Abstract Multicomponent Reactions of Salicylaldehyde, Cyclic Ketones, and Arylamines Through Cooperative Enamine-Metal Lewis

ABSTRACT

MULTICOMPONENT REACTIONS OF SALICYLALDEHYDE, CYCLIC KETONES, AND ARYLAMINES THROUGH COOPERATIVE ENAMINE-METAL LEWIS ACID CATALYSIS

by Ryan Gregory Sarkisian

Multicomponent reactions (MCRs) are the most atom economic, highly selective, and convergent type of reaction. This allows for a reaction to have a wide scope and allows for maximization of the complexity of a product. Catalyzing these MCRs with asymmetric catalysis is a novel way to introduce stereocontrol into highly complex molecules with various functional groups. Asymmetric catalysis is considered the most efficient method for constructing highly functionalized optically active stereopure compounds. There are three pillars of asymmetric catalysis: biocatalysis, transition metal catalysis, and organocatalysis. This research focuses on two of these pillars, transition metal catalysis and organocatalysis, working cooperatively to catalyze this MCR. The focus is to educate or refresh the audience on the basic topics that make up the complexity of the MCRs being catalyzed by cooperative asymmetric catalysis. Ultimately to explore the cooperative catalysts used to synthesize both the racemic and asymmetric three fused ring products (9-((4-methoxyphenyl)amino)-2,3,4,4a,9,9a-hexahydro-1H-xanthen-4a-ol).

MULTICOMPONENT REACTIONS OF SALICYLALDEHYDE, CYCLIC KETONES, AND ARYLAMINES THROUGH COOPERATIVE ENAMINE-METAL LEWIS ACID CATALYSIS

A THESIS

Submitted to the Faculty of

Miami University in partial

fulfillment of the requirements

for the degree of

Master of Science

Department of Chemistry and Biochemistry

Ryan G. Sarkisian

Miami University

Oxford, Ohio

2014

Hong Wang, Advisor

Scott Hartley, Reader

Richard Taylor, Reader

David Tierney, Reader

Table of Contents

Chapter 1: Introduction……………………………………………………………………………………..1

1.1 Introduction to Multicomponent Reactions…………………………….………………………………1 1.1.1 Selectivity…………………………………………………………………………………………2 1.1.2 Atom Economy……………………………………………………………………………………3 1.1.3 Convergence………………………………………………………………………………………3 1.1.4 History of Multicomponent Reactions………………………………..…………………………..4 1.1.5 The Strecker Reaction……………………………………..……………………………………...5 1.1.6 The Mannich Reaction……………………………………………………..……………………..7 1.1.7 Applications of Multicomponent Reactions……………………………………………………....9 1.2 Introduction to Stereochemistry…………………………………...…………………………………...9 1.2.1 The Thalidomide Tragedy……………………………………………………………………….10 1.2.2 Basic Concepts of Stereochemistry……………………………………………………...………11 1.2.3 Descriptors of Stereochemistry………………………………………………………………...... 11 1.2.4 High Pressure Liquid Chromatography and Enantiomeric Excess…………………………...…13 1.3 Introduction to Asymmetric Catalysis……………………………………………………………...... 14 1.3.1 Asymmetric Catalytic Methods………………………………………………………………….15 1.3.2 History of Asymmetric Catalysis………………………………………………………………..17 1.3.3 Enamine Catalysis……………………………………………………………………………….20 1.3.4 Transition Metal Catalysis……………………………………………………....……………….21 1.3.5 Combination of Arylamine with Hard Lewis Acid………………………………..…………….21 1.3.6 Applications of Asymmetric Catalysis…………………………………………………………..21 1.4 References…………………………………………………………………………………………….22

Chapter 2: Exploration of MCRs with Combination Catalysis……………………………………………24

2.1 Abstract………………………………………………………………………...……………………..24 2.2 Background Information……………………………………………………....……………………...24 2.2.1 Multicomponent Reactions…………………………………………………………………...…24 2.2.2 Transition Metal Catalysis………………………………………………………………………25 2.2.3 Organocatalysis…………………………………………………………………………………25 2.2.4 Combination Transition Metal-Organo Asymmetric Catalysis………………………………....25 2.3 Synthetic Methodology of Racemic Product……………………………………………………....….25 2.3.1 Condition Screening……………………………………………………………………………..26 2.3.2 Providing Proof of Product Synthesis………………………………………………………...…29 2.3.3 Substrate Scope of this Catalytic Method……………………………………………………….31 2.3.4 Proposed Mechanism……………………………………………………………………………35 2.4 Attempts on the Asymmetric Three Component Reaction……………….………………....………..38 2.5 References…………………………………………………………………………………………….44 2.6 Experimental Data…………………………………………………………………………………….45 2.6.1 Nuclear Magnetic Resonance and Structural Data………………………………………………45 2.6.2 High Pressure Liquid Chromatography Data………………………………...………………….78

Chapter 3: Conclusion……………………………………………………………………………………102

List of Tables

Table 2.1: Condition screening of the multicomponent cascade reaction………………………………...28

Table 2.2: Substrate screening of salicylaldehyde with Yb(OTf)3 and (+/-) HCPA…………………...…32

Table 2.3: Substrate scope of the aryl amines with Yb(OTf)3 and (+/-) HCPA…………………………..33

Table 2.4: Substrate scope of the cyclic ketone with Yb(OTf)3 and (+/-)-HCPA………….……………..33

Table 2.5: Multicomponent cascade reaction transformation of three fused ring products………………34

Table 2.6: Dehydroxylation reaction of MCR product for stability………………………………………39

Table 2.7: Enantiomeric excess and anti/syn of the three fused ring product……………………...……..41

iii

List of Figures

Figure 1.1: The versatility and multiple applications of MCRs………………………………………..…...2

Figure 1.2: Number of MCR publications over the last 53 years in Scifinder®…………………………...5

Figure 1.3: Thalidomide as its (+)-R-, and (-)-S- enantiomers……………………………………………10

Figure 1.4: Schematic examples of isomers……………………………………………………………….11

Figure 1.5: Assigning priority of ligands on stereogenic centers...... 12

Figure 1.6: Stereoisomers and alkenes nomenclature using the priority rules…………………….………13

Figure 1.7: Polysaccharide coated chiral stationary phases…………………………………………….....13

Figure 1.8: The activation energy comparison of catalyzed and uncatalyzed reaction………………..….15

Figure 1.9: The three main pillars of asymmetric catalysis……………………………………………….16

Figure 1.10: Structural representation of atorvastatin and (-)-daunorubicin……………………………...22

Figure 2.1: Variant of the Mannich reaction to give the three fused ring product…………..…………….26

Figure 2.2: Chiral phosphoric acids and additives utilized condition screening………………………….27

Figure 2.3: The hemiacetyl center in the three fused ring product…………………………………..……29

Figure 2.4: Racemic Single Crystal results of 4a……………………………………………………….....30

Figure 2.5: CDCl3 and DMSO NMR samples of the three fused ring project 4a…………………………30

Figure 2.6: NMR data of the 4b in CDCl3 and DMSO for increased stability……………………………31

Figure 2.7: HPLC data obtained from the dehydroxylated three fused ring product……..………………40

Figure 2.8: Chiral phosphoric acids and chiral diamine………………………………………….……….41

List of Schemes

Scheme 1.1: The advantages of multicomponent reactions.……………………………………………...... 1

Scheme 1.2: Increased activity through reversible formation of intermediates…………………………….2

Scheme 1.3: Relative atom economies for basic chemical reactions.………………………………..……..3

Scheme 1.4: Convergence of a MCR to form desired product………………………………………...…...4

Scheme 1.5: The first recorded MCR; Strecker reaction mechanism………………………………..……..6

Scheme 1.6: The asymmetric Strecker reaction………………………………………………………...…..7

Scheme 1.7: The Mechanism of the Mannich reaction under acidic conditions…………………………...8

Scheme 1.8: Organocatalysis (a) Lewis Base, (b) Lewis acid, (c) Brønsted Base, (d) Brønsted Acid……17

Scheme 1.9: The Hajos-Parrish-Eder-Sauer-Wiechert reaction…………………………………………...19

Scheme 1.10: Mechanism for the formation of enamine……………..……………..…….………………20

Scheme 2.1: Multicomponent cascade reaction…………………………………………….……………..26

Scheme 2.2: Substrate screening of multicomponent cascade reaction…………………………………...32

Scheme 2.3: Proposed mechanism of the multicomponent cascade reaction…………………...... ……...37

Scheme 2.4: Dehydroxylation reactions tested to stabilize the three fused ring product………….……...39

Abbreviations Table

I. Reagents, Solvents, Terminology

Camphorsulfonic acid…………………………………………………………………………………..CSA

Diethyl Ether…………………………………………………………………………………………....Et2O

Entgegen……………………………………………………………………………………………………E

Ethyl Acetate……………………………………………………………………………………………..EA

High Pressure Liquid Chromatography……………………………………………………………….HPLC

Multicomponent Reactions……………………………………………………………………………MCRs

Methylene Chloride……………………………………………………………………………………DCM

Methanol……………………………………………………………………………………………...MeOH

(R)-(-)-1,1’-Binaphthyl-2,2’-diyl hydrogenphosphate………………………………………..….(R)-HCPA

(R)-3,3'-Bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogenphosphate………….....(R)-TRIP

(S)-(+)-1,1’-Binaphthyl-2,2’-diyl hydrogenphosphate……………………………………..…….(S)-HCPA

(S)-2-amino-3-methyl-N-(pyridin-2-yl)butanamide…………………………………………….….Ligand 1

Tetrahydrofuran……………………………………………………………………………….………..THF

Ytterbium (III) trifluoromethanesulfonate…………………………………………………………Yb(OTf)3

Yttrium (III) Phosphate…………………………………………………………………………………YX3

Yttrium (III) trifluoromethanesulfonate………………………………………………………….…Y(OTf)3

Zusamman………………………………………………………………………………………….………Z

Chapter 1: Introduction

1.1 Introduction to Multicomponent Reactions

Multicomponent reactions (MCRs) are convergent reactions, in which three or more reactants converge together to covalently bond in a single reaction vessel to form a single product. The most common way for MCRs to progress is through the assembly of elementary chemical reactions in a cascade like process. This process is the most atom-economic method to synthesize large molecules with stereochemical complexity (Scheme 1.1). This MCR method also will allow for expediting the synthetic process along with conservation of solvents and catalysts 2. In order to have an efficient MCR, it must have compatible components that will not irreversibly react with one single reactant, but allow for all reagents to combine in the observed product.

Scheme 1.1: The advantages of multicomponent reactions.

MCRs can have a large impact on the field of organic chemistry through their high exploratory power and the ability to manipulate synthetic efficiencies. The specific synthetic efficiencies that MCRs can affect are the selectivity, atom economy and the convergence 1, 2. The selectivity is the process of forming one product when multiple reagents are used in a one pot reaction. The atom economy can be maximized through the addition of all the reagents, which eliminates waste from the starting materials. Lastly, the convergence properties of MCRs allow for multiple steps in one reaction to maximize the yield. Due to these qualities MCR methodologies have applications in multiple fields, but most importantly in pharmaceuticals. This is

1 because MCRs have multiple applications in most stages of the drug discovery process, optimization of drug toxicity, and the manufacturing of the final drug.

Figure 1.1: The Features of MCRs

1.1.1 Selectivity

A reaction can be considered selective when one product is formed with a higher yield than all the other possible products. The selectivity is an essential quality for MCRs due to multiple reagents reacting with the possibility to form differing products. The selectivity is observed through the discrimination of reagents to reacting through a preferred reaction mechanism with one of the multiple reagents in solution making the other reagents more susceptible to react with it 2. This will allow for the reagents to combine in a way to favor one product.

Scheme 1.2: Increased activity through reversible formation of intermediates.

1.1.2 Atom Economy

Atom economy is a concept developed by B. Trost from the Stanford University. Atom economy aims to maximize the efficiency of the starting reagents and minimize the waste of the reaction, all while producing the desired product. With the rise in the popularity of green chemistry over recent years, more and more reactions are being modified to react more atom-economically. The atom economy of a reaction can be calculated as a percent through dividing the molar mass of the desired product over the masses of all of the reagents. The concept of atom is shown in the examples in Scheme1.2.

Scheme 1.3: Relative atom economies for basic chemical reactions.

1.1.3 Convergence

Chemical convergence is the process of multiple starting reagents combining together to form one product. This product has characteristics of all of the starting reagents. This methodology strives to improve the efficiency of multi-step chemical syntheses. This is usually accomplished through a combination of two or more starting reagents making an intermediate. This intermediate will react more readily with the other reagents resulting in higher yielding reactions and higher product selectivity.

Scheme 1.4 Convergence of a MCR to form desired product

It can be observed in Scheme 1.3 that the MCR must undergo the formation of intermediates to form the desired product. This allows for the facilitation of the reaction through more reactive intermediates resulting in the convergence product.

1.1.4 History of Multicomponent Reactions

Multicomponent Reactions have been studied for many years to find the most efficient method to synthesize novel compounds. The first recorded multicomponent reaction was the Strecker synthesis of α- aminonitrile published 1850. This reaction began to show the importance of these MCRs through its high yielding low waste production of amino acids. This field lacked the popularity that it deserved until the early 1900s when C. Mannich synthesized a tertiary amine. It was not the isolation of the tertiary amine that made this reaction unique, but the exploratory power that could be utilized through manipulation of the reagents. These reactions set the standard which has resulted in an exponential increase in the field of MCRs over the last 20 years (Figure 1.2). The graphical representation of the popularity of MCRs can be observed through monitoring the number of articles published in the last 53 years via Scifinder®. The study of MCRs is predicted to continue to grow as more academic and industrial sectors are focusing on more efficient synthetic method for drug discovery. This field’s growth was also expedited by the economy. With MCRs cutting out solvent waste and time spent in lab, both industrial sectors and academic research could profit from utilizing MCRs.

MCRS PUBLICATIONS

4762

2914

1396

536

351

300

230

150

148

146

19 NUMBER OF JOURNAL PUBLICATIONS OF NUMBER

YEARS

Figure 1.2: Number of MCR publications over the last 53 years in Scifinder®.

1.1.5 The Strecker Reaction

The first reported MCR was published in 1850 in the German journal, Annalen der Chemie und Pharmacie. This research was conducted by A. Strecker, who was trying to discover a novel method to synthesize lactic acid. Instead of synthesizing the lactic acid, he obtained alanine after treatment of aqueous acid. This reaction allowed for the first laboratory preparation of a α-amino acid derivative, specifically α- aminonitrile. The Strecker Synthesis of α-aminonitriles are a simple, versatile synthetic method to synthesize the α-amino acid intermediates. These intermediates are widely used in the synthesis of amino acids, natural products synthesis, and other biologically active compounds. The Strecker reaction mechanism requires the condensation of an aldehyde or ketone with a primary amine or ammonium, and cyanide to synthesize the desired α-aminonitrile (Scheme 1.2). The asymmetric methodologies have been applied in both the industrial sector and in academia to discover novel methodologies to synthesize natural products (Scheme 1.4) 11, 13.

Scheme 1.5: The first recorded MCR; Strecker reaction mechanism

The mechanism of the Strecker reaction has been thoroughly studied in order to fully grasp the magnitude of this reaction. One of the most unique aspects of this reaction is that it can proceed under both acid and base catalysis. The more common catalytic root for this reaction is through utilization of acid (Scheme 1.4). The lone pairs present on the oxygen found on the aldehyde or ketone will undergo an acid-base reaction resulting in the protonation of the aldehyde or ketone, making it susceptible for nucleophilic attack from the primary amine or ammonia. This product then underwent proton transfer which results in the formation of a hemiaminal. The hemiaminal then forms a double bond with the carbonyl carbon while breaking the carbon-oxygen bond resulting in the formation of the iminium ion. The cyanide then nucleophilically attacks the α-carbon of the iminium ion. This allows for complete conversion to the desired α-aminonitrile.

Scheme 1.6: The asymmetric Strecker reaction.

