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.

An unexpected tricyclic ether formation instead of acetate addition to the double bond of a norbornene derivative aroused our interest to explore the mechanism of this reaction. Mechanistic studies showed that methylene diacetate (MDA) was formed in the stock solution (NBu4OAc + dichloromethane) and decomposed to formaldehyde under Lewis or Br&oslash / nsted acid conditions. Formaldehyde and olefin condensation (Prins reaction) clearly explains the formation of the unexpected product. Same methodology was then successfully applied to develop a one-step procedure for the synthesis of 3-chloro-3-arylpropanols, which are important starting materials for the synthesis of biologically active benzanilide derivatives. Styrenes were reacted with MDA in the presence of boron trifluoride to give the corresponding 3-chloro-3-arylpropanols in 36&amp / #8211 / 84% yield. The second part of the thesis involves kinetic resolution of 3-chloro-3-arylpropanols by lipase mediated acylation which are described for the first time. Acylation with the CCL provided the best enantioselectivity amongst the enzymes used. Enantiomerically enriched products with up to 78% ee were obtained after two successive lipase-mediated acylations. Different substituents on the aromatic ring and bromide, instead of chloride, at the benzylic position of the substrates were found to have no drastic influence on the enantioselectivity of the reaction. In the last part, easily available ferrocenyl substituted aziridinylmethanols (FAM) were complexed with nickel to catalyze the enantioselective diethylzinc addition to various enones with ee&amp / #8217 / s reaching 82%. The ligands can be recovered and used without losing their activity. The sense of asymmetric induction was found to be dependent on the configuration of the aziridine ring.

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.

<p>This thesis deals with the design and synthesis of chiralenantiopure nitrogencontaining ligands and the use of theseligands in asymmetric catalysis. A modular synthetic approachto enantiopure nitrogen-containing ligands was developed. Thesynthetic method is based on the ring-opening of activatedchiral aziridines by nitrogen nucleophiles. The aziridines areconveniently prepared from amino alcohols. The structure oftheaziridine and of the nucleophile can be extensively varied andlibraries of ligands are easily prepared. The use of primaryamines affords C₂-symmetric bis(sulfonamides), whereas the use ofammonia affords C₃-symmetric tris(sulfonamides) that can beelaborated into the corresponding tetra-amines.</p><p>The C₂- and C₃-symmetric ligands were used in the asymmetrictitaniummediated addition of diethylzinc to benzaldehyderesulting in modest enantioselection, 76% ee. A thoroughinvestigation of the reaction conditions revealed that theamount of Ti(OiPr)₄has a decisive effect on the reaction rate and thestereochemical outcome of the reaction. The reaction timedecreased from about 90 hours to 15 minutes and theenantioselectivity changed from 26% of the (R)- enantiomer to72% of the (S)-enantiomer when the Ti(OiPr)₄:benzaldehyde ratio was increased from 0.125:1 to1.48:1. Moreover, the titanium-mediated addition of diethylzincto benzaldehyde was studied in the presence of chiraladditives. The bis(sulfonamides) were also used in thecyclopropanation of cinnamyl alcohol. However, only lowenantioselection was observed, 27% ee.</p><p>The C₃-symmetric tetra-amines were reacted to formazaphosphatranes. These weak acids were only partiallydeprotonated by the strong base KOtBu to form the correspondingproazaphosphatranes. The unexpectedly strong basicity of theproazaphosphatranes was believed to be due to steric effects assuggested by DFT calculations. The tetra-amines and thesulfonamides were used for the preparation of metal complexesof Lewis acidic metals such as titanium(IV) andzirconium(IV).</p><p><b>Keywords:</b>asymmetric catalysis, aziridine, benzaldehyde,diethylzinc, enantioselective, ligand, proazaphosphatrane,ring-opening, sulfonamide, symmetry, titanium, zirconium</p>

<p>This thesis deals with the preparation and use of chiralbispyridylamides as ligands in metal-catalyzed asymmetricreactions.</p><p>The compounds were prepared by amide formation usingdifferent coupling reagents. Bispyridylamides havingsubstituents in the 4- or 6- positions of the pyridine ringswere prepared by functional group interconversion of the 4- or6- halopyridine derivatives. These synthetic approaches provedto be useful for various types of chiral backbones. Pseudo C₂-symmetric bispyridylamides were also synthesizedby means of stepwise amide formation.</p><p>The compounds were used as ligands in themicrowave-accelerated Mocatalyzed asymmetric allylic alkylationreaction. Ligands having ð-donating substituents in the4-positions of the pyridine rings gave rise to products withhigher branched to linear ratio. The catalytic reaction, whichproved to be rather general for allylic carbonates with anaromatic substituent, was used as the key step in thepreparation of (R)-baclofen. The Mo-bispyridylamide catalystprecursor was studied by NMR spectroscopy.</p><p>Bispyridylamide complexes of metal alkoxides were alsoevaluated in the asymmetric addition of cyanide to aldehydesand the metal complexes involved were studied by NMRspectroscopy and X-ray crystallography. Chiral diamines wereused as additives to study the ring opening of cyclohexeneoxide with azide, catalyzed by Zr(IV)-bispyridylamidecomplexes.</p><p>Various bispyridylamides were attached to solid supports oforganic or inorganic nature. The solid-supported ligands wereused in Mo-catalyzed asymmetric allylic alkylation reactionsand in the asymmetric addition of cyanide to benzaldehyde.</p><p><b>Keywords:</b>asymmetric catalysis, chiral ligand, pyridine,amide, allylic alkylation, enantioselective, cyanation,ring-opening, chiral Lewis acid.</p>

