to very good yields (Entries 2–4). The electronic influence of substitutents in the R1 position was studied. The second allylation step was carried out on substrates 7e and 7f to generate products 8e and 8f in up to 82% yields (Entries 5 and 6). The sec-ond allylation of sterically hindered aniline 7g generated product 8g in a very good yield (Entry 7). The electronic influence exerted upon the amine through para-subsitution of the aniline was investigated. The second allyla-tion of aromatic amines 7h and 3i were performed in up to 87% yield, and as in the previous case, the para-fluoro substituted compound led to a higher yield (8h and 8i, Entries 8 and 9). Interestingly, the Pd[P(OPh)3]3 complex was reactive for both benzyl and alkyl amines and gave products 8j and 8k in moderate yields (Entries 10-11). Gratifyingly, the second allylation of monoallylated aniline was also possible for β-substituted allyl alcohols which generated product 8l and 8m in good yields (Entries 12 and 13). It should be noted that all reactions gave full conversion of the starting materi-al; however, minor formation of symmetrical diallylated by-products were observed, which lowered the yield of the desired products.

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Table 2.2. The scope of the second allylation of monoallylated amines 7 with allylic alcohols Reaction conditions: flame-dried Schlenk tube, 7 (1.0 mmol), allyl alcohol (1 or 6) (4.0 mmol), toluene (1.5 mL), and Pd[P(OPh)3]3 (2 mol %) were stirred at 50 ⁰C for 6 h. aIsolated yields.

2.2.4. Ring-Closing Metathesis of Diallylated Amines

Ring-closing metathesis (RCM) was performed on unsymmetrical diallylated amines using (H2IMes)(PCy3)Cl2RuCHPh (5 mol%) to yield products (15) in full conversion within 12 hours (Table 2.3.). The reactions of substrates 8a–

8d generated pyrrolines 15a–15d, respectively, in good to excellent yields (Entries 1-4). The naphthyl substituted substrate 8g required 10 mol% cata-lyst loading to reach full conversion to 15g (Entry 5). The products from the RCM were purified by flash column chromatography using deactivated silica gel.

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Table 2.3. Scope of the ring-closing metatheses of diallylated amines 8 Reaction conditions: 8 (0.5 mmol), CH2Cl2 (5 mL), and Ru catalyst (5 mol %) were stirred at rt for 12 h.

.aIsolated yields. bRequired 10 mol % of Ru catalyst

2.2.5. One-Pot Two-Step Synthesis of β-Substituted Pyrroles

In order to expand the methodology, the synthesis of β–substituted pyrroles was considered. Preliminary results showed that SiO2 was able to efficiently aromatize substrates 15c and 15d to pyrroles 9c and 9d, respectively, mean-while it worked only partially for the conversion of substrates such as 15a and 15b, even after extending the reaction times. To achieve a more general procedure, a one-pot two-step reaction utilizing unsymmetrical diallylated amines as substrates was studied. A short screening of the aromatization of 15a to 9a was performed. It was found that catalytic amounts of ferric chlo-ride hexahydrate (FeCl3.6H2O) was efficient to convert 3-pyrrolines to pyr-roles.55 In order to reduce the purification steps and thereby increase envi-ronmental friendliness,9 the aromatization of the ring-closed 3-pyrrolines was performed in the same pot as the RCM reaction. After the completion of RCM, FeCl3.6H2O was added to the reaction mixture and the aromatization was completed within 6 hours. Pyrroles with alkyl, benzyl, or aryl groups in the β-position were isolated in good to excellent yields (Table 2.4.). Never-theless, the RCM of substrates 8l and 8m was unsuccessful, even using the less bulky (H2ITol) derivative of the Grubbs-Hoveyda catalyst.56 Thus, this is a general methodology to synthesize pyrroles substituted in the β–position with either alkyl, benzyl, or aryl groups. Noteworthy, these β-substituted pyrroles were synthesized from simple starting materials with only water and ethylene as by-products.

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Table 2.4. Ru-catalyzed ring-closing metathesis and Fe-catalyzed aromatiza-tion yielding β-substituted pyrroles

Reaction conditions: 8 (0.5 mmol), CH2Cl2 (5 mL), and catalysts (5 mol % of Ru catalyst, and 5 mol % of Fe catalyst) were stirred at rt for 12 h. aIsolated yields. bRequired 10 mol % of Ru catalyst

2.3. Conclusion

A general and efficient procedure for the synthesis of β-substituted pyrroles from alkyl, benzyl, and aryl amines and allyl alcohols using Pd-, Ru-, and Fe-catalysis has been developed. A variety of β-substituted pyrroles with aryl, benzyl, or alkyl groups were obtained in overall good yields. The palla-dium-catalyzed monoallylation of amines with β-substituted allylic alcohols produced monoallylated amines in moderate to good yields. By increasing the amount of allylic alcohol and lowering the reaction temperature it was possible to achieve a selective second allylation of the monoallylated amines using Pd[P(OPh)3]3 as catalyst. A one-pot two-step reaction including RCM and aromatization of the diallylated amines was performed using Grubbs 2nd generation and FeCl3.6H2O as catalysts to obtain β-substituted pyrroles in overall high yields. Thereby, the overall reaction only generated water and ethylene as by-products.

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3. Lewis Acid-Catalyzed Intramolecular Stereospecific Substitution of Non-Derivatized Alcohols (Paper II)

3.1. Background

3.1.1. Catalytic Activation of the Hydroxyl Group in Alcohols in Substitu-tion Reactions by Lewis Acids

The activation of the OH group in alcohols is required when alcohols are used as electrophiles in nucleophilic substitution reactions. Traditionally, Lewis acids are used to activate the OH group. Various metal complexes have been used in the catalytic activation of alcohols in nucleophilic substi-tution reactions including: aluminium(III),57 bismuth(III),18,58 cerium(III),59 copper(II),60 gold(III),61 indium(III),62 iron(III),63 lanthanum(III),64 mercu-ry(II),65 rhenium(V),58f,66 rhenium(VII),67 scandium(III),64,68 silver(I),69 tanta-lum(V),70 tin(II),71 tin(IV),72 ytterbium(III), 64,73 zinc(II),74 and zirconi-um(IV),75 (Scheme 3.1.).17,76

Scheme 3.1. Catalytic nucleophilic substitution of alcohols by Lewis acids.

Recently, Aponick, Widenhoefer, and Uenishi successfully performed ste-reospecific intramolecular substitution reactions of enantioenriched allylic alcohols using gold and palladium based catalysts (Scheme 3.2.a.).19,77 The chemical transformation proceeded via an SN2′-type reaction mechanism. A unique bicylic transition-state was found, by density functional theory (DFT) calculations, in which the nucleophile protonated the leaving OH group (nu-cleofuge) to promote the reaction.78 Because of this, the methodology was substrate specific, where no reactivity was observed when the OH group of the allylic alcohol was juxtaposed (Scheme 3.2.b.). In 2014, Cook reported an iron(III)-catalyzed intramolecular Friedel-Crafts (FC) alkylation of unac-tivated alcohols as shown in Scheme 1.5.c.

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Scheme 3.2. Current catalytic methodologies for direct stereospecific intramolecular substitution of alcohols.

In this chapter, we sought to develop the direct stereospecific intramolec-ular nucleophilic substitution of the OH group of non-derivatized secondary alcohols using iron(III)-catalysis (Scheme 3.3.). The OH group of enantioen-riched benzyl, allyl, and alkyl alcohols was substituted by O- and N-centered nucleophiles to generate five- and six-membered heterocyclic compounds with high enantiospecificity and water as the only by product. In addition, mechanistic studies have been performed to get a better insight into the reac-tion mechanism.

Scheme 3.3. Fe(III)-catalyzed direct stereospecific intramolecular substitution of enantioenriched secondary alcohols.