The Strecker Synthesis of α-aminonitriles can be conducted asymmetrically. This can be done through the use of optically active amines which would produce chiral iminium intermediates, or through the utilization of a chiral catalyst (Scheme 1.5). These two methodologies are utilized regularly in the synthesis of natural products and drug development 10, 13.

1.1.6 The Mannich Reaction

The Mannich reaction was first reported in 1912 in the German journal Archiv der Pharmazie11. This was where C. Mannich isolated a tertiary amine through exposing antipyrine to formaldehyde and ammonium chloride. The synthesis of this tertiary amine was conducted under identical conditions 12 years previously by B. Tollens and von Marle. It took C. Mannich’s identical synthesis of the tertiary amine for him to fully grasp the versatility of this reaction. The Mannich reaction is now generalized as the condensation of a primary or secondary amine with a non-enolizable carbonyl compound and with an enolizable carbonyl compound. This reaction forms the β-amino carbonyl compound which is also known as the Mannich base. The Mannich reaction has been utilized in many total syntheses of natural products. This reaction is another example of a multiple component reaction which has multiple applications both in the industrial sector and in academia through laboratory research 10, 11.

Scheme 1.7: The Mechanism of the Mannich reaction under acidic conditions.

The mechanism of the Mannich reaction has been researched for many years. This reaction is also unique in that it can proceed under both acid and base catalysis. The more common catalytic root for this reaction is also through the acid catalyzed process (Scheme 1.6). Under the acidic conditions the starting non- enolizable carbonyl compound undergoes an acid-bace reaction forming a protonated non-enolizable carbonyl compound with a positive charge on the oxygen. This allows the primary or secondary amine’s lone pair electrons to attack the carbonyl carbon thus forming the hemiaminal after proton transfer. This results in loss of a water molecule and production of the electrophilic iminium ion. The enolizable carbonyl compound undergoes acid catalyzed enol formation. The enolizable carbonyl compound nucleophilically attacks the iminium ion, forming a carbon-carbon bond between the α-carbon of the iminium and the β- carbon of the carbonyl compound. The deprotonation of this product leads to the β-amino carbonyl compound also known as the Mannich base 11.

1.1.7 Applications of Multicomponent Reactions

Multicomponent reactions have multiple applications in both the industrial sector and in academic research due to their wide range of reactions to be explored. These reactions had increasing interest in research over the past 20 years due to having the ability to maximize the complexity of these reactions along with monitoring the scope of these reactions 2, 9. The ability to manipulate these reactions allows for the synthesis of a library of compounds. This library of compounds allows for high-throughput screening of pharmaceuticals and agrochemical compounds. With the ability to synthesize a wide array of compounds the binding affinity testing along with agrochemical screening can be tested more readily. MCRs are productive industrial standards, which means they are economically feasible and abide by environmental standards. This is due to their one-pot syntheses, their conservation of solvents, and reduction of time spent in lab. These aspects make MCRs a powerful tool in industry. The synthesis and methodology for novel MCRs is another reason this field is thriving in academia. Research being conducted on MCRs can directly be transferred to industry, making all research potentially high impacting. MCRs are a thriving field in chemical synthesis and due to their selective, convergent, and atom economic properties, this field is predicted to continue growing.

1.2 Introduction to Stereochemistry

Stereochemistry is the study of dynamic and static special arrangements of three dimensional molecules, which gives rise to structural information along with molecular reactivity 1, 9. This field of chemistry is very important to everyday life because nature is comprised of enantiomerically pure compounds. The most essential building blocks of life are comprised of these enantiomerically pure compounds. These building blocks, like amino acids and nucleotides, are essential to the human body. When a change occurs in the stereochemistry of these biological compounds, multiple biological pathways will be affected and can lead to malformation and even death. Stereochemistry plays an essential role in drug development; this can be proven by the Thalidomide tragedy that will be discussed in the following section. Careful characterization of all drugs is now necessary to ensure the enantiopure compounds have the desired effect on the human body. All pharmaceuticals sold in the United States must obtain the approval of the Food and Drug Administration (FDA) prior to commercial availability.

1.2.1 The Thalidomide Tragedy

In the 1950s and 1960s Thalidomide (α-phthalimidoglutarimide) was a widely used drug that was used as a sedative treatment of morning sickness in pregnant mothers. This drug was on the market throughout Europe, Australia, and Japan. Over the ten year span that Thalidomide was on the market, over 10,000 children were born with Phocomelia Syndrome (PS), which resulted in severe birth defects in the upper limbs9. This correlation between Thalidomide and fetal deformations was not proven until 1961 which lead to the drug being banned in most countries 6. Thalidomide has a chiral center which physically exists as a racemate of the (+)-(R)- and (-)-(S)- enantiomers and was believed to be the cause of the fetal deformation side effects (Figure 1.3). After further studies were conducted Thalidomide was also attributed to cause malformations in the heart and the inner and outer ear 9.

Figure 1.3: Thalidomide as its (+)-R-, and (-)-S- enantiomers

The issues that were related to PS and fetal deformation were all found to be caused by the pure enantiomer tablet readily racemized in the human body. The two enantiomers of Thalidomide were found to have very different effects on the human body. While the entiopure (+)-(R)-Thalidomide was found to have sedative properties which lead to a severe drowsiness to mask the nausea felt in morning sickness, the (-)-(S)- Thalidomide enantiomer could be quite destructive 9. The pure (+)-(R)-Thalidomide can be synthesized in theory and isolated and placed into tabular form, but when placed in the acidic environment of the human stomach or even in the blood stream, Thalidomide is rapidly hydrolyzed. This hydrolysis allowed for easy conversion between the (+)-(R)-, and (-)-(S)-enantiomers. The Thalidomide tragedy is only one example of the detrimental biological effects that stereochemistry can have on the human body 6, 9.

1.2.2 Basic Concepts of Stereochemistry

As observed in the Thalidomide tragedy, stereochemistry has very important characteristics that are applied in multiple aspects of life. In order for a compound to have stereochemical properties it must be optically active. For a compound to be optically active it must rotate in a plane of polarized light due to the compound being chiral and have an excess of one enantiomer. A chiral compound is a compound that has a non-superimposable mirror image due to having one or more stereogenic centers. These chiral or stereogenic centers are an atom or bond that has an unique configuration of different ligands, and cannot have a superimposable mirror image. Then these chiral compounds have further clarification based on the configuration of the stereogenic centers1. Stereochemistry is related to compounds with the same connectivity but differ in the arrangement of atoms in space. Constitutional isomers do not contain a chiral center. A type of stereoisomer that is present as its non-superimposable mirror image is known as enantiomers 1. This type of isomer was observed in Figure 1.3. Another type of compound that is a stereoisomer, but not an enantiomer would be considered a diastereomer (Figure 1.4).

Figure 1.4: Schematic examples of stereoisomers

1.2.3 Descriptors of Stereochemistry

There are multiple ways to label stereochemistry in compounds with descriptors and they are all done by assigning the priorities of each of the groups on the stereogenic centers. The way that the priorities are assigned is though the atomic number, in the case of an isotope, the mass. The way that the atoms are assigned are that the higher the atomic number or the higher isotopic mass, the higher priority of the specific atom 1. When the atoms attached to the stereogenic center have the same atomic number and mass, the assigning is done through moving out to the next atoms until the priorities can be assigned (Figure 1.5).

Figure 1.5: Assigning priority of groups on stereogenic centers.

Assigning the priorities of compounds is essential for understanding and correctly labeling chiral compounds. Compounds that contain tetra-bonded carbon stereogenic centers will use the Cahn-Ingold- Prelog system for distinguishing between stereoisomers. The Cahn-Ingold-Prelog system is a set of rules that allows for the determination of any stereoisomer using the designation R from the Latin word rectus, which means right handed, and S from the Latin word sinister, meaning left handed. This R, S system uses the assigned priorities to distinguish between the two forms. The rules for this system of stereochemical nomenclature are that each group attached to the stereogenic center must be assigned a priority 1-4. The highest priority group would be given the number 1, while the lowest priority group will be given the number 4. This molecule will then be positioned so that the lowest priority group is positioned away from the observer 1. The three remaining priority groups will then be used to distinguish the nomenclature for this chiral compound. When looking at the three highest priority groups; moving from the highest, to the second highest, and finally the third highest. If the priority ligands revolves in the clockwise direction the stereogenic center is termed R, while if the priority ligands revolves in a counterclockwise direction the stereogenic center is termed S. A system that also uses the priority group is the E, Z system. This is a nomenclature system that relates to alkenes, olefins, to distinguish the priority of the two sides. The priority rule for this system is divided by the double bond and allows for the comparison between the two sides. For each carbon of the alkene assign one of the attached groups as high priority and one as low priority. If the two high priority groups lie on the same side of the alkene, then this compound will be labeled Z, zusammen. When the two high priority groups lie on the opposite sides of the alkene then the compound will be labeled E, entgegen 1. The more traditional way of “cis” and “trans” can be used if a hydrogen atom is attached to each carbon of the double bond. The “cis” descriptor is used when the same groups are on the same side, and “trans” is used when they are on opposite sides 1.

Figure 1.6: Stereoisomers and alkenes nomenclature using the priority rules.

1.2.4 High Pressure Liquid Chromatography and Enantiomeric Excess

High pressure liquid chromatography (HPLC), also known as high performance liquid chromatography, is an analytical technique that uses high pressure to force solvent through a closed column that contains fine particles that give high-resolution separations. These high-resolution separations, can be done to separate chiral compounds. These chiral compounds can be separated using different chiral columns. Each chiral column is composed of silica-gel which is used to support the polysaccharide coated stationary phases. In our lab there are four columns that are normally used to find the correct conditions for separating the chiral compounds. The four columns are the Chiralpak AD-H and AS-H, and the Chiralgel OD-H and OJ-H (Figure 1.7).

Figure 1.7: Polysaccharide coated chiral stationary phases.

The HPLC data that is collected is used to determine the stereoselectivity of the reaction. The stereoselectivity of a reaction can be reported as its enantiomeric excess (ee). The enantiomeric excess can

13 be defined as the mole fraction of one enantiomer shown in peak A, minus the mole fraction of the other enantiomer found in peak B 1. Where the mole fraction is simply the integration of each of the enantiomers.

1.3 Introduction to Asymmetric Catalysis

Catalysis is a process where a compound facilitates the rate of specific reaction, without being consumed in the overall reaction. A catalyst can be added in sub-stoichiometric amounts and still affect the throughput of the reaction. The catalyst’s job is usually to increase the product formation of the reaction in a timely manner. A catalyst functions through offering a pathway for the reaction to proceed with lower activation energy, thus accelerating the rate of the reaction. The thermodynamics of a reaction are unaffected by a catalytic process. In theory all reactions can be catalyzed, but not all catalytic mechanisms are known. This allows the field of catalysis to continue to grow, even after years of research. In catalysis the reagents proceed through a transition state. These transition states are normally have high energy and are significantly strained. This high energy, strained state will allow for the transformation to the product to occur (Figure 1.8). There are two forms of catalysts: heterogeneous and homogeneous. Heterogeneous catalysts are a type of catalyst that does not dissolve in the reaction mixture, but catalyzes the reaction in a separate phase1. Normally in this process the reagents will react with the surface of the catalyst, known as contact catalysts. This allow for the transformation to occur and for the product reenter into the starting phase. In homogenous catalysis the catalyst is dissolved into the same phase as the reagents, allowing for increased rate formation of the product.

푘1 푘2 퐴 + 퐶푎푡 ⇔ 퐴: 퐶푎푡 ⇔ 퐵: 퐶푎푡⇔ 퐵 + 퐶푎푡

Uncatalyzed vs Catalyzed Reactions

Uncatalyzed Catalyzed Catalyzed

G Δ

A B REACTION COORDINATE

Figure 1.8: The activation energies comparison of catalyzed and uncatalyzed reaction

In asymmetric catalysis all the catalytic processes hold true, but with the addition of stereocontrol of the product. The goal of this type of catalysis is to synthesize one pure enantiomer while increasing the rate of formation. Asymmetric catalysis has been studied for many years in order to synthesize enantiomerically pure products that can be found in all aspects of nature. In recent years three pillars have been established to be the main fields of asymmetric catalysis.

1.3.1 Asymmetric Catalytic Methods

There are three main branches of asymmetric catalysis; biocatalysis, transition metal catalysis, and organocatalysis (Figure 9.1). Asymmetric biocatalysis stems from enzymes in a living organism synthesizing enantiomerically pure amino acids, sugars, and nucleic acids. This idea has been utilized in laboratory research through using enzymes or even whole cells to help catalyze asymmetric reactions. This concept has been used for many years to synthesize many chiral compounds, even at the industrial scale. This type of catalysis has limitations. The biocatalyzed asymmetric reactions are mostly used in hydrolytic reactions and high levels of stereoselectivity could not always be achieved. The second pillar of asymmetric catalysis is transition metal catalysis. Transition metal catalysis has been long established and these synthetic transition metal complexes are one of the most powerful tools in organic catalysis 12.

Figure 1.9: The three main pillars of asymmetric catalysis.

These catalysts are particularly useful in asymmetric hydrogenations, but have the potential to leave toxic traces of heavy metals in the product. The final pillar of asymmetric catalysis is organocatalysis. This pillar is much newer than the previous two. This is the catalysis with low-molecular weight, purely organic molecules that can be used to catalyze the chemical reaction. This pillar of catalysis has dramatically increased in interest over the past decade 12. Organocatalysis can be broadly broken down into four categories: Lewis bases, Lewis acids, Brønsted bases, and Brønsted acids. An organocatalytic cycle can be shown to briefly describe each type of organocatalyst (Scheme 1.7). In Lewis base organocatalysis the corresponding Lewis base (:Base) will start the catalytic cycle by nucleophilically adding to the substrate allowing this complex to react and release a product for further catalysis. In Lewis acid catalysis the Lewis acid (Acid) will combine with nucleophilic substrates allowing complex formation and releasing of product for turnover. In the Brønsted base catalytic cycle the Brønsted base (:Base) initiates the reaction accepting a proton from the substrate, forming an intermediate that promotes formation of the protonated product and regeneration of the catalyst. Finally in the Brønsted acid catalytic cycle the Brønsted acid (Acid) protonates the substrate forming an intermediate which facilitates product formation and regenerates the acid catalyst 12.

Scheme 1.8: Illustration of orcanocatalysis; (a) Lewis Base, (b) Lewis acid, (c) Brønsted Base, (d)

Brønsted Acid.

A new area of research is being developed through combining organocatalysis and transition metal catalysis. This merging of two branches of asymmetric catalysis has huge potential in uncovering novel catalytic reactions. These catalytic systems look to facilitate novel reactions that could not proceed independently with organocatalysis or transition metal catalysis. Focusing specifically on the Lewis acid form of organocatalyst along with transition metal catalysis, new synthetic routes have already been found. There are three known mechanisms that this combined catalysis can react through: cooperative catalysis, synergetic catalysis, or sequential/relay catalysis. In cooperative catalysis the organocatalyst and the transition metal catalyst still react independently with the substrate, but work cooperatively to form a specific covalent bond. In synergetic catalysis the substrates are both activated as a nucleophile and electrophile through coupled catalytic cycles of the organocatalyst and the transition metal catalyst. These coupled cycles facilitate the formation of a new bond between the substrates and reformation of the respective catalysts. In the final mechanism, sequential/relay catalysis, a substrate will react with one catalyst, either the organocatalyst or transition metal catalyst, to produce an intermediate. This intermediate will then be activated by the other catalyst allowing for the formation of the product and the regeneration of each catalyst.

