This thesis is concerned with the use of Lewis base organocatalysts for carboxyl and acyl transfer reactions. Chapter 1 introduces the ability of organic Lewis bases other than DMAP-type to promote a range of asymmetric O-, N- and C-acyl transfer processes. This chapter summarizes the developments in catalyst architectures and approaches to these processes that have been disclosed to date in this dynamic area of asymmetric organocatalysis. Chapter 2 introduces studies into the synthesis of pyrrolyl carbonates via cyclization of gamma-amino esters and ring closing metathesis (RCM) of N-allylamides. The ability of a range of Lewis bases to promote the regioselective O- to C-carboxyl transfer of pyrrolyl carbonates is also presented. Chapter 3 introduces isothiourea DHPB as an efficient Lewis base catalyst for the diastereoselective C-acylation of silyl ketene acetals with anhydrides or benzoyl fluoride, giving 3-acyl-3-aryl or 3-acyl-3-alkylfuranones in excellent yields and stereoselectivities (up to 99:1 dr). Chapter 4 introduces C(2)-aryl substituted DHPB derived-isothioureas as efficient Lewis base catalysts for the enantioselective C-acylation of silyl ketene acetals with propionic anhydride, giving 3-acyl-3-aryl or 3-acyl-3-alkylfuranones in good isolated yields and enantioselectivities (up to 98% ee). This chapter also demonstrates that these chiral isothioureas are required for high reactivity and asymmetry in related acylation manifolds. Chapter 5 presents and overall conclusion for chapters 2,3 and 4. Chapter 6 contains full experimental procedures and characterization data for all compounds synthesized in Chapters 2, 3 and 4.

L’intérêt des peptides comme des médicaments potentiels est en constante augmentation. Des stratégies ont été développées pour améliorer la sélectivité, l’activité, et la stabilité des peptides vis-à-vis de la protéolyse. Dans ce mémoire de thèse, deux nouvelles modifications de peptides sont proposées.Dans le premier chapitre, nous présentons une nouvelle application de la réaction de transfert O-N acylique pour la synthèse de peptides agrafés (ou ‘stapled peptides’). L’introduction d’une ‘agrafe’ dans un peptide est un moyen de stabiliser une structure secondaire hélicoïdale en établissant un pont entre les résidus appropriés des chaînes latérales. Dans notre cas, l'agrafe est formée par un O-acyl isodipeptide. La liaison ester peut être convertie en liaison amide par un transfert O-N acylique. Cette stratégie permet une amélioration de la solubilité d’un peptide hydrophobe agrafé, avant son réarrangement à pH neutre.Dans le dernier chapitre, nous avons développé une méthodologie nouvelle pour la dimérisation de peptides non protégés. Cette méthode repose sur la formation de liaisons siloxane entre des peptides hybrides portant chacun un groupement dimethylchlorosilane. Nous avons ainsi dimérisé une séquence dérivée de la protéine p53, impliquée dans l’apoptose. A titre de comparaison, cette même séquence a été dimérisée en utilisant la cycloaddition d’Huisgen entre deux peptides modifiés possédant un azoture ou un alcyne en position N-terminale. Enfin, plusieurs dimères de la séquence du GHRP-6 (growth hormone releasing peptide) ont été synthétisés, avec des bras dimethylhydroxysilane placés à différentes positions. L’homodimérisation a été effectuée dans l'eau à pH neutre. / The interest in peptides as potential drug candidates was revived and is increasing constantly. Strategies have been developed to improve their selectivity and activity, and their stability toward proteolysis. In this thesis, two new peptide modifications are proposed.In the first chapter, we present a new application of the O-N acyl transfer reaction for the synthesis of stapled peptides. Peptide ‘stapling’ is a way of stabilizing secondary helical structure by establishment of a bridge between the side chains of suitable residues. In our case, the staple is formed by an O-acyl isopeptide which can be converted into amide bond by acyl migration. This strategy allows an improved solubility of the stapled hydrophobic peptide prior to rearrangement at neutral pH.In the last chapter, we developed also a new methodology for the dimerization of unprotected peptides. This method is based on siloxane bond formation between hybrid dimethylhydroxysilane peptides. A peptide derived from the tumor suppressor protein p53 was dimerized in water, at neutral pH using this methodology. The method was compared with the homodimerization carried out by Cu(I) azide-alkyne cycloaddition (CuAAC). For that purpose, p53 peptide derivative was synthesized with azide and alkyne linkers at the N-terminus. At last, several homodimers of growth hormone releasing hexapeptide (GHRP-6) were synthesized, with dimethylhydroxy silane linkers placed at various positions.