3.2. Results and Discussion

3.2.1. Substrate Scope and Synthesis

3.2.1.1. Synthesis of Starting Enantioenriched Alcohols with Nitrogen-Centered Nucleophiles

Synthesis of enantioenriched benzylic alcohols for five-membered heterocycles

An Ullmann-type reaction was used to perform the coupling of 2-pyrrolidinone and iodoaryls to obtain lactams (16), followed by ring-opening of the corresponding lactams by Grignard reagents to obtain the ketones (17). The ketones were enantioselectively reduced to alcohols (18) by a Co-rey-Bakshi-Shibata (CBS) reduction (Scheme 3.4.).

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i: Iodobenzene, K2CO3, CuI, DMF, 150 ⁰C, 24 h.; ii: R1MgBr, THF, 0 ⁰C─rt, 2 h.; iii: (R)-CBS-Ox, BH3/THF, THF, 0 ⁰C, 2 h.

Scheme 3.4. General route to enantioenriched benzylic alcohols with N-centered nucleophiles.

Synthesis of enantioenriched non-benzylic alcohols for five-membered heterocycles

Non-benzylic enantioenriched alcohols were prepared by a ring opening of lactam 16b with Grignard reagents. The corresponding ketones were then reduced in situ with NaBH4 to obtain alcohols (19), followed by kinetic reso-lution of the alcohols with Candida Antarctica lipase B (CAL-B) in the presence of vinyl acetate to obtain enantioenriched alcohols (20) and the acetylated counterparts (21). The deprotection of the acetyl group under basic conditions afforded the enantioenriched alcohols (18) (Scheme 3.5.).

i: RMgBr, THF, 0 ⁰C─rt, 2 h.; ii: NaBH4, MeOH, H2O, 0 ⁰C, 1 h.; iii: CAL-B, vinyl acetate, rt, 12 h.; iv: K2CO3, MeOH, rt, 2 h.

Scheme 3.5. General route to enantioenriched non-benzylic alcohols with N-centered nucleophile.

Synthesis of enantioenriched benzylic alcohols for six-membered heterocycles

The synthesis of starting enantioenriched benzylic alcohols with N-centered nucleophiles for six-membered heterocyclic products is similar to the sub-strate preparation for five-membered heterocycles. The synthetic procedure included Ullmann-type reactions, ring-opening of lactams (23) with a Gri-gnard reagent, and a CBS-reaction, respectively, to yield the enantioenriched alcohols (25) (Scheme 3.6.).

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i: iodoaryl, K2CO3, CuI, DMF, 150 ⁰C, 24 h.; ii: RMgBr, THF, 0 ⁰C─rt, 2 h.; iii: (R)-CBS-Ox, BH3/THF, THF, 0 ⁰C, 2 h.

Scheme 3.6. General route to enantioenriched benzylic alcohols with N-centered nucleophiles.

3.2.1.2. Synthesis of Enantioenriched Alcohols with Oxygen-Centered Nu-cleophiles

Synthesis of enantioenriched benzylic alcohols for five-membered hetero-cycles Arylbutanoic acids (26) were used to prepare the corresponding methyl es-ters (27). The corresponding esters were reduced by ruthenium-catalysed asymmetric reduction to obtain a mixture of enantioenriched hydroxy esters (28) and lactones (29), followed by LiAlH4 reduction to obtain enantioen-riched diols (30) (Scheme 3.7.).

i: Acetyl chloride, MeOH, rt, 10 h.; ii: RuCl(p-cymene)[(S,S)-Ts-DPEN], 5:2 HCO2H/Et3N, 30 ⁰C, 48 h.; iii: LiAlH4, THF, 0 ⁰C, 1 h.

Scheme 3.7. General route to enantioenriched benzylic alcohols with O-centered nucleophile.

Synthesis of enantioenriched benzylic alcohols for six-membered hetero-cycles The nucleophilic addition of Grignard reagents to chroman-2-one generated ketones (31), followed by enantioselective CBS reduction to obtain the enan-tioenriched alcohols (32) (Scheme 3.8.).

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i: RMgBr, THF, 0 ⁰C─rt, 2 h.; ii: (R)-CBS-Ox, BH3/THF, THF, 0 ⁰C, 2 h. Scheme 3.8. General route of enantioenriched benzylic alcohols with O-centered

nucleophile.

Synthesis of substrate with two nucleophiles The substitution reaction of 2-bromoacetophenone with dimethyl malonate generated dimethyl 2-(2-oxo-2-phenylethyl)malonate 33, then LiAlH4 reduc-tion yielded 3-(hydroxymethyl)-1-phenylbutane-1,4-diol 34 (Scheme 3.9.).

i: Dimethyl malonate, K2CO3, rt, 12 h.; ii: LiAlH4, THF, 0 ⁰C, 1 h. Scheme 3.9. Route to substrate with two nucleophiles.

Synthesis of substrate with two electrophiles Similarly to the synthesis of the substrate with two nucleophiles, a substitu-tion reaction of ethyl bromoacetate with dibenzoylmethane generated ethyl 3-benzoyl-4-oxo-4-phenylbutanoate 35, followed by a LiAlH4 reduction to give 2-(hydroxy(phenyl)methyl)-1-phenylbutane-1,4-diol 36 (Scheme 3.10.).

i: Ethyl bromoacetate, NaH, 0 ⁰C─rt, 12 h.; ii: LiAlH4, THF, 0 ⁰C, 1 h. Scheme 3.10. Route to substrate with two electrophiles.

3.2.2. Optimization of Reaction Parameters for Intramolecular Stereospe-cific Substitution Reaction

4-((4-methoxyphenyl)amino)-1-phenylbutan-1-ol (18a) was chosen as a model substrate for the initial screening for the intramolecular stereospecific substitution reaction to yield 1-(4-methoxyphenyl)-2-phenylpyrrolidine (37a). The p-methoxyphenyl (PMP) group on the nitrogen atom was intro-duced to enhance the nucleophilicity and thus to facilitate the substitution

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reaction. In addition, the PMP group has synthetic advantages as it can be easily removed after the reaction if desired.79

Initially, different metal-based Lewis acids were screened in the catalytic activation of the OH group in the intramolecular stereospecific substitution reaction. It was found that iron-based catalysts gave higher reactivity and stereospecificity than other Lewis acids and the counter ion had a profound effect on both the yield and the enantiospecificity (e.s.) (Table 3.1., entries 1─12). The most Lewis acidic complex, Fe(OTf)3 was found to be the most efficient catalyst in the intramolecular substitution to give pyrrolidine 37a in 62% yield with 96% e.s. (Entry 12). The purity of the Fe(OTf)3 used in this study was 90% and an Inductively Coupled Plasma Mass Spectrometry (ICP-MS) was used to detect trace elemental impurities in the Fe(OTf)3 cata-lyst. The trace metals were individually tested as catalysts in the transfor-mation, but their performance did not out-perform Fe(OTf)3.

Generally, the direct substitution of the OH group of alcohols generates water as by-product. The addition of molecular sieves (MS) (3Å) as an addi-tive improved the efficiency of the catalysis and product 37a was obtained in excellent yield and e.s. (Entry 14). A control reaction showed that the MS did not promote the reaction in the absence of Fe(OTf)3 (Entry 15).

In addition to the screening of the Lewis acid catalysts, the influence of other parameters was also studied. A solvent screening revealed that 1,2-dichloroethane (1,2-DCE) was optimal for this transformation, whereas other solvents proved to be inferior with respect to reactivity and enantiospecifici-ty. Furthermore, the effect of temperature was investigated. The starting alcohol 18a was converted to product 37a in moderate yield at 90 °C, where higher reaction temperatures resulted in high yield, however, with a decrease in enantiospecificity (Entry 13).