1.3.2 History of Asymmetric Catalysis

Over the years asymmetric catalysis has grown immensely. It is an essential part of natural product synthesis in pharmaceuticals, and also readily used in agrochemical synthesis. The three pillars have developed independently over the years, but with recent advances in these fields it is possible to combine these catalytic techniques to research new areas of asymmetric catalysis. The first enantioselective organocatalytic reaction recorded was the Hajos-Parrish-Eder-Sauer-Wiechert reaction which was published in the Journal of Organic Chemistry in 1971. This reaction was the first example of asymmetric catalysis with enamine catalysis 5,7. This reaction was catalyzed through the use of the simple chiral organic compound (S)-(-)-proline. This reaction involves an asymmetric intramolecular aldol reaction, which was also reported independently through two different companies in the industrial sector. The Hajos-Parrish- Eder-Sauer-Wiechert reaction mechanism was originally believed to function through a side chain enamine formation, but was rejected shortly after the proposal. For many years it was believed that two (S)-(-)- proline molecules complexed to catalyze this reaction with high enantioslectivity. It was not until recently that the original mechanism was proven and strengthed through theoretical, kinetic, and dilution experiments by K. N. Houk. This mechanism only differs through a chair-like transition state which allows for configurational stabilization through hydrogen bonding (Scheme 1.8). The Hajos-Parrish-Eder-Sauer- Wiechert reaction is a multistep reaction which starts with a Michael addition reaction. The Michael reaction can also be acid or base catalyzed, but normally is seen to process through the base catalyzed mechanism. In the first step an enolizable carbonyl compound’s α-carbon is deprotonated forming the enolate and a protonated base. This enolate nucleophilically attacks the second reagent, an α,β-unsaturated ketone. This forms a new carbon-carbon bond between the α-carbon of the enolizable carbonyl compound and the β-carbon of the ketone, which is now a negatively charged enolate. The protonated base is then neucleophilically attacked by the α-carbon of the enolate to reform the ketone and generate the Michael adduct. In the second step of the Hajos-Parrish-Eder-Sauer-Wiechert reaction the chiral organocatalyst, (S)- (-)-proline, enantioselectively forms the bicyclic Wieland-Miecher ketone. This is done through use of a polar aprotic solvent forming an enol with the enolizable carbonyl compound present in the Michael adducts. This then allows the (S)-(-)-proline to nucleophicalically attack the enol and undergo a proton transfer forming a hemiaminal. The hemiaminal undergoes electron migration through the lone pair of the amine forming a double bond with the non-enolizable carbonyl carbon while breaking the carbon-oxygen bond, releasing water. This forms the iminium ion intermediate and after a proton rearrangement the enamine intermediate. The enamine intermediate occurs when the (S)-(-)-proline completely coordinates with the Michael adduct through hydrogen bonding, forming the six-membered chair-like transition state. Next the enamine intermediate’s α-carbon nucleophilically attacks the ketone intramolecularlly forming carbon-carbon bond and enantioselectively forming a six-membered ring, along with reforming an iminium ion intermediate 5,7,10. The iminium ion undergoes nucleophilic attack from a water molecule forming

18 another hemiaminal. This hemiaminal undergoes a proton transfer which protonates the (S)-(-)-proline and the formation of an alcohol functional group. This complex then undergoes another proton transfer which reproduces the chirally pure (S)-(-)proline and reforms a ketone on the once α,β-unsaturated ketone. This compound then undergoes acid catalyzed dehydroxylation cleaving an alcohol functional group and a proton to reform an α,β-unsaturated ketone on the fused six-membered ring, thus yielding the Wieland- Miecher ketone (Scheme 1.8) 5, 7.

Scheme 1.9: The Hajos-Parrish-Eder-Sauer-Wiechert reaction.

1.3.3 Enamine Catalysis

Enamine Catalysis is a catalytic process that generates an enamine intermediate from primary or secondary amines via deprotonation of an iminium ion that reacts with electrophiles in electrophilic substitution at the α-position of carbonyl compounds. Organo-enamine asymmetric catalysis has roots both in biocatalysis and transition metal catalysis. This methodology stems from complex catalyzed direct asymmetric synthesis of aldol reactions. In these organo-enamine asymmetric catalyzed reaction cyclic aliphatic primary or secondary amines, such as (S)-(-)-proline seen in the Hajos-Parrish-Eder-Wiechert reaction, catalyze the transformation. This type of asymmetric organocatalysts has been widely studied and applied to form enantioselective mechanisms in the Mannich, Michael, and aldol reactions 3, 4, 10.

Scheme 1.10: Mechanism for the Formation of Enamine.

The formation of an enamine proceeds through the enolizable carbonyl compound nucleophilically attacking a hydronium ion producing an enol. The primary or secondary amine combines with the enol forming a bond with the carbonyl carbon through nucleophilic addition. Next proton transfer occurs yielding a hemiaminal. This hemiaminal undergoes electron migration forming an iminium ion and a water molecule. Deprotonation of the iminium ion then yields the enamine intermediate (Scheme 1.9)

1.3.4 Transition Metal Catalysis

Transition metal catalysis has been the focus of research in asymmetric catalysis for many years. Stemming from the asymmetric hydrogenation reaction proposed by W. Knowles and L. Horner, these catalysts are unique in that they can lend electrons and accept electrons from other molecules in the reaction mixture, through change in oxidation states. They are also known to activate reagents through forming a metal reagent complex. Through these processes it can be imagined that transition metals can increase the rate of reactions fairly readily. Transition metal catalysts can catalyze reactions through either being homogeneous catalysts or heterogeneous catalysts. These catalysts are readily used in the industrial sector and normally used in refining petroleum and polymer synthesis. Asymmetric transition metal catalysis is still widely used today and is utilized in the novel branch of combination catalysis 8.

1.3.5 Combination of Arylamine with a Hard Lewis Acid

In asymmetric organocatalysis aliphatic amines function as hard Lewis bases and can be great ligands to multiple metals, but specifically function well with hard metals. It was not until recently that arylamines were examined to function in enamine catalysis. The first report of arylamines as catalyst was published by Y. Deng and H. Wang in 2013 in Angewandte Chemie 3, 4. This idea stems from the fact that arylamines (pKa 4-6) are much softer than aliphatic amines (pKa 9-11). The significant difference in the pKa values of these amines is due to the delocalization of the lone pair into the π-system of the arylamines. Combination catalysis of arylamines with either transition metal Lewis acids and phosphoric acids have been seen to provide excellent yields and enantioselectivities (Figure 1.9). The novel concept of using arylamines as enamine catalysts has proven to catalyze a wide range of transformations. This is seen through fine tuning of the nucleophilicity of the arylamines, along with fine tuning the transition metal Lewis acids or phosphoric acids. The nucleophilicty of the arylamines can be easily controlled through the introduction of different electronic groups on the aromatic ring. Fine tuning of this cooperative catalytic mechanism can be done through utilizing different Lewis acids, or varying the bulkiness of the phosphoric acids. While this area of research is still in its infancy it has proven to be a powerful new technique in asymmetric catalysis 3, 4.

1.3.6 Applications of Asymmetric Catalysis

Asymmetric catalysis has multiple applications in both the industrial sector and in laboratory research in academia. It is present in the medication from a simple hypertension drug like Lipitor® to cancer treatment drugs like (-)-daunorubicin (Figure 1.10). It is essential for pharmaceutical companies to have efficient and highly stereoselective methods of synthesis.

Figure 1.10: Structural representation of atorvastatin and (-)-daunorubicin

This is also true in the agrochemical and materials chemistry industries. Chiral compounds are present all around us. Research laboratories in academia are necessary to discover new methods for easier, less wasteful, more efficient asymmetric syntheses. The idea of cooperative catalysis opens a new door in the field of asymmetric catalysis. While each pillar of asymmetric catalysis has its limitations the idea of cooperative catalysis helps to uncover novel methodologies that could not have been accomplished independently through research with an individual pillar. As the field of asymmetric catalysis continues to grow new out-of-the-box ideas are needed to stimulate research and funding in this field.

1.4 References:

[1] Anslyn, E. V., Dougherty, D. A. Modern Physical Organic Chemistry, 1st ed.; University Science Books: United States of America, 2006.

[2] Bienayme, H., Hulme, C., Oddon, G., Schmitt, P. “Maximizing Synthetic Efficienty: Multi-Component Transformations Lead the Way”. Chem. Eur. J. 2000, 6, 18, 3321-3329.

[3] Deng, Y., Kumar, S., Wang, H. “Synergistic-Cooperative Combination of Enamine Catalysis with Transition Metal Catalysis”. Chem Commun., 2014, 50, 4272-4284.

[4] Deng, Y., Liu, L., Sarkisian, R. G., Wheeler, K., Wang, H., Xu, Z. “Arylamine-Catalyzed Enamine Formation: Cooperative Catalysis with Arylamines and Acids”. Angrew Chem., Int. Ed. 2013, 52, 13, 3663-3667.

[5] Eder, U., Sauer, G., Wiechert, R. “ Total synthesis of optically active steroids”. Angew. Chem., Int. Ed. Engl. 1971, 10, 496-497.

[6] Eriksson, T., Bjorkman, S., Roth, B., Fyge, A., Hoglund, P. “Stereospecific Determination, Chiral Inversion In Vitro and Pharmacokinetics in Humans of the Enantiomers of Thalidomide” Chirality. 1995, 7, 44-52.

[7] Hajos, Z., Parrish, D. R. Asymmetric synthesis of optically active polycyclic organic compounds Application DE: 71-2102623, 1971, (Hoffmann-La Roche, F., und Co., A.-G.).

[8] Hayashi, T., Kumada, M. “Asymmetric Catalysis Catalyzed by Transition-Metal Complexes with Functional Chiral Ferrocenylphosphine Ligands”. Acc. Chem. Res. 1982, 15, 12, 395-401.

[9] Kim, J. H., Scialli, A. R. “Thalidomide: The Tragedy of Birth Defects and the Effective Treatment of Disease” Toxicol. Sci. 2011, 122, 1, 1-6.

[10] Kurti, L., Czako, B. Strategic Applications of Named Reactions in Organic Synthesis, 1st ed,; Elsevier Academic Press: China, 2005.

[11] Mannich C.; Krösche, W. Arch. Pharm. Pharm. Med. Chem. 1912, 250, 647–667.

[12] Reisinger, C. M., Pan, S. C., List, B. “New Concepts for Catalysis”. J. Systems Chemistry. 2009, 35- 64

[13] Strecker, A. Ann. Chem. Pharm. 1850, 75, 27

Chapter 2: Exploration of MCRs with Combination Catalysis 2 2.1 Abstract

Combination catalysis of organocatalyst and transition metal catalysis provides a cascade reaction of salicylaldehyde, arylamines, and cyclic ketones to provide a three fused ring product through a Mannich- Type Reaction. The utilization of catalytic amounts of yitterbium(III) trifluoromethanesulfonate hydrate

(Yb(OTf)3), as the Lewis acid and racemic 1,1’-binaphthyl-2,2’-diyl hydrogenphosphate ((+/-)-HCPA)), as its Brønsted acid. This duel catalytic system provides high yields in an anhydrous environment. The racemic fused three membered ring system is a novel molecule that could have potential uses in the pharmaceutical industry.

2.2 Background Information

Increased interest in discovering novel catalytic systems to catalyze multicomponent reactions continues to grow through combinations of the three pillars of asymmetric catalysis. The idea of combining a MCR with both a transition metal catalyst and an organocatalyst allows for the strengths of each field to be exploited. The vast exploratory power of MCRs combined with the activation power of a transition metal catalyst and the wide range of functional groups catalyzed by organocatalysts affords a high powered reaction which can produce high yielding, enantioselective reactions.

2.2.1 Multicomponent Reactions

Multicomponent Reactions (MCRs) are reactions that have three or more reagents that come together in a single reaction vessel to form a desired product. Starting from the first recorded MCR, the Strecker reaction, in 1850, these reactions just started to uncover their vast exploratory power. The vast exploratory power of these MCRs stems from the ability to maximize the complexity of the product and through testing the scope or versatility of the reaction mechanism. These MCRs also allow for optimal selectivity, convergence, and atom economy. MCRs are ideal in both the industrial sector and in academic laboratory research due to the conservation of solvents, reduction of time required in lab, and increase of molar yields. As this field continues to grow more and more organic transformations can be feasible by the industrial sector.

2.2.2 Transition Metal Catalysis

Transition Metal Catalysis has been studied immensely since the 1960s and has been an essential tool in organic synthesis. These catalysts became largely useful in asymmetric catalysis due to a variety of chiral ligands that can be complexed with these transition metals. These catalysts are very active and will allow for transformations to occur at low temperatures and pressures. The drawback that most transition metal catalysts face are that they can only work with a limited range of functional groups due to metal- reagent chelation.

2.2.3 Organocatalysis

Asymmetric organocatalysis is a fairly new field in the three pillars of asymmetric catalysis. Stemming from the Hajos-Parrish-Eder-Sauer-Wiechert reaction published in 1971 the utilization of organic compounds as asymmetric catalysts was not fully investigated until B. List and D. MacMillian independently researched the catalytic potential of chiral secondary amines, e.g. (S)-(-)-proline, in 1990. Organocatalysis since then has been found to catalyze numerous enantioselective transformations with a broad range of functional groups. While these transformations are still being discovered, organocatalysis is known to have limitations, including low activation of substrates. This is due to their lack of actability in transformations that require catalysis of inactive chemical bonds.

2.2.4 Cooperative-Transition Metal-Organo Asymmetric Catalysis

In combination catalysis of transition metal catalysis and organocatalysis the goal is to use the strengths of both catalytic methods to accomplish transformations that could not be conducted independently. Through the utilization of the highly activating properties of the transition metal catalysts and the broad range of functional groups that organocatalysts can catalyze, novel transformations can be uncovered through use of both in a catalytic system.

2.3 Synthetic Methodology of Racemic Product

In this multicomponent reaction of salicylaldehyde, arylamines, and cyclic ketones which follows a Mannich-Type Reaction mechanism where acetalization occurs at the final step providing a three fused ring product (Figure 2.1). This three fused ring product is the first known reported product of this type. It is believed to follow a Mannich-Type mechanism then with some catalytic assistance from the arylamine, allow acetalization occurs. While the Mannich reaction has been studied for many years and has numerous enantioselective transformations, this acetalization is a novel step in this type of organic transformations.

Figure 2.1: Variant of the Mannich Reaction to Give the Three Fused Ring Product.

In order to observe the scope and versatility of this multicomponent cascade reaction, condition screening along with substrate scope are necessary. The combination catalysis approach allows for a new activation method for further reacting of this MCR while allowing multiple different functional groups to be added to the starting reagents.

2.3.1 Condition Screening

The multicomponent cascade reaction of salicylaldehyde (1a), p-methoxyaniline (2a), and cyclohexanone (3a) react through a Mannich-Type reaction mechanism to produce a three fused ring product (4a), 9-((4-methoxyphenyl)amino)-2,3,4,4a,9,9a-hexahydro-1H-xanthen-4a-ol (Scheme 2.1). The condition screening was conducted to the yield of a reaction and to find the optimal conditions for high enantiomeric excess. The first step was looking into producing the highest yields for this reaction in the shortest amount of time. This process is conducted through changing the transition metal catalyst, Brønsted Acid (Phosphoric Acid), the solvent used, and the ratio of the three starting reagents.

Scheme 2.1: Multicomponent cascade reaction

This multicomponent cascade reaction was initially solvent screened to see which solvents would provide the highest yields. Preliminary studies were conducted previously showing that methylene chloride (DCM), tetrahydrofuran (THF), and toluene gave the highest yielding transformations. These three solvents were screened with assistance of the transition metals yttrium (III) trifluoromethanesulfonate (Y(OTf)3) and

26 ytterbium (III) trifluoromethanesulfonate (Yb(OTf)3) (Table 2.1). It was found that anhydrous THF gave the highest yields for both transition metal catalysts while needing 48h to react (entry 1-5).

Figure 2.2: Chiral phosphoric acids and additives utilized condition screening.

