Conjugate addition reactions are one of the most widely used carbon-carbon bond forming reactions in organic synthesis. This reaction can form a chiral center and can be used for the synthesis of structurally complex compounds. Until now it has been necessary to use a chiral heavy metal catalyst in order to carry out asymmetric addition of aromatic groups to α,b-unsaturated enones via conjugate addition. Recently we have been successful in achieving the same task using an arylboronate as well as a catalytic amount of a chiral substituted binaphthol (BINOL). Using this reaction method great yields and enantioselectivities were achieved when diethyl phenylboronate was added to various enones and when various diethyl arylboronates were added to chalcone. This reaction is exciting because it eliminates the chance of having trace amounts of heavy metals in the final product, which is advantageous in such areas as the pharmaceutical industry.

Conjugate addition reactions are one of the most widely used carbon-carbon bond forming reactions in organic synthesis. This reaction can form a chiral center and can be used for the synthesis of structurally complex compounds. Until now it has been necessary to use a chiral heavy metal catalyst in order to carry out asymmetric addition of aromatic groups to α,b-unsaturated enones via conjugate addition. Recently we have been successful in achieving the same task using an arylboronate as well as a catalytic amount of a chiral substituted binaphthol (BINOL). Using this reaction method great yields and enantioselectivities were achieved when diethyl phenylboronate was added to various enones and when various diethyl arylboronates were added to chalcone. This reaction is exciting because it eliminates the chance of having trace amounts of heavy metals in the final product, which is advantageous in such areas as the pharmaceutical industry.

Molecules that are non-superimposable on their mirror image are named chiral or optically active compound. Over the years, molecular chirality has played an essential role in the understanding of fundamental aspects associated the origin of life, drug and food technologies and, asymmetric catalysis, among others. Moreover, most of the groundbreaking discoveries and advances made in this field have happened due to the development of spectroscopic techniques based on the natural asymmetry of the enantiomers and their ability to preferentially absorb right or left polarized light. For instance, circular dichroism (CD), which measures the difference in absorption between these two states of polarized light, has emerged as one of the most useful spectroscopic methods to identify and characterize chiral compounds. Unfortunately, CD is based on linear absorption which, in most common organic molecules, takes place in the UV region of the spectrum where the majority of organic solvents absorb as well. This certainly imposes limitations in the indiscriminated applicability of this technique to the study of chiral chromophores of biological interest in non-aqueous solutions. Consequently, a systematic and comprehensive characterization of the electronic and optical properties of such molecular entities still remains a major issue to be addressed. On this regard, nonlinear optics offers new alternatives to overcome some of the shortcomings of the standard linear CD-based spectroscopy. In order to surmount the existent limitations in this field and deepen in the fundamental understanding of chiral systems, we have mainly directed the attention of our research to the experimental and theoretical study of the polarization dependent two-photon absorption (2PA) of several chiral azo-compounds and binaphthol derivatives in solution. The first part of this dissertation (Chapters I-IV) covers a full characterization of the linear and nonlinear optical properties of a series of non-chiral and chiral azo derivatives. The combination of experimental techniques such as absorption, fluorescence, excitation anisotropy, circular dichroism, two-photon absorption and two-photon absorption circular-linear dichroism in combination with density functional theory calculations allowed us to unambiguously distinguish and assign the spectral position of the main electronic transitions (n-[pi]* and [pi]-[pi]*) in azobenzene derivatives. Our results represent a major contribution to the understanding of the electronic structure of these organic chromophores which have been reported of potential interest in the design of optoelectronic devices. Then, Chapter V describes the development of a novel experimental technique called the synchronized double L-scan for the study of polarization dependent multiphoton absorption in chiral samples. The high sensitivity of this technique resides in the use of "twin" pulses to account for energy and mode fluctuations of the excitation pulse when determining absorption nonlinearities as a function of the light polarization. The robustness of this method was validated by measuring the first ever reported two-photon absorption circular dichroism (2PA-CD) spectrum on a chiral binaphthol derivative in solution. Finally, Chapters VI and VII compile an ample experimental and theoretical investigation of the chirality-dependent 2PA of axial enantiomers in solution. We combined the use of the synchronized double L-scan technique with state-of-the-art density functional theory calculations to provide a precise and reliable description of the contribution of the different electronic excited states to the 2PA-CD and 2PA-CLD spectra. Our findings are foreseen to have a tremendous impact in the comprehension of some of the most fundamental aspects of chiral phenomena.