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Table 3.1. Optimization of reaction conditions for the intramolecular stereo-specific nucleophilic substitution of benzylic alcohol 18a.

Entry Catalysts T(°C) Yield (%)a e.s. (%)b 1 FeF3(III) 90 15 0 2 FeCl2(II) 90 20 92 3 Fe(NO3)3·(H2O) 90 NR 0 4 Fe(acac)3 90 NR 0 5 Fe4[Fe(CN)6]3 90 NR 0 6 Fe(ClO4)2·4H2O 90 10 91 7 Fe(EDTA)sodium salt 90 NR 0 8 Fe2O3 90 10 93 9 FeCl3 90 35 92 10 Ferric citrate 90 NR 0 11 Iron(III)tartrate 90 NR 0 12 Fe(OTf)3

c 90 62 96 13 Fe(OTf)3

c 110 >90 80 14 Fe(OTf)3

c + MS (3Å) 90 >95 99 15 MS (3Å) 90 NR 0

Reaction conditions: 0.20 mmol of 18a, catalyst (10 mol %) in 1,2-DCE (1.0 mL), MS (3Å) = 300 mg, at 90 °C temperature, 24 h under argon atmosphere. aNMR yield. bEnantiospecificity was determined by chiral stationary phase HPLC analysis. cThe purity of catalyst has been determined by Inductively Cou-pled Plasma-Mass Spectroscopy (ICP-MS) Analysis (SI). NR, no reaction was observed.

3.2.3. Intramolecular Substitution to Generate Five-Membered Heterocy-cles from Benzylic Alcohols

With the optimized reaction conditions, the substrate scope was expanded to the intramolecular stereospecific substitution of various enantioenriched benzylic alcohols with N- and O-centered nucleophiles to generate 5-membered heterocycles (Table 3.2.). Substrates with N-centered nucleo-philes generated 1,2-diphenylpyrrolidine (37b) in excellent yield and e.s. (Entry 2). The substrate with a p-fluoro substituent on the benzyl group gave pyrrolidine 37c in excellent yield and e.s. (Entry 3), similar to a substrate with an electron-withdrawing meta-OCF3 group (Entry 4). Moreover, sub-strates with electron donating substituents such as p-methyl and m-methoxy, also gave excellent yields and good enantiospecificities where the electron donating groups on the phenyl ring should stabilize the formation of the car-

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benium ion (Entries 5 and 6). Substrates with O-centered nucleophiles were also studied and generated 2-phenyltetrahydrofuran 38a and 38b in excellent yields and good e.s. (Entries 7 and 8).

Table 3.2. Intramolecular substitution of benzylic alcohols to generate five-membered heterocycles

Reaction conditions: 0.20 mmol of 18 (or 25), 10 mol % of Fe(OTf)3 in 1,2-DCE (1.0 mL) at 90 °C, 24 h. aIsolated yield. The enantiospecificity was determined by HPLC analysis using chiral stationary phase.

bReaction time 48 h. cReaction temperature at 30 °C in 1,2-DCE + n-Hexane (0.5 mL: 0.5 mL).

3.2.4. Intramolecular Substitution to Generate Five-Membered Hetero-cycles from Non-Benzylic Alcohols

The substrate scope was extended to more challenging non-benzylic alcohols (Table 3.3.). Alcohol 18k activated with an allyl group generated 37k in 79% yield and 88% e.s. (Entry 1). Non-activated alkyl alcohols are challeng-ing substrates in substitution reactions due to poor reactivity and risk for competing elimination reactions. These less reactive aliphatic secondary alcohols required a higher reaction temperature (100 °C). The N-centered nucleophiles 18l and 18m generated enantioenriched 2-methyl-1-phenylpyrrolidine (37l) and 2-ethyl-1-phenylpyrrolidine (37m) in very good yields and excellent enantiospecificities, respectively (Entries 2 and 3).17

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Table 3.3. Intramolecular substitution of non-benzylic alcohols to generate five-membered heterocycles

Reaction conditions: 0.20 mmol of 18, 10 mol % of Fe(OTf)3 in 1,2-DCE (1.0 mL) at 100 °C, 48 h. aIsolated yield. The enantiospecificity was determined by HPLC analysis using chiral stationary phase.

3.2.5. Intramolecular Substitution to Generate Six-Membered Heterocy-cles from Benzylic Alcohols

Six-membered rings are more challenging to form as compared to five-membered rings due to kinetics. The six-membered heterocycles were gen-erated in very good to excellent yields and enantiospecificities (Table 3.4.). Substrate 25a required longer reaction times to obtain 39a in very good yield and e.s. (Entry 1). Substrate 25b, with a stronger nucleophile, gave tetrahy-droquinoline 39b in excellent yield and e.s. (Entry 2). Gratifyingly, sub-strates containing poor nucleophiles (phenolic-O-nucleophiles) gave chrom-anes 40a and 40b in very good yields and e.s. (Entries 3 and 4). Notably, this is the first time that a phenolic substrate has been used as a nucleophile in the stereospecific substitution of the OH group in alcohols.

Table 3.4. Intramolecular substitution of benzylic alcohols to generate six-membered heterocycles

Reaction conditions: 0.20 mmol of 25 (or 32), 10 mol % of Fe(OTf)3 in 1,2-DCE (1.0 mL) at 100 °C, 48 h. aIsolated yield. bReaction time 48 h. cReaction temperature at -20 °C in 1,2-DCE + n-Hexane (0.5 mL: 0.5 mL). The enantiospecificity was determined by HPLC analysis using chiral stationary phase.

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3.2.6. Mechanistic Studies

This direct intramolecular substitution reaction may proceed via an SN1 or an SN2 reaction pathway. Generally, rate-order determination and measurement of the enantiospecificity are used to distinguish an SN1 reaction from an SN2 reaction.9,76 The challenge in this intramolecular substitution is due to: 1) nucleophile and electrophile are present in the same molecule and therefore it is difficult to vary the concentration of the individual species in order to determine rate-order dependencies; 2) the reaction pathway can be an SN1 reaction that proceeds through a tight ion pair to give high enantiospecificity.

3.2.6.1. Rate-Order Determination

To get better insight into the reaction mechanism, rate-order determination of the catalyst was performed by varying the concentration of Fe(OTf)3 in the transformation of 18a to 37a. This revealed that there is a first-order dependence in catalyst concentration (Figure 3.1.). In addition to rate-order determination of the catalyst, the rate-order of the substrate was also investi-gated. The O-centered nucleophile 30a was chosen as a standard substrate to study the rate-order in nucleophile and electrophile. Substrates 34 and 36, which have, respectively, two nucleophiles and two electrophiles present in the same molecule were synthesized and used. The overall rate in an SN1 reaction should only show dependency on the electrophile due to the rate limiting generation of a carbenium ion. In contrast, an SN2 reaction should show dependency on both nucleophile and electrophile. Interestingly, the reaction rate is doubled in cases of substrates 34 and 36 as compared to sub-strate 30a (Scheme 3.11.). Thereby, it can be concluded that the reaction follows first-order dependence in concentration of nucleophile as well as electrophile. Thereby, the overall order of the reaction is three with first-order dependence in catalyst, internal nucleophile, and electrophile. These observations are in agreement with an SN2-type reaction mechanism where a single equivalent of iron is responsible for promoting catalysis. Even though the results support rate-order dependence in both electrophile and nucleo-phile, it cannot be ruled out that the rate enhancement may be due to a Thorpe-Ingold effect.

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Scheme 3.12. Competition experiments between substrate 18a and external electro-phile 43.