Chiral Brønsted Acids were then tested in place of the transition metal catalysts. These chiral phosphoric acids were screened with hope of observing some stereocontrol for this multicomponent cascade reaction. The chiral phosphoric acids were seen to catalyze the reaction independently with low yields and longer reaction times (entry 6-8). These reactions were also screened for stereoselectivity, but only gave messy HPLC data, leading to believe that decomposition occurred in the chiral columns. The next approach that was utilized was a combination catalysis approach using both a transition metal catalyst and Brønsted Acid catalyst. This combination catalysis was observed to have the highest yields (90, 92) and the shortest reaction time (20h, 12h) (entry 9, 10). Additives were also combined with the transition metal catalyst and the chiral phosphoric acids. These reactions were also conducted in hope of achieving some stereoslectivity, but also had the same racemic/decomposed results. Entry 11 was observed to have a similar reaction time to the combined transition metal catalyst and chiral phosphoric acid reactions. While the yield for this

27 reaction was decreased and reactions where monitored through changes in TLC plates to monitor changes in transformation. Entry 12 and 13 were observed to have a much longer reaction time and much decreased yields. Next this reaction was screened to see the effects that the transition metal catalyst along with an additive would have on the yield, reaction time and stereoslectivity. These reactions were observed to have moderate to low yields along with longer reaction times (Entry 14-18). Entry 19 was screened to observe if a transformation could occur in only the presence of the additive. This reaction was observed to have a similar reaction time to the transition metal only catalyzed reactions, while the yield greatly decreased. Entry 20 was screened to observe the effects of allowing the transformation to occur only in cyclohexanone in the presence of transition metal catalyst. This reaction gave excellent yields and short reaction time, but is unfeasible due to varying cyclic ketones being solids. The final entry, 21, was screened to observe if this transformation could occur in the absence of any catalyst. This reaction was seen to give the yellow enamine intermediate, but could not form the final three fused ring product. The optimal conditions for this reaction where found to be Yb(OTf)3 as the transition metal catalyst, along with (R)-(-)-1,1’-Binaphthyl-2,2’-diyl hydrogenphosphate ((R)-HCPA), all in the solvent anhydrous THF. With this compound giving poor enantioselective data the racemic form of this phosphoric acid was used in the substrate scope. Further studies were also conducted to prove the synthesis of this three fused ring product.

Table 2.1: Condition screening of the multicomponent cascade reaction.

Entry Solvent Metal A:B:C Brønsted Acid Additive Time Yield 2 1 c 1 DCM Y(OTf)3 1:1:5 - - 46h 68 2 1 c 2 DCM Yb(OTf)3 1:1:5 - - 46h 35 2 1 c 3 THF Y(OTf)3 1:1:5 - - 46h 69 2 1 c 4 THF Yb(OTf)3 1:1:5 - - 46h 77 2 1 c 5 Toluene Yb(OTf)3 1:1:5 - - 96h 54 63 THF1 - 1:1.2:25 (R)HCPA - 68h 34 c 73 Toluene1 - 1:1.2:25 (R)HCPA - 96h 32 c 83 Toluene1 - 1:1.2:25 (R)TRIP - 96h 28 c 3 1 c 9 THF Yb(OTf)3 1:1.2:25 (R)TRIP - 20h 90 3 1 10 THF Yb(OTf)3 1:1.2:25 (R)HCPA - 12h 92 3 1 i 11 THF Yb(OTf)3 1:1.2:25 (R)HCPA (R)BOX 17h 70 3 1 i 12 THF Yb(OTf)3 1:1.2:25 (R)HCPA (R)-pBOX 72h 34 3 1 i 13 THF Yb(OTf)3 1:1.2:25 (R)HCPA (S)-pBOX 72h 35 3 1 i 14 THF Yb(OTf)3 1:1.2:25 - (R)BINOL 72h 63

3 1 c 15 THF Yb(OTf)3 1:1.2:25 - Y(X)3 60h 54 3 1 c 16 THF Yb(OTf)3 1:1.2:25 - (D)-CSA 18h 54 3 1 c 17 THF Yb(OTf)3 1:1.2:25 - (L)-CSA 26h 52 3 1 i 18 THF Yb(OTf)3 1:1.2:25 - L1 18h 56 3 1 c 19 THF - 1:1.2:25 - (D)-CSA 42h 41 3 i 20 - Yb(OTf)3 1:1.2:25 - - 18h 99 3 1 21 THF - 1:1.2:25 - - 96h n.r All reactions were set up in small reaction vials with a stir bar at room temperature (25oC). . All transformations were performed on a 1.0 mmol scale. Reaction completion was monitored through TLC. 1Anhydrous Solvent, 210% Metal, 35% Metal, cCrude NMR Yields, iIsolated Yields.

2.3.2 Providing Proof of Product Synthesis

The asymmetric synthesis of this Mannich-Type reaction can be a powerful tool in its synthetic method of the preparation of this three fused ring product, 9-((4-methoxyphenyl)amino)-2,3,4,4a,9,9a- hexahydro-1H-xanthen-4a-ol. The asymmetric synthesis of this compound has been proven difficult to characterize due to its ability to isomerize in solution at its hemiacetal center. This can cause messy Nuclear Magnetic Resonance (NMR) spectra and extremely challenging stereochemical characterization in chiral High Pressure Liquid Chromatography (HPLC).

Figure 2.3: The hemiacetyl center in the three fused ring product.

It was believed that this isomerization could be overcome through the use of different substrates to stabilize the final compound. With growth of the single crystal, we could prove the structure of this compound and rationalize proceeding with this project. The growth of the single crystal had also proven to be rather challenging due to the solubility issues with the three fused ring product. With difficulty dissolving in acetonitrile, ethanol, and acetone, chloroform was utilized as the solvent for single crystal growth. The preparation of this single crystal sample was conducted through vapor diffusion method. This is where the three fused ring compound is completely dissolving in chloroform and placed into a small vial. This small vial was then placed inside a larger vial with a solvent that was unfavorable for dissolving this compound, hexanes. The larger vial was sealed, while the smaller vial was open, which allowed for solvent diffusion. After several weeks crystalline structure was observed and sent to Eastern Illinois University where K.

Wheeler solved the crystal structure with single crystal x-ray crystallography (Figure 2.3). While this compound is known to be racemic in solution it proved formation of the three fused ring product.

Figure 2.4: Racemic Single Crystal results of 4a.

Once uncovering the single crystal data, a cleaner NMR spectrum were needed to continue characterizing this compound. Varying temperature NMR data was then conducted on this compound to find the optimal conditions for characterization. With this compound’s solubility issues in most organic solvents, chloroform-d (CDCl3) and dimethyl sulfoxide-d6 (DMSO-d6) were used to monitor the isomerization of this three fused ring product in solution (Figure 2.4). Isomerization was observed in both deuterated solvents and concluded that differing substrates are needed to stabilize this three fused ring product.

1.0 NONAME03 NONAME04 0.15 0.9

0.8

0.7 0.10

0.6

0.5 0.05 0.4

0.3

0.2 0

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Normalized Intensity Normalized 0 Intensity Normalized -0.05 -0.1

-0.2

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8 7 6 5 4 3 2 1 0 -1 8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm) Chemical Shift (ppm)

Figure 2.5: CDCl3 and DMSO NMR samples of the three fused ring project 4a.

In order to increase the stability of the three fused ring product, synthesis was conducted using 5- chlorosalicylaldehyde to yield the 7-chloro-9-((4-methoxyphenyl)amino)-2,3,4,4a,9,9a-hexahydro-1H- xanthen-4a-ol product (Table 2.2, Entry 2). This compound was easily separable and under current conditions afforded very high yields. This compound underwent the same variable temperature screening in both deuterated solvents CDCl3 and DMSO-d6 (Figure2.5). Isomerization was slightly observed in the

CDCl3 while it was much less than observed in the original salicyaldehyde containing product. The DMSO NMR spectrum provided data, even with increased temperature the 7-chloro-9-((4-methoxyphenyl)amino)- 2,3,4,4a,9,9a-hexahydro-1H-xanthen-4a-ol would not isomerize. This data strongly supported continuing the substrate scope using the 5-chlorosalicylade as one of the three reagents in the MCR.

NONAME01 1.0 NONAME00

0.9

0.8 0.15

0.7

0.6

0.10 0.5

0.4

0.3

Normalized Intensity Normalized Normalized Intensity Normalized 0.05 0.2

0.1

0 0

-0.1

8 7 6 5 4 3 2 1 0 8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm) Chemical Shift (ppm)

Figure 2.6: NMR data of the 4b in CDCl3 and DMSO for increased stability.

2.3.3 Substrate Scope of this Catalytic Method

The versatility of this reaction was put to the test through using various starting reagents to view the transformations and stability of the product. Just like all MCRs the exploratory power of this reaction was put to the test by trying to maximize the complexity of this reaction along with observing insights about the scope and versatility of the reaction mechanism. Varying electron donating and electron withdrawing groups of salicylaldehyde in the 3, 4, and 5 positions was conducted. The same tests were conducted on the arylamines adding both electron withdrawing and donating functional groups to the 3 and 4 positions. Finally, the cyclic ketone was screened through adding varying functional group into and attached to the cycle.

Scheme 2.2: Substrate Screening of Multicomponent Cascade Reaction

The optimization of this multicomponent cascade reaction allowed for maximization of the complexity and scope of this reaction to be monitored. The first substrate that was screened was the salicylaldehydes. This reagent was monitored not only to observe the transformations, but also to monitor the stability of the three fused ring product (Table 2.2). When the salicylaldehyde had both electron withdrawing and electron donating functional groups present on the 5-position, excellent yields where observed (Entries 1-4). The 3,5-dibromosalicylaldehyde was also found to have excellent yields (Entry 5). When the nitrogen containing functional group and the methoxy functional group were added to the 4-position, decreased yields where observed. Unlike entry 5, the other di-substituted salicylaldehydes at the 3,5-positions gave decreased yields (Entries 7,8). The substrate 5-chlorosalicylaldheyde gave the highest yields and offered the most stability.

Table 2.2: Substrate screening of salicylaldehyde with Yb(OTf)3 and (+/-) HCPA

Entry R1 R2 R3 4 Solvent Metal Phosphoric Acid Yield 1 H H H 4a THF Yb(OTf)3 (+/-)-HCPA 92 2 Cl H H 4b THF Yb(OTf)3 (+/-)-HCPA 96 3 Br H H 4c THF Yb(OTf)3 (+/-)-HCPA 91 4 NO2 H H 4d THF Yb(OTf)3 (+/-)-HCPA 94 5 Br H Br 4e THF Yb(OTf)3 (+/-)-HCPA 93 6 H N(CH2CH3) H 4f THF Yb(OTf)3 (+/-)-HCPA 58 7 Cl H Cl 4g THF Yb(OTf)3 (+/-)-HCPA 67 8 NO2 H Br 4h THF Yb(OTf)3 (+/-)-HCPA 51 9 H OCH3 H 4i THF Yb(OTf)3 (+/-)-HCPA 52 All of these reactions where set up in small reaction vials with stir bar at room temperature for 20h. 5% mmol Yb(OTf)3 and 5% mmol (+/-)-HCPA where used in all reactions. Transformations 1-9 were performed on a 1.0 mmol scale. Reaction completion was monitored through TLC. Yields are isolated and characterized by NMR spectroscopy.

The substrate screening of the arylamines showed very promising data, with all substrates providing high yields except for the strong electron withdrawing nitro group (Table 2.3). The arylamine are an essential part of this reaction catalyzing both the salicylaldehydes and the cyclic ketones. The strongly electron withdrawing nitro functional group inhibit the formation of the enamine intermediate with the cyclic ketone. The only transformation observed in entry 5 was the formation of the iminium ion intermediate of the salicylaldehyde and the arylamine. While most of these transformations gave excellent yields the isolate products were found to be oil like and allowed for easy isomerization.

Table 2.3: Substrate scope of the aryl amines with Yb(OTf)3 and (+/-) HCPA

Entry R1 R4 R5 4 Solvent Metal Phosphoric Acid Yield 1 Cl H H 4j THF Yb(OTf)3 (+/-)-HCPA 96 2 Cl H Cl 4k THF Yb(OTf)3 (+/-)-HCPA 98 3 Cl Cl H 4l THF Yb(OTf)3 (+/-)-HCPA 94 4 Cl Br H 4m THF Yb(OTf)3 (+/-)-HCPA 95 5 Cl NO2 H 4n THF Yb(OTf)3 (+/-)-HCPA - All of these reactions where set up in small reaction vials with stir bar at room temperature. 5% mmol Yb(OTf)3 and 5% mmol (+/-)-HCPA where used in all reactions. Reaction completion was monitored through TLC. Yields are isolated and characterized by NMR spectroscopy.

The cyclic ketones were the final step of the substrate scope. These substrates are an essential part of the formation of the three fused ring product and were observed to be a fairly sensitive reagent (Table 2.4). While cyclohexanone and other heterocycles afforded excellent transformations with high yields and increased stability (Entries 1-4), other substrates such as cyclopentanone, cyclobutanone, and cyclohepanone could not produce complete transformation (Entries 5, 6). Uniquely, the substrate 1- methylpiperidin-4-one also could not form the three fused ring product (Entry 7).

Table 2.4: Substrate scope of the cyclic ketone with Yb(OTf)3 and (+/-)-HCPA

Entry X1 X2 X3 R6 R7 4 Solvent Metal Phosphoric Acid Yield 1 CH2 O CH2 - - 4o THF Yb(OTf)3 (+/-)-HCPA 91 2 CH2 S CH2 - - 4p THF Yb(OTf)3 (+/-)-HCPA 96 3 CH2 CH CH2 CH3 - 4q THF Yb(OTf)3 (+/-)-HCPA 92 4 O C O CH3 CH3 4r THF Yb(OTf)3 (+/-)-HCPA 90

5 CH2 CH2 - - - - THF Yb(OTf)3 (+/-)-HCPA - 6 CH2 - - - - - THF Yb(OTf)3 (+/-)-HCPA - 7 CH2 N CH2 CH3 - - THF Yb(OTf)3 (+/-)-HCPA - All of these reactions where set up in small reaction vials with stir bar at room temperature. 5% mmol Yb(OTf)3 and 5% mmol (+/-)-HCPA where used in all reactions. Transformations 1-7 were performed on a 1.0 mmol scale. Reaction completion was monitored through TLC. Yields are isolated and characterized by NMR spectroscopy.

The substrate scope proved the versatility and maximized the complexity of this multicomponent cascade reaction. The ideal substrates for further stereoselectivity research are the combination of 5- cholosalicylaldehyde, p-methoxyaniline, and the tetrahydrothiopyan-4-one. The three starting reagents produced the most stable, high yielding compound.