A number of 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-m</strong>) were prepared from the reaction between triallylborane and the corresponding 3,3'-disubstituted binaphthols. These chiral allylboronates could allylate carbonyl compounds to produce chiral homoallylic alcohols in high chemical and optical yields. Chiral ligands were readily recycled through simple acid-base extraction. Among all allylboronates tested, 3,3'-(CF₃)₂-BINOL-modified allylboronate (<strong>2. 42b</strong>) is an especially effective reagent that allows for allylborations of both aldehydes and ketones in high enantioselectivities (up to 98% yield and >99% <em>ee</em>). Reagent <strong>2. 42b</strong> represents one of the best allylation reagents for carbonyl compounds developed thus far. <br /><br /> Allylations of cyclic imines using 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-j</strong>) were carried out at low temperature. 3,3'-Bis[3,5-(CF₃)₂-C₆H₃]-binaphthol-modified allylboronate (<strong>2. 42j</strong>) gave the best enantioselectivities (91% <em>ee</em> to >99% <em>ee</em>) in the allylation of a variety of cyclic imines. This methodology represents the first successful enantioselective allylboration of cyclic imines. The versatility of the allylation products (chiral a-allyl cyclic amines) was demonstrated through efficient total syntheses of several naturally occurring alkaloids such as coniine, crispine A and corynantheidol. <br /><br /> 3,3'-Disubstituted binaphthol-modified alkynylboronates (<strong>4. 47a-g</strong>) were synthesized according to a reported procedure. It was found that these chiral alkynylboronates add to <em>N</em>-acylaldimines in an enantioselective manner to produce chiral propargylamides in excellent yields and enantioselectivities. Up to >99% <em>ee</em> could be obtained with 3,3'-diphenyl binaphthol-modified alkynylboronates (<strong>4. 47f</strong>). This represents the first direct asymmetric synthesis of chiral propargylamides. Using this methodology, an antitubulin agent (-)-<em>N</em>-acetylcolchinol (AstraZeneca® ZD6126 phenol) was synthesized in 4 steps from commercially available 3-hydroxybenzaldehyde. <br /><br /> During a study of the asymmetric conjugate alkynylation of enones via chiral alkynylboronates, it was found that achiral dialkyl alkynylboronates could add to enones enantioselectively in the presence of catalytic amounts of chiral bidentate ligands (such as 3,3'-disubstituted binaphthols, diisopropyl tartrate and activated chiral amino acids). A catalytic cycle driven by "ligand-exchange" processes was proposed to rationalize this asymmetric induction. This is the first reported example of an asymmetric reaction that is promoted by a catalytic amount of an exchangeable chiral ligand on the boron reagent. More importantly, we have demonstrated a proof of principle that ligand exchange with boronates can be sufficiently fast that catalytic amounts of chiral ligands can be used to effect high levels of stereoselectivity. This catalytic protocol can potentially be applied to other asymmetric reactions providing the following three requirements are met: (1) the starting achiral boronate does not react with the electrophile (no background reaction); (2) the chiral boronate reacts with the electrophile and (3) ligand exchange or transesterification occurs under the reaction conditions. Potential applications of this principle include asymmetric allylboration, hydroboration, aldol reaction and reduction, just to name a few.