Neste trabalho utilizaram-se dois sistemas para pesquisar alguns dos fatores que alteram a velocidade de reações em sistemas micelares. A reação de transferência de acila de S-octanoil-β-mercaptoetilamina (OMA) é catalisada 4,6 vezes por micelas de brometo de hexadeciltrimetilamônio (CTAB) e levemente inibida por Brij-35. A reação de transferência de acila de S para N da acetil-β-mercaptoetilamina (AMA) não é afetada por CTAB, porém é inibida cerca de 100 vezes por dodecil sulfato de sódio (SDS). A reação de OMA também é fortemente inibida por SDS (1.700 vezes). Estes efeitos foram atribuídos a uma alteração do pK do grupo amino e à diminuição da liberdade conformacional da molécula de substrato na fase micelar. O CTAB aumenta a velocidade de tiólise de acetato de p-nitrofenila por tiofenóis substituídos aproximadamente 50 vezes. A constante de velocidade calculada na fase micelar (k2m) é idêntica a obtida em fase aquosa (k2w) para tiofenol, p-metoxitiofenol e p-metiltiofenol. k2m é 40% menor do que k2w na reação com p-clorotiofenol. A aceleração observada em presença de CTAB pode ser atribuída, exclusivamente, à concentração de substrato na fase micelar. / Two systems were used in order to investigate some of the factors that modify the reaction rate in micelles. The rate of S to N acyl transfer of S-octanoyl-β- mercaptoethylamine (OMA) is enhanced by hexadecyl trimethylammonium bromide (CTAB) micelles by 4.6 fold and slightly inhibited by the non ionic detergent Brij-35. The rate of S to N transfer of S-acetyl-β-mercaptoethylamine (AMA) is unaffected by CTAB or Brij-35. Micelles of a negative detergent, sodium dodecyl sulfate inhibit the rate of S to N transfer of AMA by 100 fold, the inhibition in the case of OMA is 1.7 x 103 fold. An increase in the apparent pK of the ammonium ion and a decrease in the conformational mobility of OMA is proposed to account for the observed results. CTAB increases the rate of thiolysis of p-nitrophenyl acetate by substituted thiophenols by approximately 50 fold. The calculated rate constant in the micellar phase (k2m) is identical to that in the aqueous phase (k2w) for thiophenol, p-methoxithiophenol and p-metilthiophenol. k2m is 40% less than k2w in the case of p-clorothiophenol. The observed rate acceleration can be attributed, exclusively, to substrate concentration in the micellar phase.

The synthetic progress towards yaku'amide A is described. The study leads to development of new synthetic methodologies. Base-free regioselective aminohydroxylation is convenient to deliver β-tert-hydroxyamino acids. A sequence consisting of alkylative esterification, Martin sulfurane mediated anti dehydration, a tandem azide reduction-O→N acyl transfer allows the rapid access of E- and Z-dehydroisoleucine-containing peptides from β-tert-hydroxyisoleucine derivatives. Those methods are effective in constructing complicated peptides and advanced subunits of yaku'amide A.

