The Diels-Alder reaction is one of the most powerful synthetic tools in organic chemistry, and asymmetric Diels-Alder catalysis allows for rapid construction of chiral carbon scaffolds. For this reason, considerable effort has been invested in developing efficient and stereoselective organo- and biocatalysts. However, Diels-Alder is a virtually unknown reaction in Nature, and to engineer an enzyme into a Diels-Alderase is therefore a challenging task. Despite several successful designs of catalytic antibodies since the 1980’s, their catalytic activities have remained low, and no true artificial ’Diels-Alderase’ enzyme was reported before 2010. In this thesis, we employ state-of-the-art computational tools to study the mechanism of organocatalyzed Diels-Alder in detail, and to redesign existing enzymes into intermolecular Diels-Alder catalysts. Papers I–IV explore the mechanistic variations when employing increasingly activated reactants and the effect of catalysis. In particular, the relation between the traditionally presumed concerted mechanism and a stepwise pathway, forming one bond at a time, is probed. Papers V–X deal with enzyme design and the computational aspects of predicting catalytic activity. Four novel, computationally designed Diels-Alderase candidates are presented in Papers VI–IX. In Paper X, a new parameterization of the Linear Interaction Energy model for predicting protein-ligand affinities is presented. A general finding in this thesis is that it is difficult to attain large transition state stabilization effects solely by hydrogen bond catalysis. In addition, water (the preferred solvent of enzymes) is well-known for catalyzing Diels- Alder by itself. Therefore, an efficient Diels-Alderase must rely on large binding affinities for the two substrates and preferential binding conformations close to the transition state geometry. In Papers VI–VIII, we co-designed the enzyme active site and substrates in order to achieve the best possible complementarity and maximize binding affinity and pre-organization. Even so, catalysis is limited by the maximum possible stabilization offered by hydrogen bonds, and by the inherently large energy barrier associated with the [4+2] cycloaddition. The stepwise Diels-Alder pathway, proceeding via a zwitterionic intermediate, may offer a productive alternative for enzyme catalysis, since an enzyme active site may be more differentiated towards stabilizing the high-energy states than for the standard mechanism. In Papers I and III, it is demonstrated that a hydrogen bond donor catalyst provides more stabilization of transition states having pronounced charge-transfer character, which shifts the preference towards a stepwise mechanism. Another alternative, explored in Paper IX, is to use an α,β -unsaturated ketone as a ’pro-diene’, and let the enzyme generate the diene in situ by general acid/base catalysis. The results show that the potential reduction in the reaction barrier with such a mechanism is much larger than for conventional Diels-Alder. Moreover, an acid/base-mediated pathway is a better mimic of how natural enzymes function, since remarkably few catalyze their reactions solely by non-covalent interactions. / <p>QC 20120903</p>

Part 1: Transition-metal-catalyzed direct transformations of aromatic C-H bonds are emerging as valuable tools in organic synthesis. These reactions are attractive because of they allow for inherently efficient construction of organic building blocks by minimizing the pre-activation of substrates. Of these processes, direct arylation has recently received much attention due to the importance of the biaryl core in medicinal and materials chemistry. Also, alkyne hydroarylation has garnered interest because it allows for the atom-economical synthesis of functionalized alkenes directly from simple arenes and alkynes. Described in this thesis are number of advancements in these areas. First, palladium catalyzed direct arylation of azine N-oxides using synthetically important aryl triflates is described. Interesting reactivity of aryl triflates compared to aryl bromides was uncovered and exploited in the synthesis of a compound that exhibits antimalarial and antimicrobial activity. Also reported is the efficient, direct arylation enabled (formal) synthesis of six thiophene based organic electronic materials in high yields using simple starting materials. Additionally, the site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner and is applied to the synthesis of the natural products, Papaverine and Crykonisine. Mechanistic investigations point towards the intimate involvement of the base in the mechanism of these reactions. Next, the rhodium(III)-catalyzed hydroarylation of internal alkynes is described. Good yields are obtained for a variety of alkynes and arenes with excellent regioselectivity for unsymmetrically substituted alkynes. Mechanistic investigations suggest that this reaction proceeds through arene metalation with the cationic rhodium catalyst, which enables challenging intermolecular reactivity. Part 2: Access to single enantiomer compounds is a fundamental goal in organic chemistry and despite remarkable advances in enantioselective synthesis, their preparation remains a challenge. Kinetic resolution of racemic products is an important method to access enantioenriched compounds, especially when alternative methods are scarce. Described in this thesis is the resolution of tertiary and secondary alcohols, which arise from ketone and aldehyde aldol additions. The method is technically simple, easily scalable, and provides tertiary and secondary alcohols in high enantiomeric ratios. A rationale for the unique reactivity/selectivity associated with (1S,2R)-N-methylephedrine in the resolution is proposed. Organocatalysis is a rapidly developing, powerful field for the construction of enantioenriched organic molecules. Described here is a complimentary class of organocatalysis using simple aldehydes as temporary tethers to perform challenging formally intermolecular reactions at room temperature. This strategy allows for the enantioselective, intermolecular cope-type hydroamination of allylic amines with hydroxyl amines. Also, interesting catalytic reactivity for dichloromethane is revealed.