Furthermore, N-methyl anisole 45 was used as an external N-centered nu-cleophile to study the interaction between iron catalyst and nucleophile in the reaction of 18a to 37a (Scheme 3.13.a.). Interestingly, the reaction was completely inhibited in the presence of 45. This conforms with a strong co-ordination between the N-centered nucleophile and the iron, which is also supported by a color change of the solution of 45 from transparent to purple (Scheme 3.13.b.).

Scheme 3.13. Competition experiments between substrate 18a and external nucleo-phile 45.

To get further understanding of the reaction mechanism, in-situ UV-vis spectroscopy was used to study the interaction of Fe(OTf)3 with 18a and 45. In the absence of the iron catalyst, both 18a and 45 showed absorption bands at 320 cm−1. When a stoichiometric amount of Fe(OTf)3 was added, a blue shift to 275 cm−1 was observed in both cases (Figure 3.2.). These competi-tion experiments suggest that the iron may coordinate to both nucleofuge and nucleophile. In case of N-centered nucleophiles, the coordination is very strong.

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tivity is only observed in the presence of an internal nucleophile while SN1 reactivity is observed in the absence of internal nucleophile.

In the case of tertiary alcohols, which are less studied in this thesis, as shown in pathway 2, the coordination of iron to nucleofuge in C leads to C–

O bond cleavage to generate tight ion pair intermediate E. This ion pair stays tight in non-polar solvent mixtures at low reaction temperatures and upon nucleophilic attack generates products with high enantiospecificity. Howev-er, in a polar solvent the ion pairing is lost and the nucleophilic attack can occur from either side, leading to a product with low enantiospecificity. It can be concluded that solvent polarity and reaction temperature critically influence the reaction outcome in terms of the mechanism and enantiospeci-ficity for the intramolecular substitution of tertiary alcohols.

Scheme 3.14. Proposed mechanistic pathways.

3.3. Conclusion

The direct Fe(OTf)3-catalyzed intramolecular stereospecific substitution of the OH group in enantioenriched secondary alcohols has been developed to give five- and six-membered heterocycles in good to excellent yields with high enantiospecificity. The substitution of the OH group in benzylic, allylic, and aliphatic alcohols by N-, and O-centered nucleophiles generates pyrroli-dines, tetrahydrofuran, 1,2,3,4-tetrahydroquinolines, and chromane deriva-tives with conservation of the enantiomeric purity. The reaction follows first-order dependence in catalyst, internal nucleophile, and internal electrophile of the substrate. Competition experiments and in-situ UV-vis spectroscopy suggest an interaction of the iron with both nucleophile and nucleofuge of

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the substrate promoting an intramolecular SN2-type reaction mechanism. This approach enables the stereospecific intramolecular substitution of the OH groups in readily prepared enantioenriched secondary alcohols to gener-ate various heterocycles. As stated in the introduction (Chapter 1) enantioen-riched compounds are important in the pharmaceutical industry. To be able to use easily accessible enantioenriched alcohols as substrates to generate important heterocycles without generating waste is therefore noteworthy.

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4. Brønsted Acid/Base-Catalyzed Intramolecular Stereospecific Substitution of Non-Derivatized Alcohols (Paper III and IV)

4.1. Background

4.1.1. Catalytic Activation of the Hydroxyl Group in Alcohols in Substitu-tion Reactions by Brønsted Acid/Base Pairs

In addition to the Lewis acid-catalyzed substitution of alcohols that was dis-cussed in Chapter 3, another strategy is the use of Brønsted acids as cata-lysts. It is well known that Brønsted acids are efficient to activate the OH group (Scheme 4.1.). Generally, the mode of activation is protonation of the OH group by the Brønsted acid, to generate the corresponding carbocation via an SN1-reaction pathway which then reacts with the nucleophile to yield the product. Brønsted acids such as sulfuric acid,80 triflic acid,81 boronic acid,82 and sulfonic acids83 have successfully been employed in the catalytic substitution of different alcohols.17,76,84

Scheme 4.1. Catalytic nucleophilic substitution of alcohols by Brønsted acids.

4.1.2. Bifunctional Catalysis

In bifunctional catalysis, two functional moieties of the catalyst have differ-ent modes of operation. Many bifunctional catalysts operate via a coopera-tive mode of action with two complementary functional groups such as Lew-is and Brønsted acid base pairs. In such cases, simultaneous activation of both electrophilic and nucleophilic reaction partners can be achieved.85

Bifunctional catalysis can be categorized into two types depending on weather the interaction of a catalyst with the substrate(s) takes place simul-taneously or successively.86 Bifunctional catalysis can be further divided into four main groups with respect to the modes of activation of the catalyst: Lewis acid-Lewis base,87 Lewis acid-Brønsted base,88 Lewis acid-Lewis acid,89 Brønsted acid-Brønsted base catalysts.90 An example of bifunctional

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catalysis is the Mannich-type reaction that takes place via dual activation of the substrate by a chiral phosphoric acid (Scheme 4.2.).91 In this case, the hydrogen of the acidic site of the phosphoric acid protonates the substrate and the oxo group operates by a partial deprotonation. Thus, a formal shuffle of the protons from the acidic site to the basic site of the catalyst takes place during the transformation.

Scheme 4.2. Chiral phosphoric acid-catalyzed Mannich-type reaction

The aim of this project is to develop a direct stereospecific intramolecular nucleophilic substitution of the OH group of non-derivatized secondary al-cohols by Brønsted acid/base catalysis (Scheme 4.3.). The OH group of en-antioenriched benzyl, allyl, propargyl, and alkyl alcohols has been substitut-ed by O-, N-, and S-centered nucleophiles to generate five- and six-membered heterocyclic compounds with high enantiospecificity and water as the only by-product. Mechanistic studies using both experimental and com-putational methods have been performed to get better insight into the reac-tion mechanism.

Scheme 4.3. Brønsted acid/base-catalyzed direct stereospecific intramolecular sub-stitution of enantioenriched secondary alcohols.

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4.2. Results and Discussion

4.2.1. Substrate Scope and Synthesis

In this project, a similar substrate scope to that discussed in Chapter 3, con-taining O- and N-centered nucleophiles, has been used. In addition, the scope was expanded to substrates containing S-centered nucleophiles.

4.2.1.1. Synthesis of Starting Enantioenriched Alcohols with Nitrogen-Centered Nucleophile

Synthesis of enantioenriched non-benzylic alcohols for five-membered heterocycles

A method to prepare non-benzylic enantioenriched alcohols involved the ring opening of lactam 16a with Grignard reagents. The corresponding ke-tones were then reduced enantioselectively without purification to the corre-sponding alcohols (18) by a CBS reduction (Scheme 4.4.).

i: RMgBr, THF, 0 ⁰C─rt, 2 h.; ii: (R)-CBS-Ox, BH3/THF, THF, 0 ⁰C, 2 h. Scheme 4.4. Route to enantioenriched non-benzylic alcohols with N-centered nucle-

ophile.

4.2.1.2. Synthesis of Starting Enantioenriched Alcohols with Sulfur-Centered Nucleophile

Synthesis of enantioenriched benzylic alcohols for five-membered heterocycles

The substrate with S-centered nucleophiles were synthesized using a substi-tution reaction of 4-chloro-1-arylbutan-1-ones (47) with KSAc to obtain thioacetates (48), followed by asymmetric CBS reduction of the obtained ketones and deprotection of the acetate group under basic conditions to yield the desired enantioenriched alcohols (50) (Scheme 4.5.).

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i: KSAc, DMF, rt, 12 h.; ii: (R)-CBS-Ox, BH3/THF, THF, 0 ⁰C, 2 h. iii: KOH, 1:1 EtOH:H2O, reflux, 4 h.

Scheme 4.5. Route to enantioenriched benzylic alcohols with S-centered nucleo-phile.