A number of 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-m</strong>) were prepared from the reaction between triallylborane and the corresponding 3,3'-disubstituted binaphthols. These chiral allylboronates could allylate carbonyl compounds to produce chiral homoallylic alcohols in high chemical and optical yields. Chiral ligands were readily recycled through simple acid-base extraction. Among all allylboronates tested, 3,3'-(CF₃)₂-BINOL-modified allylboronate (<strong>2. 42b</strong>) is an especially effective reagent that allows for allylborations of both aldehydes and ketones in high enantioselectivities (up to 98% yield and >99% <em>ee</em>). Reagent <strong>2. 42b</strong> represents one of the best allylation reagents for carbonyl compounds developed thus far. <br /><br /> Allylations of cyclic imines using 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-j</strong>) were carried out at low temperature. 3,3'-Bis[3,5-(CF₃)₂-C₆H₃]-binaphthol-modified allylboronate (<strong>2. 42j</strong>) gave the best enantioselectivities (91% <em>ee</em> to >99% <em>ee</em>) in the allylation of a variety of cyclic imines. This methodology represents the first successful enantioselective allylboration of cyclic imines. The versatility of the allylation products (chiral a-allyl cyclic amines) was demonstrated through efficient total syntheses of several naturally occurring alkaloids such as coniine, crispine A and corynantheidol. <br /><br /> 3,3'-Disubstituted binaphthol-modified alkynylboronates (<strong>4. 47a-g</strong>) were synthesized according to a reported procedure. It was found that these chiral alkynylboronates add to <em>N</em>-acylaldimines in an enantioselective manner to produce chiral propargylamides in excellent yields and enantioselectivities. Up to >99% <em>ee</em> could be obtained with 3,3'-diphenyl binaphthol-modified alkynylboronates (<strong>4. 47f</strong>). This represents the first direct asymmetric synthesis of chiral propargylamides. Using this methodology, an antitubulin agent (-)-<em>N</em>-acetylcolchinol (AstraZeneca® ZD6126 phenol) was synthesized in 4 steps from commercially available 3-hydroxybenzaldehyde. <br /><br /> During a study of the asymmetric conjugate alkynylation of enones via chiral alkynylboronates, it was found that achiral dialkyl alkynylboronates could add to enones enantioselectively in the presence of catalytic amounts of chiral bidentate ligands (such as 3,3'-disubstituted binaphthols, diisopropyl tartrate and activated chiral amino acids). A catalytic cycle driven by "ligand-exchange" processes was proposed to rationalize this asymmetric induction. This is the first reported example of an asymmetric reaction that is promoted by a catalytic amount of an exchangeable chiral ligand on the boron reagent. More importantly, we have demonstrated a proof of principle that ligand exchange with boronates can be sufficiently fast that catalytic amounts of chiral ligands can be used to effect high levels of stereoselectivity. This catalytic protocol can potentially be applied to other asymmetric reactions providing the following three requirements are met: (1) the starting achiral boronate does not react with the electrophile (no background reaction); (2) the chiral boronate reacts with the electrophile and (3) ligand exchange or transesterification occurs under the reaction conditions. Potential applications of this principle include asymmetric allylboration, hydroboration, aldol reaction and reduction, just to name a few.

Le présent mémoire décrit la synthèse et l’utilité de complexes Cu-NHC. En premier lieu, la synthèse de complexes de cuivre porteurs de ligand(s) de type carbène-N-hétérocyclique (NHC) via une génération décarboxylative de carbènes sera présentée. En effet, de précédents rapports font état de l’utilisation de carboxylates d’imidazol(in)ium en tant que précurseurs carbéniques sous conditions thermolytiques. Ainsi, la présente étude montre l’utilisation de ces espèces zwitterioniques pour la synthèse de complexes de cuivre(I) mono- et bis-NHC comportant divers substituants et contre-ions. Une seconde partie du projet se concentrera sur l’évaluation de complexes Cu-NHC en tant que catalyseurs pour la synthèse de 2,2’-binaphtols via une réaction de couplage oxydatif de naphtols. L’objectif de ce projet de recherche est d’étudier les effets de variations structurales de différents complexes Cu-NHC afin de construire un processus catalytique plus efficace. Les effets de la structure du catalyseur sur la réaction de couplage ont été évalués en variant son contre-ion, le nombre de ligands NHC se coordonnant au cuivre, ainsi que la nature des substituants du ligand. / The present thesis describes the synthesis and utility of NHC-Cu complexes. First, the synthesis of N-heterocyclic carbene (NHC) copper complexes via the decarboxylative generation of carbenes is presented. Indeed, literature precedents reported that imidazol(in)ium-2-carboxylates may be used as carbene precursors under thermolytic conditions. As such, the present study demonstrates how zwitterionic carboxylates may be utilized in the formation of both mono- and bis-NHC Cu complexes with various substitution patterns and counterions. Secondly, the NHC-Cu complexes were evaluated for the synthesis of 2,2’-binaphthols via the oxidative coupling of naphthol derivatives. The objective of the study was to investigate how structural variations to various NHC-Cu catalysts may generate a more efficient catalytic process. Effects of the structure of the catalyst on the coupling reaction have been studied by varying the number of NHC ligands coordinating to Cu, as well as the nature of the NHC ligand substituents and the counterions.

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