The last decade has been marked by a large increase of demand for green chemistry processes. Consequently, chemists have focused their efforts on the development of more direct routes toward different classes of targets. In that regard catalysis has played a crucial role at enabling key bond formations that were otherwise inaccessible or very energy and resources consuming. The central theme of this body of work concerns the formation of C–N bonds, either through transition metal catalysis or organocatalysis. These structural units being highly recurrent in biologically active molecules, the establishment of more efficient routes for their construction is indispensable. The first part of this thesis describes a new method for the synthesis of isoquinolines from the oxidative coupling/annulation of alkynes with N-tert-butyl benzaldimines via Rh(III) catalysis (Chapter 2). Preliminary mechanistic investigations of this system pointed to the involvement of Rh(III) in the C–H bond cleavage step as well as in the C–N bond reductive elimination that provides the desired heterocycle. Following this oxidative process, a Rh(III)-catalyzed redox-neutral approach to isoquinolones from the reaction of benzhydroxamic acids with alkynes is presented (Chapter 3). The discovery that an N–O bond contained in the substrate can act as an internal oxidant was found to be very enabling. Indeed, it allowed for milder reaction conditions, broader scope (terminal alkyne and alkene compatible) and low catalyst loadings (0.5 mol%). Mechanistic investigations on this system were also conducted to identify the nature of the C–N bond formation/N–O bond cleavage as well as the rate-determining step. The second part of this work presents mechanistic investigations performed on a recently developed intermolecular hydroamination reaction catalyzed through tethering organocatalysis (Chapter 4). This transformation operates via the reversible covalent attachment of two reactants, a hydroxylamine and an allylamine, to an aldehyde catalyst by the formation of a mixed aminal. This allows a difficult intermolecular Cope-type hydroamination to be performed intramolecularly. The main kinetic parameters associated with this reaction were determined and they allowed the generation of a more accurate catalytic cycle for this transformation. Attempts at developing new families of organocatalysts are also discussed.