Table 2.5: Multicomponent cascade reaction transformation of three fused ring products

92% 96% 91% 4a 4b 4c 9-((4-methoxyphenyl)amino)-2,3,4,4a,9,9a- 7-chloro-9-((4-methoxyphenyl)amino)- 7-bromo-9-((4-methoxyphenyl)amino)- hexahydro-1H-xanthen-4a-ol 2,3,4,4a,9,9a-hexahydro-1H-xanthen-4a-ol 2,3,4,4a,9,9a-hexahydro-1H-xanthen-4a-ol

94% 4d 93% 67% 9-((4-methoxyphenyl)amino)-7-nitro- 4e 4f 2,3,4,4a,9,9a-hexahydro-1H-xanthen-4a-ol 5,7-dibromo-9-((4- 5,7-dichloro-9-((4-methoxyphenyl)amino)- methoxyphenyl)amino)-2,3,4,4a,9,9a- 2,3,4,4a,9,9a-hexahydro-1H-xanthen-4a-ol hexahydro-1H-xanthen-4a-ol

52% 51% 4i 4h 58% 6-methoxy-9-((4-methoxyphenyl)amino)- 4g 2,3,4,4a,9,9a-hexahydro-1H-xanthen-4a-ol

6-(diethylamino)-9-((4- 5-bromo-9-((4-methoxyphenyl)amino)-7- methoxyphenyl)amino)-2,3,4,4a,9,9a- nitro-2,3,4,4a,9,9a-hexahydro-1H- hexahydro-1H-xanthen-4a-ol xanthen-4a-ol

96% 94% 4j 4l 7-chloro-9-(phenylamino)-2,3,4,4a,9,9a- 98% 7-chloro-9-((4-chlorophenyl)amino)- hexahydro-1H-xanthen-4a-ol 4k 2,3,4,4a,9,9a-hexahydro-1H-xanthen-4a-ol 7-chloro-9-((3-chlorophenyl)amino)- 2,3,4,4a,9,9a-hexahydro-1H-xanthen-4a-ol

95% 96% 4m 91% 4p 9-((4-bromophenyl)amino)-7-chloro- 4o 8-chloro-10-((4-methoxyphenyl)amino)- 2,3,4,4a,9,9a-hexahydro-1H-xanthen-4a-ol 8-chloro-10-((4-methoxyphenyl)amino)- 1,3,4,4a,10,10a-hexahydrothiopyrano[4,3- 1,3,4,4a,10,10a-hexahydropyrano[4,3- b]chromen-4a-ol b]chromen-4a-ol

92% 90% 4q 4r 7-chloro-9-((4-methoxyphenyl)amino)-2- 8-chloro-10-((4-methoxyphenyl)amino)-2,2- methyl-2,3,4,4a,9,9a-hexahydro-1H- dimethyl-4,4a,10,10a-tetrahydro- xanthen-4a-ol [1,3]dioxino[5,4-b]chromen-4a-ol

2.3.4 Proposed Mechanisms

This multicomponent reaction is believed to follow a Mannich-Type mechanism, but with an acetylation reaction that fuses the two ring systems together. This reaction proceeds through the utilization of transition metal catalysis, along with arylamine organocatalysis. The addition of catalytic amounts of Bronsted acid further facilitated this reaction (Scheme 2.3). Under the acidic conditions the starting non- enolizable carbonyl group of the salicylaldehyde undergoes an acid-base reaction forming a protonated

35 non-enolizable carbonyl compound with positively charged oxygen. This allows the arylamine’s lone pair electrons to attack the carbonyl carbon of the salicylaldehyde. This compound then undergoes a proton transfer forming a hemiaminal. The hemiaminal then undergoes electron migration through the lone pair of the amine forming a double bond with the α-carbon of the salicylaldehyde’s while cleaving a water molecule. This results in the formation of the electrophilic iminium ion intermediate. The enolizable carbonyl compound, the cyclohexanone, undergoes arylamine catalyzed enamine formation. The enamine intermediate then nucleophilically attacks the iminium ion, after deprontation by a water molecule. This forms a carbon-carbon bond between the α-carbon of the iminium and the β-carbon of the enamine compound. This forms the Mannich-Type product which undergoes further cyclization through acid assisted catalysis. Once the three fused rings are formed the aryl amine attached to the enamine intermediate will undergo hydrolysis. This is where the lone pair on the aryl amine nucleophillically attacks a hydronium ion protonating the aryl amine. This allows for the enolizable carbon to be susceptible to nucleophilic attack from a surrounding water molecule. The water molecule removes the aryl amine from the enolizable carbon. The positive charge on the alcohol group is then removed through nucleophilic attack from a water molecule reproducing the acid and allowing for formation of the final three fused ring product.

Scheme 2.3: Proposed Mechanism of the Multicomponent Cascade Reaction

2.4 Attempts on the Asymmetric Three-Component Reactions

Initially it was believed that the best way to provide stability to our three-fused ring product was to dehydroxylate the hemiacetayl group. This proved to be more difficult than expected, likely due to the bulkiness of the cycles on either side of the hemiacetyl group. Multiple different methodologies were used to try to increase yields and perform complete transformation but only one reaction pathway proved to be successful (Scheme 2.4). The drawback of this reaction pathway is that the yields were found to be low (20%). This reaction proved to be unfeasible due to the extensive time spent on setup and limited yields (Table 2.6). The ideal conditions, even with the limited yields, were found to remove the alcohol (-OH) functional group allowing for stability and observation of the HPLC data (Figure 2.6). With this minor setback in the asymmetric portion of this project condition screening was explored to find a more stable starting product.

Scheme 2.4: Dehydroxylation Reactions tested to stabilize the three fused ring product.

While dehydroxylation of the hemiacetyl group was the only way to observe a stable compound for HPLC data, the reaction was not the answer for exploring this reactions asymmetric potential. Once a more stable product was discovered, such as the three fused ring product, 8-chloro-10-((4-methoxyphenyl)amino)- 1,3,4,4a,10,10a-hexahydrothiopyrano[4,3-b]chromen-4a-ol, further stereochemical testing could be conducted without the need of this dehydroxylation step.

Table 2.6: Dehydroxylation reaction of MCR product for stability.

Entry Name Solvent Ratio T(⁰C) Rxn Time Yieldh eei A:B:C

1 RS-1-135 DCM 1:3:3 0-25 20h ~25 Racemic 2 RS-1-136 DCM 1:30:30 0-25 1h ~25 Racemic 3 RS-1-140 DCM 1:5:5 0-25 48h ~25 Racemic 4 RS-1-144 DCM 1:3:3 0-25 20h trace - 5 RS-1-146 DCM 1:3:3 0-25 20h trace - 6 RS-1-148 DCM 1:5:5 0-25 46h ~25 Racemic 7 RS-1-159 DCM 1:6:6 0-25 20h ~25 Racemic All of these reactions where set up in small reaction vials with stir bar at 0oC and brought to room temperature. Transformations 1-7 were performed on a 0.1 mmol scale. hCrude yields were monitored on NMR. iEnantiomeric excess and anti/syn data was determined by HPLC.

Figure 2.7: HPLC data obtained from the Dehydroxylated Three Fused Ring Product.

This further exploration proved to be successful by synthesizing 8-chloro-10-((4-methoxyphenyl)amino)- 1,3,4,4a,10,10a-hexahydrothiopyrano[4,3-b]chromen-4a-ol which is stable under HPLC conditions. Once this three fused ring product was obtained multiple conditions were screened to control the stereochemistry. Initially phosphoric acids were explored. These phosphoric acids were combined with transition metal catalysts. Different catalytic methods were explored through solely using a transition metal catalyst and chiral Brønsted acid, the phosphoric acid catalysts. The transition metal catalysts used to facilitate this transformation were ytterbium (III) trifluoromethanesulfonate (Yb(OTf)3), yttrium (III)

40 trifluoromethanesulfonate (Y(OTf)3), and yttrium (III) phosphate (YX3). The chiral phosphoric acids used independently and as cooperative catalysts where (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl- 2,2'-diyl hydrogenphosphate (R-TRIP) 5b, (R)-(-)-1,1’-binaphthyl-2,2’-diyl hydrogenphosphate (R- HDPA) 5a, (S)-(+)-1,1’-binaphthyl-2,2’-diyl hydrogenphosphate (S-HCPA) 6a, and (R)-3,3′-bis[3,5- bis(trifluoromethyl)phenyl]-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate 5c (Figure 2.7). Chiral aryl amines were also explored to control stereochemistry. The chiral amine that was explored in this reaction was the (R)-(+)-1,1’-Binapthyl-2,2’-diamine 7a.

Figure 2.8: Chiral Phosphoric Acids and Chiral Diamine

Multiple chiral conditions were screened using the most stable three fused ring product, 8-chloro-10-((4- methoxyphenyl)amino)-1,3,4,4a,10,10a-hexahydrothiopyrano[4,3-b]chromen-4a-ol, to find a methodology that gave stereocontrol to this reaction. Reactions were setup using both the sequential and cooperative catalysis conditions, which would allow for thorough investigation of the reaction mechanism. Transition metal catalysts, chiral phosphoric acids, and additives were all tested independently along with combinations of various catalysts (Table 2.7).

Table 2.7: Enantiomeric excess and anti/syn of the three fused ring product

Entry Name Solvent Metal Phosphoric Acid Additive Reaction Time dri eei

1 RGS-2-22 THF Yb(OTf)3 (+/-)-HCPA - 8h 4:1 Racemic 2 RGS-2-25a THF Yb(OTf)3 5a - 8h 4:1 Racemic

3 RGS-2-25b THF - 5a - 96h - - 4 RGS-2-27a Toluene Y(OTf)3 - YX3 20h 4:1 Racemic 5 RGS-2-27b Dioxine - - YX3 96h - - 6 RGS-2-28 THF Y(OTf)3 5a - 16h 4:1 Racemic 7 RGS-2-29 Toluene Yb(OTf)3 5a - 48h 4:1 Racemic 8 RGS-2-30 THF - 5b - 72h 3:1 Racemic 9 RGS-2-32 THF - 5c - 72h 3:1 8 10 RGS-2-34 THF Y(OTf)3 5b - 72h 3:1 15 11 RGS-2-36a DCM - 5b - 84h 4:1 Racemic 12 RGS-2-36b Toluene - 5b - 84h 4:1 Racemic 13 RGS-2-37 THF Y(OTf)3 - L1 24h 4:1 Racemic 14 RGS-2-38a Toluene Y(OTf)3 5b - 72h 3:1 8 15 RGS-2-38b DCM Y(OTf)3 5b - 72h 4:1 Racemic 16 RGS-2-39 THF Y(OTf)3 5b - 72h 3:1 10 17 RGS-2-40 Dioxane Y(OTf)3 5b - 96h - - 18 RGS-2-41 Diethyl Ether Y(OTf)3 5b - 48h 4:1 6 19 RGS-2-42 Ethyl Acetate Y(OTf)3 5b - 72h 4:1 Racemic 20 RGS-2-43 Methanol Y(OTf)3 5b - 84h 3:1 Racemic 21 RGS-2-44 Dimethylformamide Y(OTf)3 5b - 96h - - 22 RGS-2-45 Acetonitrile Y(OTf)3 5b - 84h 4:1 Racemic 23 RGS-2-47 DCM Y(OTf)3 (+/-)-HCPA 7a 48h 5:1 10 24 RGS-2-49 DCM Y(OTf)3 5a 7a 48h 5:1 14 25 RGS-2-50 DCM Y(OTf)3 6a 7a 48h 8:1 42 26 RGS-2-51 DCM Y(OTf)3 5b 7a 48h 5:1 3 27 RGS-2-55 DCM Y(OTf)3 6a 7a 6h 6:1 35 28 RGS-2-56 DCM - 6a 7a 24h 7:1 46 All of these reactions were set up in small reaction vials with stir bar at room temperature. Transformations 1-7, 23-25, 27-28 were performed on a 0.1 mmol scale. Transformations 8-22, 26 were performed on a 0.025 mmol scale. iEnantiomeric excess and anti/syn data was determined by HPLC.

The racemic stable three fused ring product, 8-chloro-10-((4-methoxyphenyl)amino)-1,3,4,4a,10,10a- hexahydrothiopyrano[4,3-b]chromen-4a-ol, was synthesized using the transition metal catalyst Yb(OTf)3, and the racemic phosphoric acid, (+/-)-1,1’-binaphthyl-2,2’-diyl hydrogenphosphate (Entry 1). This was found to have two sets of peaks for the anti/syn conformations. The two major peaks had a longer retention time. Racemic data was observed when the chiral phosphoric acid (R)-(-)-1,1’-binaphthyl-2,2’-diyl hydrogenphosphate, 5a was used along with various solvents, THF and toluene (Entries 2, 3, 6, 7). When the YX3 was utilized both individually and as a co-catalyst with Y(OTf)3 no stereocontrol was observed (Entries 4, 5). The two metals yttrium (III) trifluoromethanesulfonate and ytterbium (III) trifluoromethanesulfonate were both screened to observe stereoselectivity, while no change was found. It is known from our previous research that Y(OTf)3 allows for better stereocontrol, so this transition metal catalyst was used in further screening. When (R)-3,3'b(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl hydrogenphosphate, (R-TRIP) 5b, a much bulkier phosphoric acid was screened independently, no stereocontrol was observed (Entry 8). Another bulky phosphoric acid with electron withdrawing functional groups, (R)-3,3′-bis[3,5-bis(trifluoromethyl)phenyl]-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate 5c, was screened, slight stereoselectivity was observed (Entry 9). The widely used chiral phosphoric acid, 5b, was also screened using various solvents showing no stereocontrol (Entries 11, 12). Next, a cooperative method was explored to see if our chiral ligand 1 would allow stereocontrol when combined with the transition metal catalyst Y(OTf)3. This method only gave racemic product (Entry 13). When the chiral phosphoric acid, 5b, was used cooperatively with Y(OTf)3 more stereocontrol was observed (Entry 10). Multiple

42 solvents were screened to observe effect on stereoselectivity (Entries 14-22). To our disappointment, the change in solvent gave no increase in stereoselectivity. Finally, a three catalyst system was explored. This was conducted both sequentially and cooperatively. The sequential setup of the reaction was conducted through allowing the transition metal catalyst to activate the iminium ion intermediate formed between the salicylaldehyde and the aryl amine. Next the cyclic ketone and chiral catalytic aryl amine were added and allowed to react. Once this reaction came to completion the chiral phosphoric acid was added allowing for complete transformation to the three fused ring product (Entries 23-26). The highest enantiomeric excess was observed with the chiral phosphoric acid, (S)-(+)-1,1’-binaphthyl-2,2’-diyl hydrogenphosphate, 6a. This reaction was then setup cooperatively by adding the transition metal catalyst, the chiral phosphoric acid, and the chiral aryl amine and allowing to complex for two hours. After complexation the three components were added and complete transformation occurred in 6 hours with higher stereoselectivity (Entry 27). Lastly, this reaction was setup through allowing only the chiral phosphoric acid, 6a, and the chiral aryl amine, 7a, to complex. Followed by the addition of the three components, this reaction resulted in the best enantiomeric excess recorded for this project (Entry 28).

Future study with the utilization of the (S)-(-)-1,1’-binapthyl-2,2’-diamine will allow for screening of the bulky chiral phosphoric acids that we have in our lab to be tested to optimize the conditions for high enantiomeric excess.

2.5 References

[1] Chen, D., Han, Z., Zhou, X., Gong, L. “Asymmetric Organocatalysis Combined with Metal Catalysis Concept, Proof of Concept, and Beyond”. Acc. Chem. Res. 2014, DOI: 10.1021/ar500101a

[2] Deng, Y., Kumar, S., Wang, H. “Synergistic-Cooperative Combination of Enamine Catalysis with Transition Metal Catalysis”. Chem Commun., 2014, 50, 4272-4284.

[3] Deng, Y., Liu, L., Sarkisian, R. G., Wheeler, K., Wang, H., Xu, Z. “Arylamine-Catalyzed Enamine Formation: Cooperative Catalysis with Arylamines and Acids”. Angrew Chem., Int. Ed. 2013, 52, 13, 3663-3667

[3] Liu, L., Sarkisian, R. G., Deng, Y., Hong, W. “Sc(OTf)3-catalyzed three-component cyclization of arylamines, β,γ-unsaturated α-ketoesters, and 1,3-dicarbonyl compounds for the synthesis of highly substituted 1,4-dihydropyridines and tetrahydropyridines”. J. Org. Chem. 2013, 78(11):5751-5775

[4] Liu, L., Sarkisian, R. G., Xu, Z., Hong, W. “Asymmetric Michael Addition of ketones to alkylidene malonate via enamine-metal Lewis acid bifunctional catalyst”. J. Org. Chem., 2012, 77(17):7693- 9

2.6 Experimental Data

All the NMR spectra were accumulated using the Bruker 300 and 500 MHz instruments and spectra analysis was edited on 1D ACD/ChemSketch. Exact mass and molecular weight were calculated using ChemBioDraw.

2.6.1 Nuclear Magnetic Resonance and Structural Data

Label Name: RGS-1-175

Chemical Formula: C20H23NO3

Exact Mass: 325.17

Molecular Weight: 325.40

Chiral phosphoric acid, HCPA, (0.05mmol, 17.9 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.05mmol, 30.4 mg) were mixed in anhydrous tetrahydrofuran, THF, at room temperature for one hour. Next, salicylaldehyde (1.0 mmol, 122.8 mg), p-methoxyaniline (1.2 mmol, 148.7 mg), and cyclohexanone (2.5 mmol, 2.5 mL) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, a brown and white solid was observed. Washing this solid with DCM allowed for the accumulation of pure product as white solid (4a, 92%).

Growth of single crystal has proven to be rather difficult due to the solubility of the three fused ring product. With difficulty dissolving in acetonitrile, ethanol, and acetone, chloroform was utilized as the solvent for single crystal growth.

