This thesis deals with the preparation and use of chiralbispyridylamides as ligands in metal-catalyzed asymmetricreactions. 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. 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. 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. 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. Keywords:asymmetric catalysis, chiral ligand, pyridine,amide, allylic alkylation, enantioselective, cyanation,ring-opening, chiral Lewis acid.

During attempted enzyme-catalysed resolution of sterically hindered secondary alcohols, hemiacetals and their esters were unexpectedly detected. Hemiacetal esters are reactive compounds that decompose to alcohol, aldehyde and acid under ordinary work-up conditions i.e. in contact with water, acid, or silica gel. Thus, the presence of these side products might decrease the enantiomeric excess of the residual alcohol after workup of a lipase-catalysed resolution. The formation of these hemiacetal esters were further studied using both terpenoid and non-terpenoid substrate alcohols, various acyl donors, and lipases. The prerequisite for their formation is the presence of a sterically hindered substrate alcohol, an aldehyde or an aldehyde releasing acyl donor, and a lipase (PCL-L6, PCL-PS and CAL-B). Enantioselective synthesis of (S)- and (R)-cryptone was performed via a ring closing metathesis (RCM) of (S)- and (R)-6-isopropyl-1,7-octadien-3-one. The stereochemistry was induced by using pseudoephedrine as chiral auxiliary in an alkylation reaction which provided a chiral octadienone. Problems with removal of the RCM-catalyst resulted in low yields and low enantiomeric purity. In an alternative approach, racemic cryptone was subjected to conjugate addition with thiophenol followed by reduction to the corresponding alcohol. Lipase-catalysed resolution of this alcohol yielded, after oxidation and elimination, (R)- and (S)- cryptone with 76% and 98% ee, respectively. Marine fouling of immersed objects is a serious problem. Many coatings contain effective antifouling compounds having the drawback of being toxic to the marine environment. The marine natural product 10-isocyano-4-cadinene is a potentially non-toxic antifouling agent against the barnacle Balanus amphitrite and therefore an interesting target for organic synthesis. Cryptone was used as a starting material in attempted syntheses of this compound and other similar model compounds. / QC 20100901

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.

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>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>

Asymmetric synthesis has become an important tool to prepare enantiomerically pure compounds because it avoids the wasteful discarding of the undesired enantiomer. Combinatorial libraries allow for much faster screening for new and better asymmetric catalysts/auxiliaries, but they generate a large number of samples whose enantiomeric excess (ee) cannot be determined rapidly. This bottleneck currently limits the applicability of such approaches. We propose here the use of faster optical techniques for the determination of ee using common instrumentation, such as UV-vis spectrophotometers, and circular dichroism (CD) spectrophotometers. Our methods are easily transitioned to the microwell format commonly used in parallel/combinatorial chemistry endeavors, just by using common microplate readers: this allows for an even more rapid analysis of samples and a seamless integration in a high-throughput workflow. We have shown that enantioselective indicator displacement assays can be developed to determine ee in a high-throughput fashion utilizing either a UV-vis spectrophotometer or a 96-well plate reader. Two chiral receptors and a commercial pH indicator were used to enantioselectively discriminate α-amino acids by monitoring the degree of indicator displacement. The two receptors were able to enantioselectively discriminate 13 of the 17 analyzed α-amino acids and accurately determine ee values of independent test samples with the use of ee calibration curves. Moreover, a sample of valine was synthesized through an asymmetric reaction, whose ee was then determined with our assay and compared to chiral HPLC and 1H NMR chiral shift reagent analysis, with excellent correlation. An artificial neural network was also successfully employed in the analyses, as an alternative to ee calibration curves. Both techniques consistently produced results accurate enough for preliminary determination of ee in a rapid manner, allowing for high throughput screening (HTS) of asymmetric reactions. The use of circular dichroism spectroscopy with chiral BINAP was also explored to enantioselectively discriminate α-chiral ketones. The ketones were derivatized with pyridyl hydrazines to produce hydrazones, which were then bound to enantiomerically pure [Cu(I)(BINAP)]+, forming diastereomeric complexes with differential steric interactions leading to different degrees of twist in the BINAP moiety and characteristic signatures in the CD spectrum, as a function of sample ee. / text

Determining the presence of an analyte of interest, and finding the enantiomeric purity of chiral molecules are challenging tasks. This work in molecular recognition is carried out routinely by many different researchers, including both academic as well as industrial research groups. The following dissertation presents original research directed toward two different areas of interest to the molecular recognition community: enantioselective sensing in solution, and sensing at a defined interfacial environment. This work begins with a review of the non-chromatographic ways that the enantiomeric purity of chiral carboxylic acids is determined, presented in Chapter 1. Carboxylic acids are important functional groups, both for organic synthesis as well as pharmaceutical drug development. Chapter 2 presents efforts that have been made to rapidly assess both the enantiomeric purity and identity of chiral carboxylic acids, utilizing the technique of exciton-coupled circular dichroism (ECCD). A twist is imparted on a complex, and can be correlated with the absolute configuration of the stereocenter. The enantiomeric composition can be rapidly determined. After creating the assay, the focus of the work shifted toward applying this system to new classes of analytes. Chapter 3 covers chemo- and enantioselective differentiation of [mathematical symbol]-amino acids, and continues to discuss the expansion to [mathematical symbol]-homoamino acids. Then a synthetic substrates was tested, and a series of reactions screened to determine if any enantioselectivity had been imparted by a Baeyer-Villiger oxidation. Finally, the enantiomeric composition of a biaryl atropisomer, a compound lacking a stereocenter, was determined. The signal produced from this assay is at a relatively short wavelength, and efforts were undertaken to push this signal to longer wavelength. Chapter 4 is a compendium of the lessons that were learned upon attempting to create a self-assembled sensing system. The final chapter details work that was done in collaboration with Professor Katsuhiko Ariga at the National Institute of Materials Science in Tsukuba, Japan. In this chapter, an indicator displacement assay was carried out for the first time at the air-water interface. This contribution opens the door for sensing to be carried out at defined regions, rather than free in bulk solution. / text

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.

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