Addition reactions of nucleophilic trifluoromethyltrimethylsilane (CF3TMS) to acyl phosphonates were investigated. Various acyl phosphonates reacted readily with CF3TMS in the presence of K2CO3 to give 1-alkyl-2,2,2-trifluoro-1-trimethylsilyloxyethylphosphonate in 70-90% yields. When benzoyl phosphonates were used as starting material, after addition of CF3, the formed alcoholate undergoes phosphonatephosphate rearrangement to form the acyl anion, followed by elimination of F- to give 1-aryldifluoroethenyl phosphates in 87-97% yields. The proline&ndash / thiourea host&ndash / guest complex catalyzed intermolecular aldol reaction of aromatic aldehydes with cyclohexanone is developed. The anti-configured products were obtained in high yields and exclusively excellent nantioselectivities. The reaction is proposed to proceed according to a modified Houk&ndash / List model, in which the carboxylate moiety of the proline forms an assembly with the thiourea. These results clearly demonstrate the enormous effect of the thiourea on the reactivity and selectivity, even in an unconventional non-polar reaction medium, without the need to use low temperatures. A proline&ndash / thiourea host&ndash / guest complex is described as a good catalyst for the enantioselective nitro-Michael addition of aldehydes to nitroalkenes. The reaction is efficient with 5% of the thiourea, to give moderate to good enantioselectivity (up to 76% ee). High syn-selectivity was obtained with both branched and unbranched aliphatic aldehydes. This is the first example of self-assembly of organocatalysts with an achiral additive in a Michael addition wherein aldehydes are utilized as donors. An aldol reaction catalyzed by a proline&ndash / thiourea host&ndash / guest complex in a nonpolar solvent shows excellent nonlinear effects. This proline&ndash / thiourea system has the ability to form a hydrogen-bonding network. The enantiomeric excess of proline in a solution can be significantly enhanced by its incorporation with a urea molecule into its solid racemate. This suggests a general and facile route to homochirality, which may be involved in the origin of chirality on earth.

Part 1: Transition-metal-catalyzed direct transformations of aromatic C-H bonds are emerging as valuable tools in organic synthesis. These reactions are attractive because of they allow for inherently efficient construction of organic building blocks by minimizing the pre-activation of substrates. Of these processes, direct arylation has recently received much attention due to the importance of the biaryl core in medicinal and materials chemistry. Also, alkyne hydroarylation has garnered interest because it allows for the atom-economical synthesis of functionalized alkenes directly from simple arenes and alkynes. Described in this thesis are number of advancements in these areas. First, palladium catalyzed direct arylation of azine N-oxides using synthetically important aryl triflates is described. Interesting reactivity of aryl triflates compared to aryl bromides was uncovered and exploited in the synthesis of a compound that exhibits antimalarial and antimicrobial activity. Also reported is the efficient, direct arylation enabled (formal) synthesis of six thiophene based organic electronic materials in high yields using simple starting materials. Additionally, the site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner and is applied to the synthesis of the natural products, Papaverine and Crykonisine. Mechanistic investigations point towards the intimate involvement of the base in the mechanism of these reactions. Next, the rhodium(III)-catalyzed hydroarylation of internal alkynes is described. Good yields are obtained for a variety of alkynes and arenes with excellent regioselectivity for unsymmetrically substituted alkynes. Mechanistic investigations suggest that this reaction proceeds through arene metalation with the cationic rhodium catalyst, which enables challenging intermolecular reactivity. Part 2: Access to single enantiomer compounds is a fundamental goal in organic chemistry and despite remarkable advances in enantioselective synthesis, their preparation remains a challenge. Kinetic resolution of racemic products is an important method to access enantioenriched compounds, especially when alternative methods are scarce. Described in this thesis is the resolution of tertiary and secondary alcohols, which arise from ketone and aldehyde aldol additions. The method is technically simple, easily scalable, and provides tertiary and secondary alcohols in high enantiomeric ratios. A rationale for the unique reactivity/selectivity associated with (1S,2R)-N-methylephedrine in the resolution is proposed. Organocatalysis is a rapidly developing, powerful field for the construction of enantioenriched organic molecules. Described here is a complimentary class of organocatalysis using simple aldehydes as temporary tethers to perform challenging formally intermolecular reactions at room temperature. This strategy allows for the enantioselective, intermolecular cope-type hydroamination of allylic amines with hydroxyl amines. Also, interesting catalytic reactivity for dichloromethane is revealed.