The development of novel asymmetric reaction methodologies has been invaluable in both the academic and industrial world. In just 15 years, organocatalysis has provided a new means of developing asymmetric reaction methodologies using catalysts that are environmentally benign, relatively inexpensive, bench stable, and non-toxic. One development in organocatalysis that is important to our group in particular is chiral phosphoric acid-catalysis. BINOL-derived and VAPOL-derived phosphoric acids have proven to be excellent catalysts for a number of reactions. The two projects I will discuss my efforts on are acetalization and iso-Pictet-Spengler reactions. These were projects that I performed during my first two years as a graduate student. The acetalization was particularly fascinating as only one literature report existed for the catalytic asymmetric variant of a reaction that makes such important compounds--O,O-acetals. The acetalization reaction proved to be a formidable opponent, and to this date no research report has been published documenting the intra-, or intermolecular catalytic asymmetric acetalization of vinyl ethers or the intermolecular catalytic asymmetric transacetalization. The iso-Pictet-Spengler reaction is one that is interesting because exhaustive research has been conducted into the development of catalytic asymmetric Pictet-Spengler reactions, but at the time of my research, not a single catalytic asymmetric method existed to synthesize tetrahydro-γ-carbolines, the product of the iso-Pictet-Spengler reaction. Structurally, the tetrahydro-γ-carboline is isomeric to the tetrahydro-β-carboline, the product of the Pictet-Spengler reaction. They differ only in the position of nitrogen in the annulated product. This reaction seemed attractive to investigate, since independent elegant reports by Professors Benjamin List, Henk Hiemstra, and Darren Dixon documented the excellent control over enantioselectivity that chiral phosphoric acid have in the Pictet-Spengler reaction. Concurrent with the beginning stages of this project, Professor Eric Jacobsen reported the enantioselective thiourea-catalyzed iso-Pictet-Spengler reaction. The results were very good but not as great as the Pictet-Spengler work he pioneered. Around the time this report came out I commenced my reaction studies, and this thesis is the sum of just two projects I worked on. There were many more including halolactonization, VAPOL synthesis, chiral phosphoric acid synthesis, catalytic asymmetric hydroamination, and others.

The cation&ndash;&pi; interaction has been long-established to play an important role in molecular recognition, supramolecular chemistry, and molecular biology. In contrast, its potential application in small-molecule catalysis, especially as a selectivity-determining factor in asymmetric synthesis has been overlooked until very recently. This dissertation begins with an extensive literature review on the state-of-the-art research on the application of cation&ndash;&pi; interactions in non-enzymatic catalysis of organic and organometallic transformations. The research in this field has been largely inspired and guided by the related biosynthetic systems incorporating the same type of interactions.</p> / Chemistry and Chemical Biology

In asymmetric catalysis, interactions between multiple molecules of catalyst can be important for achieving high catalyst activity and stereoselectivity. In Chapter 1 of this thesis, we introduce catalyst-catalyst interactions in the context of the classic Kagan nonlinear effect (NLE) experiment, and present examples of the strengths and drawbacks of the NLE experiment. For the remainder of the thesis, we explore catalyst-catalyst interactions in the context of two different reactions. First, in Chapter 2, we apply a combination of reaction kinetics and computational chemistry to a reaction that is well known to require the cooperative action of two molecules of catalyst: the (salen)Co(III)-catalyzed hydrolytic kinetic resolution (HKR) of terminal epoxides. In our investigation, we demonstrate that stereoselectivity in the HKR is achieved through catalyst-catalyst interactions and provide a model for how high selectivity and broad substrate scope are achieved in this reaction. In Chapter 3, we focus our attention on the thiourea-catalyzed enantioselective alkylation of alpha-chloroethers with silyl ketene acetal nucleophiles, a reaction that was not known to require the cooperative action of two molecules of catalyst at the outset of our investigation. By using a wide range of physical organic chemistry tools, we established that the resting state of the optimal thiourea catalyst is dimeric under typical reaction conditions, and that two molecules of catalyst work cooperatively to activate the alpha-chloroether electrophile. The implications of this mechanism for catalyst design are discussed. / Chemistry and Chemical Biology

This thesis is focused on two main areas of organic synthesis, palladium-catalyzed functionalization of alkenes and allylic alcohols, as well as development of new allylboration reactions. We have developed a palladium-catalyzed selective allylic trifluoroacetoxylation reaction based on C−H functionalization. Allylic trifluoroacetates were synthesized from functionalized olefins under oxidative conditions. The reactions proceed under mild conditions with a high level of diastereoselectivity. Mechanistic studies of the allylic C−H trifluoroacetoxylation indicate that the reaction proceeds via (η3-allyl)palladium(IV) intermediate. Palladium-catalyzed regio- and stereoselective synthesis of allylboronic acids from allylic alcohols has been demonstrated. Diboronic acid B2(OH)4 was used as the boron source in this process. The reactivity of the allylboronic acids were studied in three types of allylboration reactions: allylboration of ketones, imines and acyl hydrazones. All three processes are conducted under mild conditions without any additives. The reactions proceeded with remarkably high regio- and stereoselectivity. An asymmetric version of the allylboration of ketones was also developed. In this process chiral BINOL derivatives were used as catalysts. The reaction using γ-disubstituted allylboronic acids and various aromatic and aliphatic ketones afforded homoallylic alcohols bearing two adjacent quaternary stereocenters with excellent regio-, diastereo- and enantioselectivity (up to 97:3 er) in high yield. The stereoselectivity in the allylboration reactions could be rationalized on the basis of the Zimmerman-Traxler TS model.