1H NMR: (500 MHz, DMSO) 훿: 073(q, 1H), 1.07 (q, 1H), 1.45 (q, 1H), 1.55(q, 4H), 2.03 (q, 2H), 3.64 (s, 3H), 5.05 (dd, 1H), 5.26 (d, 1H), 6.57(m, 1H), 6.73 (m, 5H), 6.88 (q, 1H), 7.40(d, 1H)

RS-1-175 T.005.001.1r.esp Water

0.30

0.25 DMSO

0.20

0.15 3.64

Normalized Intensity Normalized

0.10

6.73

6.72

6.75 0.05 6.70

6.58

1.57

1.55

6.87

5.25

7.40

7.41

5.27

2.04

1.43

2.01 1.52

1.60

1.99

5.05 1.45

2.06

6.88

5.06

5.05

5.04 0.74

0.72

1.08

1.05

6.55

0 1.00 1.20 1.09 5.23 1.36 0.99 1.02 3.35 2.44 3.95 1.16 1.04 1.02

8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm)

13C NMR: (500 MHz, DMSO) 훿: 21.86, 22.68, 23.99, 38.12, 38.64, 47.41, 55.28, 98.05, 113.71, 114.76, 115.96, 120.01, 123.63, 126.74, 127.78, 142.45, 150.78, 152.16

LL-1-148.013.001.1r.esp

39.84 39.67 39.50 39.33 39.16

0.25

0.20

0.15

Normalized Intensity Normalized

0.10

114.76

113.71

55.28

0.05 98.05

115.96

120.01 23.99

38.64

22.68

152.16

127.78 47.41

38.12

21.86

150.78

142.45

180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

13 CDEPT 135 NMR: (500 MHz, DMSO) 훿: CH,CH3: 38.37, 47.14, 55.22, 113.45, 114.50, 115.71, 119.76,

126.51, 127.53; CH2: 21.62, 22.43, 23.74, 27.87; C: 98.05, 123.63, 142.45, 150.78, 152.16

LL-1-148.014.001.1r.esp

39.50 1.0

0.9

114.50 0.8

39.67

0.7 39.33

113.45 0.6

0.5

126.51

119.76

127.53

38.37

55.02 0.4 39.84

39.16

47.14 0.3

0.2

Normalized Intensity Normalized

0.1

-0.1

-0.2

23.74 -0.3 21.62

37.87

180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

1.0 NONAME03

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2 0.1 55oC

Normalized Intensity Normalized 0

-0.1 45oC -0.2

-0.3 35°C -0.4

-0.5 25°C

8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm)

NONAME04 0.15

0.10

0.05

75oC

0 65oC

Normalized Intensity Normalized o -0.05 55 C

45oC

-0.10 35oC

o -0.15 25 C

8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm)

Label Name: RGS-1-185

Chemical Formula: C20H22ClNO3

Exact Mass: 359.13

Molecular Weight: 359.85

Chiral phosphoric acid, HCPA, (0.05mmol, 17.9 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.05mmol, 30.4 mg) were mixed in anhydrous tetrahydrofuran, THF, at room temperature for one hour. Next, 5-chlorosalicylaldehyde (1.0 mmol, 122.8 mg), p-methoxyaniline (1.2 mmol, 148.7 mg), and cyclohexanone (2.5 mmol, 2.5 mL) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, a brown and white solid was observed. Washing this solid with DCM allowed for the accumulation of pure product as white solid (4b, 96%).

1H NMR: (500 MHz, DMSO) 훿: 0.69 (q, 1H), 1.06 (q, 1H), 1.35 (q, 1H), 1.41-1.61(m, 4H), 2.03 (m, 2H), 3.65 (s, 3H), 5.049 (dd, 1H), 5.39 (d, 1H), 6.69-6.82 (m, 6H), 7.16 (d, 1H), 7.38 (s, 1H)

RS-1-185.007.001.1r.esp Water

1.0

0.9

0.8

0.7 3.65

0.6

0.5

0.4

Normalized Intensity Normalized

6.75 DMSO

6.72 0.3

6.76

0.2 7.38

6.70

6.79

1.57 1.55

5.38

5.40

2.04

1.52

2.07 1.60 1.46

5.05 2.01

1.99

5.04

5.06

5.03

0.71

0.1 1.38

1.44

0.68

1.08

0 0.99 1.09 6.41 1.00 1.01 3.24 2.24 4.43 1.04 0.99 0.97

8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm)

13C NMR: (500 MHz, DMSO) 훿: 21.83, 22.64, 23.91, 37.92, 38.32, 47.48, 55.26, 98.59, 113.88, 114.81, 117.92, 123.78, 125.89, 126.44, 127.64, 142.07, 151.01, 151.17

RS-1-195.001.001.1r.esp

39.51 1.0

39.79

0.9

39.23

0.8

0.7

0.6

40.06

0.5

38.96

Normalized Intensity Normalized 0.4

113.88

114.81 0.3

40.35

55.26

98.59

151.01

142.07 0.2 38.68

125.89

38.32

151.17

123.78

126.44

127.64 117.92

47.48

22.64 21.83

23.91

37.92 0.1

180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

1.0 NONAME00

0.9

0.8

0.7

0.6

0.5

0.4

0.3

Normalized Intensity Normalized

0.2

0.1

-0.1

8 7 6 5 4 3 2 1 0 Chemical Shift (ppm)

NONAME01

0.15

0.10

Normalized Intensity Normalized 0.05

8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm)

Label Name: RGS-1-191

Chemical Formula: C20H22BrNO3

Exact Mass: 404.08

Molecular Weight: 404.30

53 reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, brown and yellow solids were observed. Washing this solid with DCM allowed for the accumulation of pure product as yellow solid (4c, 91%).

1H NMR: (500 MHz, DMSO) 훿: 0.65 (q, 1H), 1.06 (q, 1H), 1.35 (q, 1H), 1.41-1.61(m, 4H), 2.02 (m, 2H), 3.64 (s, 3H), 5.05 (dd, 1H), 5.39 (d, 1H), 6.69-6.82 (m, 6H), 7.28 (d, 1H), 7.51 (s, 1H)

RS-1-191.005.001.1r.esp Water

1.0

0.9

0.8

0.7

0.6

0.5

3.65

0.4

Normalized Intensity Normalized DMSO

6.74 0.3 6.72

6.76

0.2

7.51

1.57 1.54

7.28

5.39

7.29

5.41

2.04

5.06

1.46

2.01 1.60 0.1 5.05 2.06

1.37 0.70

0.68

1.07

1.05

1.35

1.40

0 1.02 1.07 6.15 1.00 1.03 3.37 2.18 4.12 1.03 1.00 1.00

8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm)

13C NMR: (500 MHz, DMSO) 훿: 20.93, 21.75, 23.03, 38.31, 38.47, 46.66, 97.72, 110.65, 112.98, 113.87, 117.55, 125.54, 128.49, 129.69, 141.17, 150.152, 150.75

RS-1-191.007.001.1r.esp

39.50 1.0

0.9

0.8

39.96 0.7

39.13

0.6

0.5

39.04

40.16 Normalized Intensity Normalized 0.4

0.3

38.47

0.2

38.31

97.72

141.17

110.65

112.98

150.75

113.87 0.1 150.15 125.54

21.75

128.49

117.55

129.69 46.66

20.93

23.03

180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

Label Name: RGS-1-192

Chemical Formula: C20H22N2O5

Exact Mass: 370.15

Molecular Weight: 370.40

Chiral phosphoric acid, HCPA, (0.05mmol, 17.9 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.05mmol, 30.4 mg) were mixed in anhydrous tetrahydrofuran, THF, at room

55 temperature for one hour. Next, 2-hydroxy-5-nitrobenzaldehyde (1.0 mmol, 167.1 mg), p-methoxyaniline (1.2 mmol, 148.7 mg), and cyclohexanone (2.5 mmol, 2.5 mL) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, brown and yellow solid were observed. Recrystalizing this solid with hexanes and isopropanol allowed for the accumulation of a pure product as yellow solid (4d, 94%).

1H NMR: (500 MHz, DMSO) 훿: 0.69 (q, 1H), 1.09 (q, 1H), 1.36 (q, 1H), 1.51-1.68 (m, 4H), 2.14 (m, 2H), 3.66 (s, 3H), 5.14 (dd, 1H), 5.51 (d, 1H), 6.77 (s, 4H), 6.98 (d, 1H), 7.18 (s, 1H), 8.06 (d, 1H), 8.34 (s, 1H)

RS-1-192.005.001.1r.esp

3.66 1.0

0.9

0.8

6.77

0.7

0.6

0.5

1.58 0.4

Normalized Intensity Normalized

8.35

7.18

0.3 1.56

6.97

6.99

2.12

1.53

8.08 8.06 5.51

0.2 5.53

5.14

2.14

1.50

1.37

0.67

0.64

1.11

1.35

1.09 0.1

1.66

8.02

0 1.081.05 1.00 1.20 4.20 1.00 1.03 3.38 2.11 4.38 1.21 1.09 1.04

8 7 6 5 4 3 2 1 0 Chemical Shift (ppm)

13C NMR: (300 MHz, DMSO) 훿: 21.68, 22.47, 23.65, 37.51, 38.12, 47.46, 55.25, 100.25, 111.89, 114.09, 114.84, 117.13, 123.26, 124.11, 124.98, 140.62, 141.74, 151.25, 158.41

RS-1-192.006.001.1r.esp

39.51 1.0

0.9 39.68

39.34

0.8

0.7

0.6

0.5 39.84

39.18

Normalized Intensity Normalized 0.4

0.3

40.01

0.2 55.26

39.01

114.85

114.10

124.12

141.75

100.26

23.66

38.13

47.47

117.14

22.48

123.27 37.52

21.68 0.1 151.26

140.63

125.00 111.91

158.42

180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

Label Name: RGS-2-1a

Chemical Formula: C20H21Br2NO3

Exact Mass: 480.99

Molecular Weight: 483.14

Chiral phosphoric acid, HCPA, (0.05mmol, 17.9 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.05mmol, 30.4 mg) were mixed in anhydrous tetrahydrofuran, THF, at room

57 temperature for one hour. Next, 3,5-dibromosalicyladehyde (1.0 mmol, 279.9 mg), p-methoxyaniline (1.2 mmol, 148.7 mg), and cyclohexanone (2.5 mmol, 2.5 mL) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, brown and yellow solids was observed. Recrystalizing this solid with hexanes and isopropanol allowed for the accumulation of a pure product as yellow solid (4e, 93%).

1H NMR: (500 MHz, DMSO) 훿: 0.61 (q, 1H), 1.04 (q, 1H), 1.35 (q, 1H), 1.41-1.61(m, 4H), 2.00 (s, 1H), 2.12 (s, 1H), 3.61 (s, 3H), 5.09 (dd, 1H), 5.32 (d, 1H), 6.72 (q, 4H), 7.16 (s, 1H), 7.50 (s, 1H), 7.59 (s, 1H)

RS-1-193.007.001.1r.esp Water

0.25

0.20

0.15

3.62

Normalized Intensity Normalized 0.10 DMSO

6.73

6.71

0.05

1.55

7.59

7.50

7.16

1.57

5.32

5.34

1.48

5.09

2.11

2.14

5.08

2.01

1.99

1.45 0.62

1.36

1.05 0.60

1.34 1.03

7.20

0 0.94 1.03 1.04 4.37 1.00 1.00 3.41 1.07 0.98 3.87 0.96 0.94 0.92 0.88

8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm)

13C NMR: (300 MHz, DMSO) 훿: 22.06, 22.98, 24.34, 38.47, 47.49, 55.33, 55.60, 98.73, 101.48, 106.82, 114.22, 115.10, 116.12, 127.77, 142.70, 151.18, 153.40, 159.60,

RS-1-193.001.001.1r.esp

39.50 1.0

39.78 0.9

39.22

0.8

0.7

0.6

114.22

115.10

40.05 0.5 55.60

55.33

98.73

38.94

Normalized Intensity Normalized 0.4

159.60

142.70

153.40

151.18

0.3 116.12

106.82

47.49

101.48

127.77

22.98

24.34

40.33 22.06 0.2 38.47

38.66

0.1

180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

Label Name: RGS-2-24

Chemical Formula: C24H32N2O3

Exact Mass: 396.14

Molecular Weight: 396.52

Chiral phosphoric acid, HCPA, (0.05mmol, 17.9 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.05mmol, 30.4 mg) were mixed in anhydrous tetrahydrofuran, THF, at room

59 temperature for one hour. Next, 4-(dietheylamino)salicyladehyde (1.0 mmol, 193.2 mg), p-methoxyaniline (1.2 mmol, 148.7 mg), and cyclohexanone (2.5 mmol, 2.5 mL) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, a brown and white solid was observed. Washing this solid with DCM allowed for the accumulation of pure product as white-yellow solid (4g, 58%).

Label Name: RGS-1-195

Chemical Formula: C20H21Cl2NO3

Exact Mass: 394.09

Molecular Weight: 394.29

Chiral phosphoric acid, HCPA, (0.05mmol, 17.9 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.05mmol, 30.4 mg) were mixed in anhydrous tetrahydrofuran, THF, at room temperature for one hour. Next, 3,5-dichlorosalicylaldehyde (1.0 mmol, 191.0 mg), p-methoxyaniline (1.2 mmol, 148.7 mg), and cyclohexanone (2.5 mmol, 2.5 mL) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, a brown and white solid was observed. Recrystalizing this solid with hexanes and isopropanol allowed for the accumulation of pure product as white solid (4f, 67%).

Label Name: RGS-1-196

Chemical Formula: C20H21BrN2O5

Exact Mass: 449.06

Molecular Weight: 449.30

Chiral phosphoric acid, HCPA, (0.05mmol, 17.9 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.05mmol, 30.4 mg) were mixed in anhydrous tetrahydrofuran, THF, at room temperature for one hour. Next, 3-bromo-5-nitrosalicylaldehyde (1.0 mmol, 246.0 mg), p-methoxyaniline (1.2 mmol, 148.7 mg), and cyclohexanone (2.5 mmol, 2.5 mL) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, a brown and white solid was observed. Recrystalizing this solid with hexanes and isopropanol allowed for the accumulation of product as orange solid (4h, 51%).

Label Name: RGS-1-197

Chemical Formula: C21H25NO4

Exact Mass: 355.18

Molecular Weight: 355.43

Chiral phosphoric acid, HCPA, (0.05mmol, 17.9 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.05mmol, 30.4 mg) were mixed in anhydrous tetrahydrofuran, THF, at room temperature for one hour. Next, 2-hydro-4-methoxybenzaldehyde (1.0 mmol, 152.1 mg), p-methoxyaniline (1.2 mmol, 148.7 mg), and cyclohexanone (2.5 mmol, 2.5 mL) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, a brown and white solid was observed. Washing this solid with DCM allowed for the accumulation of pure product as white solid (4i, 52%).

1H NMR: (500 MHz, DMSO) 훿: 0.75 (q, 1H), 1.03 (q, 1H), 1.37 (q, 2H), 1.41-1.58(m, 3H), 2.03 (m, 2H), 3.61 (s, 3H), 3.67 (s, 3H), 5.01 (s, 2H), 6.32 (s, 1H), 6.46 (d, 1H), 6.68 (s, 1H), 6.72 (s, 4H) 7.30 (d, 1H)

RS-1-197.001.001.1r.esp Water

0.40

0.35

0.30

0.25

0.20 3.62

6.72

3.67

Normalized Intensity Normalized 0.15

0.10 DMSO

5.01

6.68

6.32

1.56

7.29 0.05 7.31

1.53

6.47

2.04

1.42

1.50

1.58

2.01

1.45

2.06

1.99

0.76

1.48

0.74

1.04

0 1.02 3.77 0.97 1.03 1.02 2.01 3.28 3.33 2.12 3.10 1.88 0.99 0.98

8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm)

13C NMR: (300 MHz, DMSO) 훿: 22.00, 22.84, 23.96, 37.91, 38.67, 47.13, 55.57, 99.95, 111.048, 111.67, 114.33, 115.12, 128.09, 129.16, 133.18, 142.07, 148.61, 151.50

RS-1-197.001.001.1r.esp

39.50 1.0

39.78

0.9

39.22

0.8

0.7

0.6

40.06

0.5

38.95

Normalized Intensity Normalized 0.4

114.33

115.12

55.57 0.3

99.95

38.67

142.07

133.18 128.09 111.67

151.50

0.2 48.13

148.61

129.16

23.96

111.04

37.91

22.84

22.00

0.1

180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

Label Name: RGS-1-198

Chemical Formula: C19H20ClNO2

Exact Mass: 329.12

Molecular Weight: 329.82

63 mg), and cyclohexanone (2.5 mmol, 2.5 mL) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, a brown and white solid was observed. Washing this oil with hexanes and isopropanol allowed for the accumulation of pure product as white/clear oil. This oil turned into a foam under high vacuum which allowed for accumulation of while solid (4j, 96%).