Synthesis of enantioenriched propargylic alcohol for five-membered heterocycle

4-Chlorobutyryl chloride was used to perform the substitution reaction with phenylethyl magnesium bromide, a ruthenium-catalyzed asymmetric reduc-tion afforded the enantioenriched alcohol precursor 52. The alcohol was protected as a tetrahydropyranyl ether 53, followed by a substitution reaction with KSAc and deprotection to obtain the enantioenriched propargylic alco-hol (56) containing an S-centered nucleophile (Scheme 4.6.).

i: Phenylethyl magnesium bromide, CuI, Et2O, 0 ⁰C-rt, 3 h.; ii: RuCl(p-cymene)[(S,S)-Ts-DPEN], 5:2 HCO2H/Et3N, 30 ⁰C, 48 h.; iii: DHP, p-TSA, DCM,

rt, 12 h.; iv: KSAc, DMF, rt, 12 h.; v: p-TSA, MeOH, rt, 4 h.; vi: KOH, 1:1 EtOH:H2O, reflux, 4 h.

Scheme 4.6. Route to enantioenriched propargylic alcohol with S-centered nucleophile.

4.2.2. Optimization of the Reaction Parameters for Intramolecular Stereo-specific Substitution

To perform the intramolecular stereospecific substitution reaction, a weakly nucleophilic O-centered substrate (S)-1-phenylbutane-1,4-diol (30a) that will yield (R)-2-phenyltetrahydrofuran (38a) was chosen as substrate for optimiz-ing of the reaction conditions. An initial screening of Lewis acids (Fe(III), Au(I), and Au(III)) that previously have been reported to activate the OH group was carried out.61,63 It was found that these catalysts showed high re-activity, however the enantiospecificity was low (Table 4.1., Entries 1–4).

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Only, the use of Lewis acidic Fe(OTf)3 as a catalyst in the mixture of 1,2-DCE and n-hexane gave product 38a in excellent yield with 88% enanti-ospecificity (Entry 1, as can be seen in Chapter 3, Table 3.2.). Brønsted acid catalysts were evaluated (Entries 5–20): acetic, trifluorometanesulfuric, sul-furic, p-toluenesulfunic, and phosphinic acids (H3PO2, H3PO3, H3PO4, PhH2PO2, and Ph2HPO2). In the presence of 10 mol% of H3PO2, compound 38a was formed in excellent yield and with 91% enantiospecificity (Entry 9). Although stronger acids than H3PO2 led to high conversion, the enantiospec-ificity was lower (Entries 6–8). Weaker, acids such as acetic acid as well as phosphinic acids bearing similar structural motif to phosphinic acid (O=P,–OH) did not show any reactivity under the employed reaction conditions (Entries 5, 10–13). The pKa of the acid is crucial and should be less than 2 for the substitution reaction to take place. However, there is no clear correla-tion between the acidity and the observed enantiospecificty.

The solvent effect was investigated. It was found that 1,2-DCE was op-timal for the reaction. Employing solvents with lower polarity than 1,2-DCE, such as cyclohexane and toluene, led to slightly lower yields of product 38a (Entries 14 and 15). When solvents of higher polarity were used, e.g. ace-tonitrile or nitromethane, the reaction proceeded to give 38a in higher yields, however, with lower enantiospecificities (Entries 16 and 17).

To study the temperature effect on the reaction, toluene was used as a solvent due to its higher boiling point. The conversion increased when the temperature was raised, however, the enantiospecificity decreased at temper-atures above 80 �C (Entries 18–20).

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Table 4.1. Optimization of reaction conditions for the intramolecular nucle-ophilic substitution reaction

Entry Catalyst pKa

Solvent T (°C) t (h) Yield (%)b e.s.(%)

c

1a Fe(OTf)3 -

1,2-DCE + n-hexane

30 12 >95 88

2 FeCl3 1,2-DCE 40 12 >95 0 3 AuCl - 1,2-DCE 80 12 90 0 4 NaAuCl4 - 1,2-DCE 40 12 >95 19 5 AcOH 4.76 1,2-DCE 80 48 0 0 6 TfOH -12.0 1,2-DCE 40 12 >95 23 7 H2SO4 -3.00 1,2-DCE 40 12 >95 0 8 p-TSA -2.80 1,2-DCE 40 12 >95 84 9 H3PO2 1.07 1,2-DCE 80 24 >95 91 10 H3PO3 2.00 1,2-DCE 80 24 0 0 11 H3PO4 2.12 1,2-DCE 80 48 0 0 12 PhH2PO2 1.86 1,2-DCE 80 48 0 0 13 Ph2HPO2

2.30 1,2-DCE 80 48 0 0

14 H3PO2 1.07 cyclohexane 80 24 >80 73 15 H3PO2 1.07 Toluene 80 24 >90 91 16 H3PO2 1.07 MeCN 80 24 >95 65 17 H3PO2 1.07 MeNO2 80 24 >95 60 18 H3PO2 1.07 Toluene 100 12 >95 21 19 H3PO2 1.07 Toluene 110 12 >95 9 20

d H3PO2 1.07 Toluene 160 2 >95 0

Reaction condition: 30a (0.3 mmol), solvent (1.0 mL) and catalyst (10 mol%) was heated in an oil bath. aSolvent used: 1,2-DCE + n-Hexane (0.5 mL + 0.5 mL). bYield was determined by NMR. cEnantiospeci-ficity was determined by chiral stationary phase HPLC analysis. dReaction was performed using micro-wave reactor (3 bar, autogenous pressure).

4.2.3. Water Effect

The phosphinic acid used in this study was employed as an aqueous solution (50 w/w%) whereas the rest of the catalysts used were dry. Thus, the reac-tion with H3PO2 contained water from the beginning of the reaction. In addi-tion, water will be generated during the course of the reaction. Therefore, the effect of water concentration on the reaction was investigated by studying the initial rates and monitoring the enantiospecificity of the products (Table 4.2.). The initial rates were determined at conversions below 20% and the enantiospecificity was determined after 24 hours. Dried CaSO4 was used as a

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neutral drying agent in the reaction where CaSO4∙2H2O will form. The initial rate of the standard reaction without any CaSO4 added was 3.6×10-6 M∙s-1 with 91% e.s. (Table 4.2., Entry 1). By varying the amount of CaSO4, it was shown that water does not affect either the initial rate or enantiospecificity of the reaction (Entries 2–6). Furthermore, the influence of CaSO4 was studied. When equimolar amounts of water and CaSO4 were added to the reaction, no effect on either the rate or enantiospecificity in this transformation was ob-served (Entry 7). CaSO4 did not catalyze the reaction (Entry 8).

Table 4.2. Water effect on the initial rate and enantiospecificity of the reac-tion

Entry Amount of water

(%) CaSO4

a

(mmol)

Initial rate (×10

-6 M.s

-1)

e.s.

(%)b

1 100 - 3.6 91 2 0 0.070 3.1 90 3 20 0.056 4.1 91 4 40 0.042 3.1 91 5 60 0.028 4.1 91 6 80 0.014 3.6 91 7 100 0.14 3.1 90 8 - 0.14 N/A -

Reaction condition: 30a (0.3 mmol), 1,2-DCE (1.5 mL), H3PO2 (10 mol%), CaSO4, and H2O was heated in an oil bath at 80 °C. aDried CaSO4 (oven, 250 °C, 3 h). bEnantiospecificity was determined by chiral stationary phase HPLC analysis.