<p>Carbon–carbon bond-forming reactions comprise the most important class of synthetic transformations. The development of improved and simplified approaches to these reactions will make important and useful contributions not only to the field of synthetic organic chemistry, but also to the many other areas of science that rely on it. Enolate based carbon–carbon bond formation is fundamental to synthetic organic chemistry and has provided the foundation for advancement to its present state. Herein, an important aspect of enolate chemistry is explored: the development of direct methods for carbon–carbon bond formation based on soft enolization of thioesters. Both metal-mediated and organocatalytic approaches to soft enolization are described.</p><p>MgBr₂·OEt₂-promoted soft enolization conditions were developed and successfully applied to the aldol addition and Mannich reactions, resulting in a mild and efficient direct reaction that is inexpensive and can be used under atmospheric conditions. A conjugate addition approach to chemoselective deprotonation was also explored and applied to the aldol. In addition, the first organocatalytic Mannich reaction based on proximity-accelerated intramolecular soft enolization of thioesters was developed. Given the advantages of soft enolization, including the inherent operational simplicity, and the accessibility of thioesters, we expect these methods to meet with wide application.</p> / Dissertation

The thiourea derivatives have become a main focus of research in asymmetric synthesis as an organocatalyst in recent years. In the first part, the thiourea catalysts are synthesized starting from easily available L-tartaric acid and application of the catalysts to some addition reactions showed no significant asymmetric induction. A number of HDAC inhibitors have been developed as anti-cancer agent at the present time.In the second part, some aryl butenoic acid derivatives are synthesized as HDAC inhibitors starting from substituted benzaldehyde and pyruvic acid. The HDAC activity studies showed comparable results with known molecules. In the last part, some acyl phosphonates are synthesized and addition of ethylcyanoformate to acyl phosphonates furnished the products in good yields.

Acyl phosphonates are interesting precursors for the synthesis of biologically active compounds. In the first part, the acyl phosphonates are synthesized starting from the corresponding acyl chloride. The acyl chlorides are converted into acyl phosphonates by using trialkylphosphites. The reaction of acyl phosphonates with aldehydes in the presence of proline furnished not the suggested aldol products via proline catalyzed aldol reaction but bicyclic products via one pot tricomponent 1,3-dipolar cycloaddition reaction. The formation of the bicyclic compound was suggested as followed / The formation of iminium salt of proline with aldehyde followed by decarboxylation furnished azomethine. The 1,3-dipolar cycloaddition of the formed azomethine with carbonyl group of acyl phosphonate afforded substituted hexahydro pyrrolo oxazole structures. 1,3-Dipolar cycloaddition forms the basis of the most preparatively useful procedures for the synthesis of five-membered heterocycles. One example is the 1,3-dipolar cycloaddition of azomethine ylides (from imines) and alkenes, which allows the stereoselective synthesis of pyrrolidines or proline derivatives.

A new class of pyridine and sulfur containing chiral compounds are synthesized. Camphor sulfonyl chloride is chosen as a valuable chiral starting compound. In our synthetic strategy, sulfonylchloride moiety is first reduced to corresponding thiol compound by using triphenylphosphine and then the resultant thiol will be converted to various alkyl, aryl substituted derivatives. The second part of our strategy includes the pyridine ring construction on the carbonyl side of camphor with the formation of &beta / -hydroxymethylene moiety followed by further reaction with various enamines. The resultant chiral ligands are characterized and used as a chiral ligand in asymmetric transfer of hydrogenation. Also novel class of organocatalysts synthesized from C2-symmetrical chiral diamine backbones and halopyridine derivatives are also synthesized and tested for their performance in kinetic resolution of racemic secondary alcohols. Also, a base mediated aromatization reaction is investigated in terms of both scope and mechanism.

Synthesis and evaluation of catalytic performances of novel bifunctional 2- aminoDMAP-Thiourea/ Sulfonamide/ Squaramide organocatalysts derived from trans-(R,R)-cyclohexane-1,2-diamine forms the main goal of this thesis. For this purpose, direct selective mono-N-pyridilization of trans-(R,R)-cyclohexane-1,2- diamine via Pd and Cu catalysis is described successfully first. Facile preparation of chiral 2-aminoDMAP core catalaphore led to the development of various 2- aminoDMAP- Thiourea/ Sulfonamides/ Squaramides as bifunctional acid/base organocatalyst libraries (most in two-steps overall) which showed good results in asymmetric conjugate addition of 1,3-dicarbonyls to trans-(&beta / )-nitrostyrene. Enantiomeric excesses (ee) up to 93% were attained.