1H NMR: (500 MHz, DMSO) 훿: 0.74 (q, 1H), 1.06 (q, 1H), 1.48 (q, 1H), 1.52-1.61(m, 4H), 2.05 (m, 1H), 2.24(s,1H,) 5.139 (dd, 1H), 5.82 (d, 1H), 6.57 (m, 1H), 6.71-6.82 (m, 4H), 7.11 (d, 3H), 7.34 (s, 1H)

NOTE: This product readily isomerizes in solution ~5:1

RS-1-198.005.001.1r.esp Water

0.09

0.08

0.07

0.06

0.05 DMSO

0.04

6.80

Normalized Intensity Normalized

0.03

6.80

6.78

6.76

7.11 0.02 6.74

7.34

2.24

7.09

6.57

1.58

1.08

1.56

5.81

5.83 2.05

2.04

7.17

2.22

1.74

1.48

2.25

1.09

1.06

6.56

5.14

5.15 0.01 5.13

5.12

0.74

4.72 4.70 4.69

4.68

0 1.08 2.92 4.28 1.44 1.00 1.00 0.17 1.33 1.41 4.36 1.35 1.32 1.01

8 7 6 5 4 3 2 1 0 Chemical Shift (ppm)

13C NMR: (500 MHz, DMSO) 훿: 21.99, 22.65, 23.94, 37.92, 38.42, 46.76, 98.60, 112.60, 116.27, 118.02, 123.85, 125.55, 126.49, 127.74, 129.18, 148.17, 151.21

RGS-1-198.002.001.1r.esp

39.67 39.50

39.34

0.8

0.7

0.6

0.5

39.84

39.17

129.18

0.4

Normalized Intensity Normalized

0.3 112.60

98.60

38.42

148.17

46.76

151.21

22.65

127.74

118.02 0.2 126.49 125.55

23.94

37.92

40.00

21.99

0.1

41.23

180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

Label Name: RGS-1-199

Chemical Formula: C19H19Cl2NO2

Exact Mass: 364.08

Molecular Weight: 364.27

Chiral phosphoric acid, HCPA, (0.05mmol, 17.9 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.05mmol, 30.4 mg) were mixed in anhydrous tetrahydrofuran, THF, at room

65 temperature for one hour. Next, 5-chlorosalicylaldehyde (1.0 mmol, 122.8 mg), 3-chloroaniline (1.2 mmol, 156.6 mg), and cyclohexanone (2.5 mmol, 2.5 mL) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, a brown and white solid was observed. Washing this oil with hexanes and isopropanol allowed for the accumulation of pure product as brown-yellow oil. This oil turned into a foam under high vacuum which allowed for accumulation of brown solid (4k, 98%).

1H NMR: (500 MHz, DMSO) 훿: 0.72 (q, 1H), 1.08 (q, 1H), 1.47 (q, 1H), 1.59-1.75(m, 4H), 2.24 (m, 2H), 5.12 (dd, 1H), 6.23 (d, 1H), 6.54-6.59 (m, 3H), 6.76-6.91 (m, 3H), 7.12 (m, 1H), 7.30 (s, 1H)

NOTE: This product readily isomerizes in solution ~5:1

RS-1-199.001.001.1r.esp Water

0.8

DMSO 0.7

0.6

0.5

0.4

6.83

Normalized Intensity Normalized 0.3

6.58

1.08

2.24

6.76

0.2 7.12

1.75

2.23

7.29

7.30

1.59

2.25

1.09

1.73

1.07

6.22

7.07

6.24

2.04

2.02

1.47

1.17

0.1 5.12

6.54

5.11

5.13

5.10

0.74

0.72

0.71

4.40

1.05

6.91

4.33 3.90

4.38

4.42

5.78 5.76 5.52

5.54

4.31

1.98

2.33

3.43 3.43

0 1.09 1.58 3.29 3.13 1.02 1.01 0.17 2.25 4.21 1.451.390.99

8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm)

13C NMR: (500 MHz, DMSO) 훿: 22.03, 22.55, 23.77, 37.76, 38.43, 46.83, 98.46, 115.62, 118.10, 123.82, 124.81, 126.32, 127.90, 130.71, 133.79, 149.66, 151.11

RS-1-199.002.001.1r.esp

39.83 39.67 39.50 39.33 39.17

0.30

0.25

0.20

40.00 0.15 39.00

Normalized Intensity Normalized

0.10

0.05 98.46

46.83

22.55

115.62

149.66 118.10

126.36

130.71 124.81

133.79

127.90 23.77

22.03

37.76

123.82

151.11

180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

Label Name: RGS-1-200

Chemical Formula: C19H19Cl2NO2

Exact Mass: 364.08

Molecular Weight: 364.27

156.6 mg), and cyclohexanone (2.5 mmol, 2.5 mL) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, a brown and white solid was observed. Washing this oil with hexanes and isopropanol allowed for the accumulation of pure product as white/clear oil. This oil turned into a foam under high vacuum which allowed for accumulation of while solid (4l, 94%).

1H NMR: (500 MHz, DMSO) 훿: 0.73 (q, 1H), 1.10 (q, 1H), 1.45 (q, 1H), 1.67-1.76(m, 4H), 2.24 (m, 2H), 5.10 (dd, 1H), 6.09 (d, 1H), 6.72-6.84 (m, 5H), 7.13(m, 2H), 7.31 (s, 1H)

NOTE: This product readily isomerizes in solution ~5:1

RGS-1-200.001.001.1r.esp DMSO

1.0

0.9

0.8 2.24

0.7

6.82

7.13

0.6 6.76

2.23

1.75

7.14

6.74 0.5 2.25

1.73 0.4

Normalized Intensity Normalized

1.76

7.31

7.31 0.3

1.62

6.07

6.09

7.08

2.03

2.05

0.2 1.47

6.64

6.57

1.38

5.10

5.09

1.45

5.11

7.06

5.08

1.36

1.45

1.10 0.73 0.73 0.1

4.37

5.40

6.16

6.18 5.42

5.62 5.60 4.39 4.35

4.28 4.26 1.83

6.97

1.30

4.69

0 1.07 2.60 5.35 0.99 0.14 1.00 0.13 1.91 4.49 1.49 1.51 0.99

8 7 6 5 4 3 2 1 0 Chemical Shift (ppm)

13C NMR: (500 MHz, DMSO) 훿: 21.96, 22.58, 23.81, 37.80, 38.24, 46.95, 98.49, 113.89, 118.07, 119.37, 123.81, 125.05, 126.382, 127.84, 128.86, 147.06, 151.11

RGS-1-200.002.001.1r.esp

39.50 1.0

39.33 0.9 39.66

0.8

0.7

0.6

0.5

39.83

39.16

Normalized Intensity Normalized 0.4

0.3

0.2

40.00

39.00

0.1 128.86

98.49

113.89

126.38

46.95

38.24

127.84

125.05 119.37 22.56

118.07

123.81

151.11 147.06 23.81

21.96

37.80

180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

Label Name: RGS-2-4

Chemical Formula: C19H19BrClNO2

Exact Mass: 407.03

Molecular Weight: 408.72

206.4 mg), and cyclohexanone (2.5 mmol, 2.5 mL) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, a brown and white oil was observed. Washing this oil with hexanes and isopropanol allowed for the accumulation of pure product as yellow-white oil. This oil turned into a foam under high vacuum which allowed for accumulation of while solid (4m, 95%).

Label Name: RGS-2-5

Chemical Formula: -

Exact Mass: -

Molecular Weight: -

Label Name: RGS-2-14

Chemical Formula: C19H20ClNO4

Exact Mass: 361.11

Molecular Weight: 361.82

Chiral phosphoric acid, HCPA, (0.05mmol, 17.9 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.05mmol, 30.4 mg) were mixed in anhydrous tetrahydrofuran, THF, at room temperature for one hour. Next, 5-chlorosalicylaldehyde (1.0 mmol, 122.8 mg), p-methoxyaniline (1.2 mmol, 148.7 mg), and dihydro-2-pyran-4-one (10.0 mmol, 1.0 mL) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, a brown and white solid was observed. Washing this solid with DCM allowed for the accumulation of pure product as white solid (4o, 91%).

1H NMR: (500 MHz, DMSO) 훿: 1.74(q, 1H), 1.94 (q, 1H), 2.33 (q, 1H), 2.90 (q, 1H), 3.65 (qn, 5H), 3.79 (q, 1H), 5.07 (dd, 1H), 5.44 (d, 1H), 6.70-6.80 (m, 4H), 6.85 (d, 1H), 7.15 (s, 1H), 7.22 (d, 1H),7.39 (s, 1H)

RGS-2-14.002.001.1r.esp Water

0.7

0.6

3.65

0.5

0.4

0.3

Normalized Intensity Normalized

0.2 6.74

6.77

7.15 DMSO

6.79

7.39

6.72

0.1 5.43

2.90

5.45

1.96

1.99

3.68

3.78

5.07

3.79 2.33

5.06 2.32

3.80

5.08

2.31 1.75

3.36 2.87 1.74

3.63 2.92

5.05

2.34

0 1.03 1.05 1.17 1.08 4.42 1.01 1.04 1.16 4.64 1.03 1.05 1.22 1.02

8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm)

13C NMR: (500 MHz, DMSO) 훿: 38.37, 38.43, 45.68, 55.31, 64.63, 96.51, 114.16, 114.89, 118.26, 124.27, 125.18, 126.26, 128.05, 141.77, 150.88, 151.32

RGS-2-14.003.001.1r.esp

39.67 39.50 39.33

0.70

0.65

0.60

0.55

0.50

0.45 39.83

39.17

0.40

0.35

Normalized Intensity Normalized 0.30

0.25

114.89 0.20 114.16

55.31

40.00

39.00

0.15 96.51

38.37

45.68

141.77

151.32

150.88

118.26

126.26

128.05

64.63 0.10 125.18

0.05

180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

Label Name: RGS-2-15

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral phosphoric acid, HCPA, (0.05mmol, 17.9 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.05mmol, 30.4 mg) were mixed in anhydrous tetrahydrofuran, THF, at room

72 temperature for one hour. Next, 5-chlorosalicylaldehyde (1.0 mmol, 122.8 mg), p-methoxyaniline (1.2 mmol, 148.7 mg), and Tetrahydrothiopyran-4-one (2.5 mmol, 580.1 mg) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, a brown and white solid was observed. Washing this solid with DCM allowed for the accumulation of pure product as off-white solid (4p, 96%).

1H NMR: (500 MHz, DMSO) 훿: 1.77(dt, 1H), 2.07 (t, 1H), 2.26 (td, 1H), 2.37 (m, 2H), 2.51 (s, 1H), 2.73 (dt, 1H), 3.65 (s, 3H), 5.18 (dd, 1H), 5.79(d, 1H), 6.75 (q, 4H), 7.05 (s, 1H), 7.21 (dd, 1H),7.40 (s, 1H)

RGS-2-15.001.001.1r.esp Water

0.7

0.6

0.5

0.4

3.65 0.3

Normalized Intensity Normalized

0.2 DMSO

6.77

6.72 0.1 7.05

6.79

6.71

7.40

5.58

5.60

2.07

2.37

7.21

2.37

7.22

2.51 2.40 2.35

2.73 2.10

5.18 2.25 1.77 1.76

5.19

5.17

5.16 2.26

2.75

0 0.98 1.01 1.00 1.08 4.32 1.00 1.02 3.15 1.05 0.70 2.15 1.06 1.05 1.04

8 7 6 5 4 3 2 1 0 Chemical Shift (ppm)

13C NMR: (500 MHz, DMSO) 훿: 24.56, 24.90, 39.93, 47.73, 55.29, 96.40, 114.06, 114.92, 118.29, 124.37, 125.52, 126.38, 128.02, 141.57, 150.50, 151.25

RGS-2-15.002.001.1r.esp

39.50 1.0

0.9 39.67

0.8

0.7

0.6

0.5

39.84

39.17

Normalized Intensity Normalized 0.4

0.3

0.2

40.00

39.00

114.92 55.29

114.06

97.40

0.1 47.73

141.57

151.25

126.38 124.37

128.02

125.52 118.29

24.90

150.50 24.56

180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

Label Name: RGS-2-19

Chemical Formula: C21H24ClNO3

Exact Mass: 373.14

Molecular Weight: 373.87

Chiral phosphoric acid, HCPA, (0.05mmol, 17.9 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.05mmol, 30.4 mg) were mixed in anhydrous tetrahydrofuran, THF, at room

74 temperature for one hour. Next, 5-chlorosalicylaldehyde (1.0 mmol, 122.8 mg), p-methoxyaniline (1.2 mmol, 148.7 mg), and 4-methylcyclohexanone (2.5 mmol, 2.5 mL) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, a brown and white solid was observed. Washing this solid with DCM allowed for the accumulation of pure product as white solid (4q, 92%).

1H NMR: (500 MHz, DMSO) 훿: 0.45(q, 1H), 0.79 (d, 2H), 1.03 (d, 3H), 1.53 (q, 3H), 2.07 (q, 2H), 3.65 (s, 3H), 5.04 (dd, 1H), 5.44 (d, 1H), 6.70-6.82 (m, 6H), 7.16 (dd, 1H), 7.38 (s, 1H)

RGS-2-19.001.001.1r.esp

3.65 1.0

0.9

0.8

0.7

0.6

1.02

1.04

0.5

6.72

0.4

0.80

0.78

Normalized Intensity Normalized

6.75

6.81 0.3

6.70 0.2 7.38

1.51

1.54

2.07

5.43

7.15

5.45

7.16 2.04

1.48

0.46 0.43

5.04

5.03

5.05

2.09

5.02

0.1 1.57

0.41

0.48

0 0.99 1.12 6.15 0.99 1.02 3.32 2.21 3.26 3.12 2.37 1.01

8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm)

13C NMR: (500 MHz, DMSO) 훿: 22.10, 25.51, 37.77, 47.32, 55.28, 62.05, 98.48, 113.75, 114.81, 117.93, 123.78, 125.82, 126.41, 127.66, 142.06, 150.96, 151.16

RGS-2-19.002.001.1r.esp

39.50

39.67

39.33

0.8

0.7

0.6

0.5

39.17

39.84

0.4

Normalized Intensity Normalized

0.3

55.26

113.75

25.51 0.2 114.81

22.10

40.00 39.00

98.48

47.32 37.89

142.06

151.16 123.78

117.93

127.66

150.96

126.41 0.1 62.05 37.77

180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

Label Name: RGS-2-21

Chemical Formula: C20H22ClNO5

Exact Mass: 391.12

Molecular Weight: 391.85

Chiral phosphoric acid, HCPA, (0.05mmol, 17.9 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.05mmol, 30.4 mg) were mixed in anhydrous tetrahydrofuran, THF, at room

76 temperature for one hour. Next, 5-chlorosalicylaldehyde (1.0 mmol, 122.8 mg), p-methoxyaniline (1.2 mmol, 148.7 mg), and 2,2-dimethyl-1,3-dioxan-5-one (10.0 mmol, 1.0 mL) were mixed into the solution. After 17 h the reaction was rotovapped and separated using silica (40-63 µm) column chromatography. After accumulation and drying of the pure product, a brown and white solid was observed. Washing this solid with DCM allowed for the accumulation of pure product as white solid (4r, 90%).