4.2.4. Intramolecular Substitution to Generate Five-Membered Heterocy-cles from Benzylic Alcohols

Having the optimized reaction conditions in hand, the substrate scope with respect to both nucleophiles and benzylic alcohols was studied (Table 4.3.). Substrates containing O-, N-, and S-centered nucleophiles generated tetrahy-drofuran 38a, pyrrolidine 37b, and tetrahydrothiophene 57a in excellent yields and e.s. (Entries 1–3). Substrates with the p-fluoro group on the phe-nyl group generated heterocyclic products 38b, 37g, and 57b in excellent yields with high to excellent e.s. (Entries 4–6). In the presence of the strong-ly deactivating p-trifluoromethyl substituent, the reaction gave pyrrolidine 37h in high yield with full e.s. (Entry 7). In contrast, a substrate containing

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an electron-donating PMP group generated product 37i in excellent yield, although with lower e.s. (Entry 8). However, when exchanging the N-centered nucleophile (aniline) with an electron-richer p-anisidine to enhance the nucleophilicity and thus to facilitate the substitution reaction, products 37a, 37c, 37d, and 37j were obtained in good to excellent yields and excel-lent e.s. (Entries 9–12).

Table 4.3. Intramolecular substitution of benzylic alcohols to generate five-membered heterocycles

Reactions condition: 0.30 mmol of 18 (30 or 50)10 mol% of H3PO2 in 1,2-DCE (1.5 mL) at 80 °C, 24 h. aIsolated yield. bReaction temperature at 50 °C, 24 h. Enantiospecificity was determined by HPLC analy-sis using chiral stationary phase.

4.2.5. Intramolecular Substitution to Generate Five-Membered Heterocy-cles from Non-Benzylic Alcohols

The substrate scope was expanded to more challenging non-benzylic alco-hols (Table 4.4.). The H3PO2-catalyzed stereospecific substitution of activat-ed allylic alcohol 18n yielded pyrrolidine 37n in 85% yield and 93% e.s. (Table 4.4., Entry 1). Exchanging the nucleophilic moiety from aniline to the stronger nucleophilic p-anisidine improved the e.s. to 99% (Entry 2).10 In the case of a less reactive propargylic alcohol with an S-centered nucleophile, the tetrahydrothiophene 57c was generated in excellent yield and e.s. (Entry 3).

The nucleophilic substitution of secondary aliphatic alcohols remains challenging due to the relative difficulty in activating the OH group and the risk for dehydration reactions.92 Remarkably, the intramolecular stereospe-

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cific reaction of aliphatic alcohols with N-centered nucleophiles 18o, 18l, and 18m generated pyrrolidines 37o, 37l, and 37m in very good yields and excellent enantiospecificities, respectively (Entries 4-6).

Table 4.4. Intramolecular substitution of non-benzylic alcohols to generate five-membered heterocycles

Reactions condition: 0.30 mmol of 18 (or 56), 10 mol% of H3PO2 in 1,2-DCE (1.5 mL) at 80 °C, 24 h. aIsolated yield. Enantiospecificity was determined by HPLC analysis using chiral stationary phase.

4.2.6. Intramolecular Substitution to Generate Six-Membered Heterocy-cles from Benzylic Alcohols

The scope was further expanded to substrates that could generate six-membered heterocycles. Substrate 25b with an N-centered nucleophile was reacted to generate tetrahydroquinoline 39b in excellent yield with high e.s. (Table 4.5., Entry 1). Encouraged by the good result, more challenging phe-nols were examined as nucleophiles. The substitution reaction of alcohol 32a generated chromane 40a in 85% yield with 92% e.s. (Entry 2, a slightly higher temperature 100 °C was required). Alcohol with the para-fluoro sub-stituent on the benzylic group gave product 40b in 90% yield and 90% e.s. (Entry 3).93

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4.2.7.2. Interaction of H3PO2 Dimer with the Substrates

Phosphinic acid has a O=X–OH motif similar to carboxylic acids that can form dimers by hydrogen bonding in solution, which a Lewis base can dis-sociate into monomers. Substrates used in this system contain both nucleo-phile and nucleofuge in the same molecule which will operate as Lewis ba-ses. To study how the nucleophilic and nucleofugic parts of the substrates could promote this dissociation, the interactions between the substrates and H3PO2 were monitored by 31P NMR spectroscopy (Figure 4.2.). H3PO2 has a chemical shift at 12.5 ppm of 31P NMR (JP-H = 568 ppm). Addition of 1-phenylethanol (43), representing the nucleofuge in a benzylic alcohol, leads to a slight move of the chemical shift upfield to 11.9 ppm, while the coupling constant keeps unchanged.. When N-methylaniline (58), representing the N-centered nucleophile, was added to H3PO2 the chemical shift changed to 6.9 ppm (JP-H = 532 ppm). Then, the interaction of H3PO2 with substrates with O-, N-, and S-centered nucleophiles was examined. When the weakly nucle-ophilic O-centered substrate 30a was mixed with H3PO2, the chemical shift changed marginally to 10.3 ppm (JP-H = 560 ppm). With the stronger N-centered nucleophile substrate 18b, the chemical shift of H3PO2 changed to 8.2 ppm and a lower coupling constant was observed (JP-H = 548 ppm). The substrate containing an S-centered nucleophile 50a gave the strongest shift to 7.6 ppm with the coupling constant being the smallest of those examined (JP-

H = 544 ppm). Thereby, both nucleophile and nucleofuge interact with H3PO2 and promote the dissociation of dimeric H3PO2 to the reactive mono-meric form. These results are in accordance with previous studies of dimeric and monomeric forms of H3PO2 in which the dimeric form of H3PO2 dissoci-ated to the reactive monomeric form, upon addition of bases.94

Figure 4.2. 31P NMR spectra of a 1:1 mixture of phosphinic acid and substrates in

0.5 mL of CDCl3 at 25 °C.

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Scheme 4.7. Initial rate differences between substrates 30a, 34, and 36.

4.2.7.5. Competition Experiments

Competition experiments between substrate 18a and external electrophile or nucleophile were performed to study the effect on both the initial rate of the reaction as well as the enantiospecificity (Table 4.6.). The reaction of sub-strate 18a generated product 37a with the rate of 5.1×10-7 M∙s-1 and 96% e.s. after 8 hours reaction time (Entry 1). Addition of 1-phenylethanol (43) as an external electrophile to the reaction mixture only slightly affected the rate but not the enantiospecificity (Entry 2). Similarly, addition of external N-methylaniline (58) did not inhibit the reaction (Entry 3). Instead a small in-crease of the rate was observed. One explanation could be that N-methylaniline acts as a Brønsted base and promotes dissociation of dimeric H3PO2 to the reactive monomeric form as can be seen in the interaction of H3PO2 dimer with substrates (Figure 4.2.). Interestingly, no side-reactions were observed in these competition experiments. These experiments showed that the reaction is very selective towards the intramolecular substitution reaction and this is different to the iron-catalyzed reaction described in Chapter 3.

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Table 4.6. Competition experiments of 18a

Entry Additive Initial rate (×10-7 M∙s-1)a e.s.(%)b

1 - 5.1 96 2

1-phenylethanol (43) 4.4 98

3 N-methylaniline (58) 5.9 98

Reaction Conditions: 18a (0.08 mmol), additive (0.08 mmol), 1,2-DCE (1 mL), and H3PO2 (10 mol %) was heated in an oil bath. aInitial rate of the reaction at 8 h determined by 1H-NMR spectroscopy. bEnan-tiospecificity was determined by chiral stationary phase HPLC analysis.

It can be concluded that the rate of the reaction is dependent on the catalyst, the internal nucleophile, and the electrophile. Thus, the overall reaction shows a third-order rate law as shown in the equation:

4.2.7.6. Experiments to exclude the SN1 reaction

To distinguish between SN1- and SN2-type mechanisms is challenging for intramolecular substitution reactions. Rate-order determination studies showed that the rate depends on both internal nucleophile and electrophile. This is in agreement with the bimolecular reaction mechanism and suggests an SN2 reaction pathway. To further exclude the SN1 pathway, the following reaction was studied. Enantioenriched (S)-1-phenylethanol (43) was mixed with different acids to determine whether an intermolecular substitution re-action occurred to generate symmetrical ether 44 through an SN1 reaction (Table 4.7.). Reaction of 43 generated trace amount of symmetrical ether 44 when H3PO2 was employed as catalyst, and only 43 was recovered after the reaction with a negligible loss of e.e. (Entry 1). Other catalysts, that gave low to good enantiospecificities in the intramolecular substitution reaction (see Table 4.1.), gave racemic 44. The reaction with TfOH as catalyst gave full conversion of 43 to 44, along with side-products (Entry 4). This shows that stronger acids promote the SN1 pathway. Moreover, these experiments demonstrate that H3PO2 is a unique catalyst in the activation of the OH group and does not promote SN1 reactivity.

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Table 4.7. Excluding the SN1 reactivity in the etherification of 43 to 44

Entry Catalyst 44a T (°C) Recovered 43a

1 - - 80 > 99% (S/R) = 98:2) 2 H3PO2 < 5% 80 > 95% (S/R) = 96:4) 3 p-TSA > 95% 40 0% 4

TfOH > 20% 40 0%

5 FeCl3 > 95% 40 0%

Reaction Condition: 43 (1.0 mmol), 1,2-DCE (1.5 mL) and catalyst (10 mol %) was heated in an oil bath. aNMR yield.

4.2.7.7. Density Functional Theory Calculations

The experimental results showed that phosphinic acid promotes the intramo-lecular stereospecific substitution reaction with high enantiospecificity through a unique reaction mechanism. The phosphinic acid catalyst has a Brønsted acid site that presumably protonates the OH group of the nucleo-fuge in the TS. However, this activation is not sufficient to promote C─O

bond cleavage. Thereby, H3PO2 might have an additional role in the reaction. Plausibly, the O═P–OH motif of H3PO2 has a dual mode of activation and acts as a bifunctional catalyst that simultaneously activates both the nucleo-phile and the nucleofuge in an SN2-type reaction. This was supported by previous reports in which the oxo group in phosphorous acids may act as a Brønsted base (Scheme 4.2.).91,95 To further investigate possible mecha-nisms, DFT calculations were employed to study the transformations of O-, N-, and S-centered nucleophiles from 30a to 38a, 18b to 37b, and 50a to 57a, respectively. This study was conducted by Dr. Christian Dahlstrand, Pemikar Srifa in collaboration with Prof. Fahmi Himo and Dr. Genping Huang.

The optimized structures of the TSs are shown in Figures 4.4. and 4.5. All TSs were calculated at B3LYP/6-1G(d,p) along with the calculated barriers and reaction free energies. The results showed that low TSs were located in which H3PO2 showed a bifunctional role. The acidic proton of H3PO2 proto-nates the oxygen of the leaving hydroxyl group, promoting the C–O bond cleavage. Simultaneously, the oxo-group of the catalyst partially deproto-nates the nucleophile, thus increasing its nucleophilicity (Figure 4.4.) This results in an SN2-type reaction mechanism

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Figure 4.4. Calculated transition state structures with H3PO2 and their calculated energies (kcal/mol) for transformations from 30a to 38a, 18b to 37b, and 50a to

57a. In addition, TSs of other Brønsted acids (p-TSA, Ph2HPO2 and AcOH) as

shown in Figure 4.5., seemingly similar to H3PO2, were also calculated using the O-centered nucleophile 30a as a model substrate. The TS calculated for p-TSA was 21.1 kcal/mol. This result corresponds to the experimental out-come in which the stronger acid promotes the reaction at a lower tempera-ture (at 40 ⁰C). On the other hand, weaker acids, i.e. acetic acid, did not promote any reactivity in the intramolecular substitution and this is in agreement to the calculated transition state (36.6 kcal/mol). Ph2HPO2 having a similar structural motif to H3PO2, gave a slightly higher calculated transi-tion state of 27.6 kcal/mole. Accordingly, when employing Ph2HPO2 as cata-lyst, the reaction of 30a required a higher temperature to react and yield 38a.

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Figure 4.5. Calculated transition state structures with AcOH, Ph2HPO2, H3PO2, and p-TSA and their calculated energies (kcal/mol) for transformations from 30a to 38a.

4.3. Conclusion

The direct intramolecular stereospecific substitution of the hydroxyl group of enantioenriched secondary alcohols catalyzed by phosphinic acid has been developed. The hydroxyl group of aryl, allyl, propargyl, and alkyl alcohols was substituted by O-, S-, and N-centered nucleophiles to generate five- and six-membered heterocycles in good to excellent yields with high enanti-ospecificities. This enables the generation of synthetically relevant heterocy-cles from easily accessible enantioenriched alcohols. Mechanistic studies using both experiments and density functional theory calculations were per-formed. Experimental studies showed that phosphinic acid does not promote an SN1 reactivity. Rate-order determination indicated that the reaction fol-lows first-order dependence in catalyst, nucleophile, and electrophile. DFT calculations corroborated a reaction pathway in which the phosphinic acid operates as a bifunctional Brønsted acid/Brønsted base to simultaneously activate both the nucleophile and nucleofuge in an SN2-type TS. In this TS, the acidic proton of the phosphinic acid protonates the hydroxyl group to enhance its leaving group ability, and simultaneously, the oxo group of phosphinic acid partially deprotonates the nucleophile to enhance its nucleo-philicity.

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5. Concluding Remarks

Alcohols are an important and abundant class of compounds in nature which have been widely used for various purposes. In organic synthesis, alcohols are often used as nucleophiles. In contrast, better methodologies are needed to use alcohols as electrophiles, to enable their utilisation as a sustainable feedstock for the production of valuable chemicals.

This thesis describes the development of new methods for the activation of the hydroxyl group in the direct nucleophilic substitution of non-derivatized alcohols promoted by transition metal, Lewis acid, and Brønsted acid catalysis. These methodologies do not require derivatization of the hy-droxyl group to form a better leaving group prior to the substitution reac-tions. Hence, these developed methodologies reduce the number of reaction steps and thereby decrease the waste produced from the overall transfor-mation. These transformations can be further used in various applications such as the synthesis of biologically active compounds.

In the palladium catalyzed nucleophilic substitution reaction, an im-provement on the chemoselective mono- and diallylation of amines by al-lylic alcohols is described with minimization of unwanted side-products, with the C–O bond cleavage as keystone. Moreover, an application for the diallylated compounds was developed: a one-pot two-step procedure where the ring-closing metathesis and aromatization generate β-substituted pyrroles in the same vessel.

In the intramolecular stereospecific nucleophilic substitution reaction of enantioenriched alcohols, two different approaches have been developed by Lewis or Brønsted acid catalysis. The substitution reactions of different al-cohols with different type of internal nucleophiles provide five and six membered heterocycles in high to excellent yields with high enantiospecific-ities. Experimental results showed that the Lewis acid catalyst promotes the substitution reaction by activating the hydroxyl group, which is then dis-placed preferentially by an internal nucleophile which is favored over an external nucleophile. In the case of Brønsted acid/base catalysis, a combina-tion of experimental and computational studies revealed a dual activation mode, where the catalyst simultaneously activates the hydroxyl group and the nucleophile resulting in a unique transition state which is selective for the intramolecular substitution reaction. Even though the two catalysts oper-

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ate differently, the outcome of both systems is enantiomerically enriched heterocycles from easily accessible alcohols.

The results described in this thesis increase the understanding of activa-tion of the hydroxyl group in alcohols in substitution reactions. Hopefully, this will inspire other scientists for further development, enabling the usage of biomass as a carbon feedstock in chemical industries.

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Appendix A: Contribution List

The author wishes to clarify his contribution to publications and manuscripts in the thesis.