2.6.2 High Pressure Liquid Chromatography Data

Label Name: RGS-2-22

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Racemic phosphoric acid, (+/-) HCPA, (0.05mmol, 17.9 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.05mmol, 31.5 mg) were mixed in anhydrous tetrahydrofuran, THF, at room temperature for one hour. Next, 5-chlorosalicylaldehyde (1.0 mmol, 122.8 mg), p-methoxyaniline (1.2 mmol, 148.7 mg), and tetrahydrothiopyran-4-one (2.5 mmol, 303.2 mg) were mixed into the solution. After 8 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 4:1, ee: Racemic)

Label Name: RGS-2-25a

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral phosphoric acid, (R)-HCPA, (0.005mmol, 1.8 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.005mmol, 3.2 mg) were mixed in anhydrous tetrahydrofuran, THF, at room temperature for one hour. Next, 5-chlorosalicylaldehyde (0.1 mmol, 122.8 mg), p-methoxyaniline (0.12 mmol, 14.8 mg), and tetrahydrothiopyran-4-one (0.25 mmol, 29.0 mg) were mixed into the solution. After 8 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 4:1, ee: Racemic)

Label Name: RGS-2-27a

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Yttrium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.05mmol, 31.5 mg) and yttrium

(III) phosphate, YX3, were mixed in anhydrous toluene at room temperature for one hour. Next, 5- chlorosalicylaldehyde (1.0 mmol, 122.8 mg), p-methoxyaniline (1.2 mmol, 148.7 mg), and tetrahydrothiopyran-4-one (0.25 mmol, 29.0 mg) were mixed into the solution. After 20 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 4:1, ee: Racemic)

Label Name: RGS-2-28

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral phosphoric acid, (R)-HCPA, (0.005mmol, 1.8 mg) and yttrium (III) trifluoromethanesulfonate hydroxide, Y (OTf)3, (0.005mmol, 2.7 mg) were mixed in anhydrous tetrahydrofuran, THF, at room temperature for one hour. Next, 5-chlorosalicylaldehyde (0.1 mmol, 15.7 mg), p-methoxyaniline (0.12 mmol, 14.8 mg), and tetrahydrothiopyran-4-one (0.25 mmol, 29.0 mg) were mixed into the solution. After 16 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 4:1, ee: Racemic)

Label Name: RGS-2-29

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral phosphoric acid, (R)-HCPA, (0.005mmol, 1.8 mg) and ytterbium (III) trifluoromethanesulfonate hydroxide, Yb(OTf)3, (0.005mmol, 3.2 mg) were mixed in anhydrous toluene at room temperature for one hour. Next, 5-chlorosalicylaldehyde (0.1 mmol, 15.7 mg), p-methoxyaniline (0.12 mmol, 14.8 mg), and tetrahydrothiopyran-4-one (0.25 mmol, 29.0 mg) were mixed into the solution. After 48 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 4:1, ee: Racemic)

Label Name: RGS-2-30

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral phosphoric acid, (R)-TRIP, (0.0025mmol, 1.9 mg) was dissolved in anhydrous tetrahydrofuran, THF, at room temperature and stirred for one hour. Next, 5-chlorosalicylaldehyde (0.025 mmol, 3.9 mg), p-methoxyaniline (0.030 mmol, 3.7 mg), and tetrahydrothiopyran-4-one (0.0625 mmol, 7.3 mg) were mixed into the solution. After 72 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 3:1, ee: Racemic)

Label Name: RGS-2-32

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral phosphoric acid, (R)-CF3-PA, (0.0025mmol, 1.9 mg) was dissolved in anhydrous tetrahydrofuran, THF, at room temperature and stirred for one hour. Next, 5-chlorosalicylaldehyde (0.025 mmol, 3.9 mg), p-methoxyaniline (0.03 mmol, 3.7 mg), and tetrahydrothiopyran-4-one (0.0625 mmol, 7.3 mg) were mixed into the solution. After 72 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 3:1, ee: 8%)

Label Name: RGS-2-34

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral phosphoric acid, (R)-TRIP, (0.0025mmol, 0.9 mg) and yttrium (III) trifluoromethanesulfonate hydroxide, Y(OTf)3, (0.0025mmol, 0.7 mg) were dissolved in anhydrous tetrahydrofuran, THF, at room temperature and stirred for one hour. Next, 5-chlorosalicylaldehyde (0.025 mmol, 3.9 mg), p-methoxyaniline (0.030 mmol, 3.7 mg), and tetrahydrothiopyran-4-one (0.0625 mmol, 7.3 mg) were mixed into the solution. After 72 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 3:1, ee: 15%)

Label Name: RGS-2-36a

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral phosphoric acid, (R)-TRIP, (0.0025mmol, 1.9 mg) was dissolved in anhydrous methylene chloride, DCM, at room temperature and stirred for one hour. Next, 5-chlorosalicylaldehyde (0.025 mmol, 3.9 mg), p-methoxyaniline (0.030 mmol, 3.7 mg), and tetrahydrothiopyran-4-one (0.0625 mmol, 7.3 mg) were mixed into the solution. After 84 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 4:1, ee: Racemic)

Label Name: RGS-2-37

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral Ligand 1, L1, (0.005mmol, 1.0 mg) and Yttrium (III) trifluoromethanesulfonate hydroxide,

Y(OTf)3, (0.005mmol, 2.7 mg) were dissolved in anhydrous Toluene at room temperature and stirred for one hour. Next, 5-chlorosalicylaldehyde (0.1 mmol, 15.6 mg), p-methoxyaniline (0.12 mmol, 14.8 mg), and tetrahydrothiopyran-4-one (0.25 mmol, 29.0 mg) were mixed into the solution. After 48 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 4:1, ee: Racemic)

Label Name: RGS-2-38a

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral phosphoric acid, (R)-TRIP, (0.0025mmol, 0.9 mg) and yttrium (III) trifluoromethanesulfonate hydroxide, Y(OTf)3, (0.0025mmol, 0.7 mg) were dissolved in anhydrous toluene at room temperature and stirred for one hour. Next, 5-chlorosalicylaldehyde (0.025 mmol, 3.9 mg), p- methoxyaniline (0.030 mmol, 3.7 mg), and tetrahydrothiopyran-4-one (0.0625 mmol, 7.3 mg) were mixed into the solution. After 72 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 3:1, ee: 8%)

Label Name: RGS-2-38b

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral phosphoric acid, (R)-TRIP, (0.0025mmol, 0.9 mg) and yttrium (III) trifluoromethanesulfonate hydroxide, Y(OTf)3, (0.0025mmol, 0.7 mg) were dissolved in anhydrous methylene dichloride, DCM, at room temperature and stirred for one hour. Next, 5-chlorosalicylaldehyde (0.025 mmol, 3.9 mg), p-methoxyaniline (0.030 mmol, 3.7 mg), and tetrahydrothiopyran-4-one (0.0625 mmol, 7.3 mg) were mixed into the solution. After 72 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 4:1, ee: Racemic)

Label Name: RGS-2-39

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Label Name: RGS-2-41

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral phosphoric acid, (R)-TRIP, (0.0025mmol, 0.9 mg) and yttrium (III) trifluoromethanesulfonate hydroxide, Y(OTf)3, (0.0025mmol, 0.7 mg) were dissolved in anhydrous diethyl ether, Et2O, at room temperature and stirred for one hour. Next, 5-chlorosalicylaldehyde (0.025 mmol, 3.9 mg), p-methoxyaniline (0.030 mmol, 3.7 mg), and tetrahydrothiopyran-4-one (0.0625 mmol, 7.3 mg) were mixed into the solution. After 48 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 4:1, ee: 6%)

Label Name: RGS-2-42

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral phosphoric acid, (R)-TRIP, (0.0025mmol, 0.9 mg) and yttrium (III) trifluoromethanesulfonate hydroxide, Y(OTf)3, (0.0025mmol, 0.7 mg) were dissolved in anhydrous ethyl acetate, EA, at room temperature and stirred for one hour. Next, 5-chlorosalicylaldehyde (0.025 mmol, 3.9 mg), p-methoxyaniline (0.030 mmol, 3.7 mg), and tetrahydrothiopyran-4-one (0.0625 mmol, 7.3 mg) were mixed into the solution. After 72 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 4:1, ee: Racemic)

Label Name: RGS-2-43

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral phosphoric acid, (R)-TRIP, (0.0025mmol, 0.9 mg) and yttrium (III) trifluoromethanesulfonate hydroxide, Y(OTf)3, (0.0025mmol, 0.7 mg) were dissolved in anhydrous methanol, MeOH, at room temperature and stirred for one hour. Next, 5-chlorosalicylaldehyde (0.025 mmol, 3.9 mg), p-methoxyaniline (0.030 mmol, 3.7 mg), and tetrahydrothiopyran-4-one (0.0625 mmol, 7.3 mg) were mixed into the solution. After 84 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 4:1, ee: Racemic)

Label Name: RGS-2-45

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral phosphoric acid, (R)-TRIP, (0.0025mmol, 0.9 mg) and yttrium (III) trifluoromethanesulfonate hydroxide, Y(OTf)3, (0.0025mmol, 0.7 mg) were dissolved in anhydrous acetonitrile, at room temperature and stirred for one hour. Next, 5-chlorosalicylaldehyde (0.025 mmol, 3.9 mg), p-methoxyaniline (0.030 mmol, 3.7 mg), and tetrahydrothiopyran-4-one (0.0625 mmol, 7.3 mg) were mixed into the solution. After 84 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 4:1, ee: Racemic)

Label Name: RGS-2-47

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Yttrium (III) trifluoromethanesulfonate hydroxide, Y(OTf)3, (0.005 mmol, 2.7 mg), 5- chlorosalicylaldehyde (0.1 mmol, 15.6 mg), and p-methoxyaniline (0.1 mmol, 12.3 mg), were dissolved in anhydrous methylene chloride, DCM, at room temperature and stirred for two hours. Next, (R)-(+)-1,1’- binaphthyl-2,2’-diamine, and tetrahydrothiopyran-4-one (0.25 mmol, 29.0 mg) were mixed into the solution and stirred for 24 h. Finally racemic phosphoric acid, (+/-)-HCPA, (0.005 mmol, 1.8 mg) was added to complete transformation. After 48 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 5:1, ee: 10%)

Label Name: RGS-2-49

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Yttrium (III) trifluoromethanesulfonate hydroxide, Y(OTf)3, (0.005 mmol, 2.7 mg), 5- chlorosalicylaldehyde (0.1 mmol, 15.6 mg), and p-methoxyaniline (0.1 mmol, 12.3 mg), were dissolved in anhydrous methylene chloride, DCM, at room temperature and stirred for two hours. Next, (R)-(+)-1,1’- binaphthyl-2,2’-diamine, and tetrahydrothiopyran-4-one (0.25 mmol, 29.0 mg) were mixed into the solution and stirred for 24 h. Finally chiral phosphoric acid, (R)-HCPA, (0.005 mmol, 1.8 mg) was added to complete transformation. After 48 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 5:1, ee: 14%)

Label Name: RGS-2-50

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Yttrium (III) trifluoromethanesulfonate hydroxide, Y(OTf)3, (0.005 mmol, 2.7 mg), 5- chlorosalicylaldehyde (0.1 mmol, 15.6 mg), and p-methoxyaniline (0.1 mmol, 12.3 mg), were dissolved in anhydrous methylene chloride, DCM, at room temperature and stirred for two hours. Next, (R)-(+)-1,1’- Binaphthyl-2,2’-diamine, and tetrahydrothiopyran-4-one (0.25 mmol, 29.0 mg) were mixed into the solution and stirred for 24 h. Finally chiral phosphoric acid, (S)-HCPA, (0.005 mmol, 1.8 mg) was added to complete transformation. After 48 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 8:1, ee: 42%)

Label Name: RGS-2-51

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Yttrium (III) trifluoromethanesulfonate hydroxide, Y(OTf)3, (0.00125 mmol, 0.7 mg), 5- chlorosalicylaldehyde (0.025 mmol, 3.8 mg), and p-methoxyaniline (0.025 mmol, 3.1 mg), were dissolved in anhydrous methylene chloride, DCM, at room temperature and stirred for two hours. Next, (R)-(+)-1,1’- binaphthyl-2,2’-diamine, and tetrahydrothiopyran-4-one (0.0625 mmol, 7.3 mg) were mixed into the solution and stirred for 24 h. Finally chiral phosphoric acid, (R)-TRIP, (0.00125 mmol, 0.9 mg) was added to complete transformation. After 48 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 5:1, ee: 3%)

Label Name: RGS-2-54

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Yttrium (III) trifluoromethanesulfonate hydroxide, Y(OTf)3, (0.005 mmol, 2.7 mg), 5- chlorosalicylaldehyde (0.1 mmol, 15.6 mg), and p-methoxyaniline (0.1 mmol, 12.3 mg), were dissolved in anhydrous methylene chloride, DCM, at room temperature and stirred for two hours. Next, (R)-(+)-1,1’- binaphthyl-2,2’-diamine, and tetrahydrothiopyran-4-one (0.25 mmol, 29.0 mg) were mixed into the solution and stirred for 24 h. Finally chiral phosphoric acid, (S)-HCPA, (0.005 mmol, 1.8 mg) was added to complete transformation. After 48 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 5:1, ee: 28%)

Label Name: RGS-2-55

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Yttrium (III) trifluoromethanesulfonate hydroxide, Y(OTf)3, (0.005 mmol, 2.7 mg), (R)-(+)-1,1’- binaphthyl-2,2’-diamine, and chiral phosphoric acid, (S)-HCPA, (0.005 mmol, 1.8 mg) were dissolved in anhydrous methylene dichloride, DCM, at room temperature and stirred for two hours. Next, 5- chlorosalicylaldehyde (0.1 mmol, 15.6 mg), p-methoxyaniline (0.1 mmol, 12.3 mg), and tetrahydrothiopyran-4-one (0.25 mmol, 29.0 mg) were mixed into the solution. After 6 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 6:1, ee: 35%)

100

Label Name: RGS-2-56

Chemical Formula: C19H20ClNO3S

Exact Mass: 377.09

Molecular Weight: 377.88

Chiral diamine, (R)-(+)-1,1’-Binaphthyl-2,2’-diamine, and chiral phosphoric acid, (S)-HCPA, (0.005 mmol, 1.8 mg) were dissolved in anhydrous methylene dichloride, DCM, at room temperature and stirred for two hours. Next, 5-chlorosalicylaldehyde (0.1 mmol, 15.6 mg), p-methoxyaniline (0.1 mmol, 12.3 mg), and tetrahydrothiopyran-4-one (0.25 mmol, 29.0 mg) were mixed into the solution. After 24 h the reaction was separated using silica (40-63 µm) thin layer chromatography (TLC) plates. After the pure product was accumulated, it was dissolved in pure HPLC grade 2-propanol and injected into the HPLC. (dr: 6:1, ee: 46%)

101

Chapter 3: Conclusion

The studies in this thesis show that a multicomponent cascade can be catalyzed by two of the pillars of asymmetric catalysis. This allows for a reaction to have a wide scope and allow for maximization the complexity of the product. Catalyzing these MCRs with asymmetric catalysis is novel way to introduce stereocontrol into highly complexed molecules with varying functional groups. Asymmetric catalysis is considered the most efficient method for constructing highly functionalized optically active stereopure compounds. There are two pillars of asymmetric catalysis that are utilized in this reaction: transition metal catalysis, and organocatalysis.

The studies in the thesis have proven that arylamines be used as an effective way to promote organocatalyzed emamine formation. The arylamines can either be an reagent in slight excess or catalytic amounts of chiral arylamine additive, such as (R)-(+)-1,1’-binaphthyl-2,2’-diamine. These arylamine could work cooperatively with Bronsted acids (BINOL derived phosphoric acids), and transition metal Lewis acid catalysts (ytterbium (III) trifluoromethanesulfonate hydroxide and yttrium (III) trifluoromethanesulfonate hydroxide).

Utilizing this cooperative catalytic system for this Mannich-Type reaction allowed the observation of high yielding reactions for a wide range of reagents. The complexity of combining MCRs with cooperative asymmetric catalysis has proven to be difficult in controlling stereochemistry. There are numerous factors that play roles in the strereochemistry of the transformation of this three-component, cooperatively catalyzed reaction. While it was shown in Chapter 2, slight strereoselective can be observed through the use of chiral arylamines. More research needs to be conducted on this MCR with the (S)-(-)- 1,1’-binaphthyl-2,2’-diamine along with the (R)-BINOL derived phosphoric acids to further explore its stereoselctivity.

102