I. Minor contribution on the synthesis of starting allylic alcohols and monoallyaltion reactions. Major contribution on the second allylation reactions. Performed ring-closing metathesis and aromatization reac-tions. Wrote the manuscript and supporting information.

II. Major contribution on the screening of catalysts, the synthesis of sec-ondary alcohol substrates, and substrate scope studies. Minor contribu-tion on the tertiary alcohol substrates. Contributed in the mechanistic studies. Involved in the preparation of the manuscript and supporting information.

III. Major contribution on the synthesis of substrates and substrate scope studies. Minor contribution on the screening of catalysts. Performed mechanistic studies. Interacted with the computational chemists on the DFT calculations. Involved in the preparation of the manuscript and supporting information.

IV. Major contribution on the synthesis of substrates and substrate scope studies. Minor contribution on the screening of catalysts. Performed mechanistic studies. Interacted with the computational chemists on the DFT calculations. Wrote the manuscript and supporting information.

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Appendix B: Reprint Permissions

Reprint permissions were kindly granted for each publication by the follow-ing publishers:

I. A General Route to β-Substituted Pyrroles by Transition-Metal

Catalysis Anon Bunrit, Supaporn Sawadjoon, Svetlana Tšupova, Per J. R.

Sjöberg, and Joseph S. M. Samec J. Org. Chem., 2016, 81 (4), 1450–1460. Copyright © 2016 American Chemical Society

II. -

III. Brønsted Acid-Catalyzed Intramolecular Nucleophilic Substitu-tion of the Hydroxyl Group in Stereogenic Alcohols with Chirality Transfer Anon Bunrit, Christian Dahlstrand, Sandra K. Olsson, Pemikar Srifa, Genping Huang, Andreas Orthaber, Per J. R. Sjöberg, Srijit Biswas, Fahmi Himo, and Joseph S. M. Samec J. Am. Chem. Soc., 2015, 137 (14), 4646–4649. Copyright © 2015 American Chemical Society

IV. -

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Acknowledgements

“There's a difference between knowing the Path and walking the Path” Morpheus ─ The Matrix, 1999

One chapter of my life has come this far, and there are so many people

who have walked along with me, guiding, helping, and supporting me through this achievement. Without these people, I could not imagine how my Ph.D. journey would have been possible.

First and foremost, I would like to express my sincere and deepest grati-tude to my supervisor, Prof. Joseph S.M. Samec for the opportunity to per-form Ph.D. studies, and for his teaching, guidance, valuable advice, supervi-sion, encouragement, enormous patience and time throughout my research.

Grateful Thanks to Prof. Timo Repo at Department of Chemistry, Univer-sity of Helsinki (UH), Finland for his kindness and a great opportunity to perform research at UH.

I am Thankful to Prof. Belén Martín-Matute, for being my co-supervisor and for her advice and guidance.

I would like to Thank Prof. Pher G. Andersson for his valuable time, in-terest and patience to correct my thesis.

I would like to thank my thesis committee: Prof. Sascha Ott, Assoc. Prof. Annette Bayer, and Assoc. Prof. Peter Dinér who spent their precious time to read my thesis. I would like to deeply thank Assoc. Prof. Joseph Moran for taking time out from his busy schedule to serve as my opponent.

Also deep gratitude goes to Prof. Jan E Bäckvall, Prof. Fahmi Himo, Prof. Kálmán J Szabó, Prof. Berit Olofsson, Prof. Björn Åkermark , Prof. Göran Widmalm, Prof. Timofei Privalov, Dr. Nicklas Selander, Dr. Abra-ham Mendoza, Dr. Eric Johnston for a fruitful discussion and knowledge during SDM meeting and seminars.

Special thanks to my master’s degree supervisor and co-supervisor at Chulabhorn Graduate Institute (CGI): Dr. Charnsak Thongsornkleeb and Prof. Somsak Ruchirawat for their teaching, encouragement and supportive to continue with Ph.D. education.

I would like to express my Thankfulness to the past and present members of a Joseph’s research group and RenFuel company: Dr. Supaporn S. (P’Su), Dr. Srijit B., Dr. Sunisa A. (P’Ni), Dr, Rahul W., Dr. Christian D., Dr. Max-

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im G., and Dr. Joakim L. for their suggestions, advice, support and delightful discussions. Also, thanks to Dr. Alban C., Dr. Baliram H., Dr. Alexander P., Dr. Sari R.(also, when we were at UH), Dr. Jéssica M., Dr. Johan V., Dr. Karin L., Pemikar (Cherry) S. (being great friend since doing Bachelor at PSU), Elena S., Davide D. F., Ivan K. for having wonderful moment in these four years. Moreover, Thanks to Timo’s group members for a wonderful

time at Helsinki: Emi L., Eeva H., Kalle L. (also when you were at SU) and the rest of the group.

Thanks to proofreaders for feedback, proof reading and correcting the thesis.

I am grateful to every co-author the papers who have been working so hard in each project since the beginning till the end.

Thanks to all my friends in the department of organic chemistry, Stock-holm University (SU) for your friendship and for sharing wonderful moment with me: Sutthichat (Kim) K., Suppachai (Boy) K, Rabten W.(being great friend since doing Master at CGI), Dr. Greco G.M., Cristiana M., Dr. Xu Q., Daniels P., Jonas O., Aitor B. M., Dr. Guru B.R., Elis E., Arnar G., Gabriel-la K., Dr. Erik L., Marvin L., Dr. Marc M., Michael O., Stalin R. P., Dr. Nibadita P., Alexander R., Alessandro R., Andrey S., Dr. Jianguo L., Haibo W., Viola H., Dr. Bin Y. and everyone at the department.

I would like to thank Prof. Adolf Gogoll and Dr. Lukasz Pilarski, for be-ing my co-supervisors at the department of chemistry – BMC, Uppsala Uni-versity (UU) and Thanks to everyone before I moved to complete my Ph.D. education at Stockholm University: Prof. Helena G., Prof. Henrik O., Prof. Lars E., Prof. Olle M. and Dr. Eszter B., for their knowledge, kindness and delightful discussion during CCC (Coffee, Cakes, and Chemistry) seminars, also to: Dr. Jia-Fei P. Dr. Karthik D., Dr. Vijay P. S., Dr. Anna A., Carina S., Jia-Jie Y., Aleksandra D., Sandra K., Kjell J., Rabia A., Xiao H., Hao H., Michael N., Ruisheng X. and all Kemi ─ BMC members for our great mo-ments at UU.

Also thanks to the staffs for their general supports from both departments: Jenny K., Louise L., Sigrid M., Christina W., Carin L., Kristina R., Matrin R., Ola A. at SU and Eva O., Johanna J., Gunnar S., Bo F. at UU.

Special Thanks to my Thai friends and Thai people in Uppsala and Stockholm for having very warm welcome, taking care and sharing happi-ness through colorful brightness during spring to autumn, sadness through cold darkness during winter in Sweden and especially Thai food during all this time: Dr. P’Dew, Dr. P’Bow, Dr. P’Tong, Dr. P’Tuk, P’Noon, P’Tiger from SLU; Dr. P’Ae, Dr. P’Win, MD. P’Rong, Dr.P’Tae, P’View, P’M,

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P’Joy, Toon, Bier, Hackung, Nun from UU; Dr. P’Ying from SU; Dr. Blue from KTH (my undergraduate friend) who firstly showed me the capital of Sweden.

Thanks to everyone whom I may have missed that is making my life more memorable.

Last but not least, I want to extent my gratitude to all agencies (VR, FORMAS) that offered financial support to Joseph’s research group and my

Ph.D. education. And finally, after all this time, my beloved parents and family for always

giving me their unconditional love, deepest-intention, encourage, support me and everything through my life.

“Everything that has a Beginning, has an End”

The Oracle ─ The Matrix Revolutions, 2003

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