Devant l’intérêt grandissant pour le développement de stratégies innovantes applicables à la synthèse de molécules complexes, notre groupe s’est orienté vers la construction de motifs présents dans un grand nombre de produits biologiquement actifs : les tétrahydropyranes (THP) et les polypropionates. Notre stratégie, basée sur la formation diastéréosélective de diols méso primaires, fait intervenir une étape inédite de désymétrisation organocatalysée par transfert d’acyle asymétrique. Cette approche permet la synthèse énantiosélective de THP pentasubstitués qui par la suite peuvent être valorisés par l’obtention de polypropionates fonctionnalisés, possédant quatre centres stéréogènes contigus. Par ailleurs, cette nouvelle méthodologie de désymétrisation donne accès à des motifs cycliques et acycliques comportant plusieurs centres stéréogènes quaternaires. Elle constitue, de plus, l’unique exemple de désymétrisation énantiosélective de diols méso primaires catalysée par une dialkylaminopyridine chirale. Bien que le transfert d’acyle asymétrique organocatalysé ait été très largement étudié depuis la fin des années 90, de nombreuses études sont en cours pour accéder à des catalyseurs plus sélectifs et plus nucléophiles. Inspiré des récents travaux de Steglich et Vedejs, notre deuxième objectif s’est porté sur la synthèse énantiosélective et modulaire d’une nouvelle famille d’organocatalyseurs chiraux plus polyvalents dérivés de la 1,6-naphtyridine. Leur application, en catalyse nucléophile, a pu être évaluée dans des réactions de dédoublement cinétique d’alcools et dans les réarrangements de Steglich. / Alongside metallocatalysis and biocatalysis, organocatalysis has emerged as a complementary and powerful tool that can circumvent limitations associated to the use of metals or enzymes. Because of the growing interest for new innovative methodologies useful for complex molecules synthesis, we get interested in the preparation of versatile building blocks present in many bioactive molecules: tetrahydropyrans (THP) and polypropionates. Based on the diastereoselective formation of primary meso diols, our strategy involves an original organocatalyzed desymmetrization of these compounds by asymmetric acyl transfer. This approach allows the enantioselective synthesis of pentasubstituted THP which were valorized through the synthesis of polypropionates bearing four consecutive stereogenic centers. In addition, this new methodology provides cyclic and acyclic scaffolds with several all carbon quaternary stereogenic centers. It represents the first example in organocatalyzed asymmetric desymmetrization by acyl transfer using a chiral dialkylaminopyridine. Although asymmetric organocatalyzed acyl transfer has been widely studied since the late 90s, several investigations are currently underway to access to new chiral nucleophilic catalysts. Following the recent work of Steglich and Vedejs, we were interested in the development of new chiral organocatalysts derived from 1,6-naphthyridine. Their applications in nucleophilic catalysis have then been evaluated in kinetic resolutions of alcohols and in asymmetric Steglich rearrangements.

Neste trabalho utilizaram-se dois sistemas para pesquisar alguns dos fatores que alteram a velocidade de reações em sistemas micelares. A reação de transferência de acila de S-octanoil-β-mercaptoetilamina (OMA) é catalisada 4,6 vezes por micelas de brometo de hexadeciltrimetilamônio (CTAB) e levemente inibida por Brij-35. A reação de transferência de acila de S para N da acetil-β-mercaptoetilamina (AMA) não é afetada por CTAB, porém é inibida cerca de 100 vezes por dodecil sulfato de sódio (SDS). A reação de OMA também é fortemente inibida por SDS (1.700 vezes). Estes efeitos foram atribuídos a uma alteração do pK do grupo amino e à diminuição da liberdade conformacional da molécula de substrato na fase micelar. O CTAB aumenta a velocidade de tiólise de acetato de p-nitrofenila por tiofenóis substituídos aproximadamente 50 vezes. A constante de velocidade calculada na fase micelar (k2m) é idêntica a obtida em fase aquosa (k2w) para tiofenol, p-metoxitiofenol e p-metiltiofenol. k2m é 40% menor do que k2w na reação com p-clorotiofenol. A aceleração observada em presença de CTAB pode ser atribuída, exclusivamente, à concentração de substrato na fase micelar. / Two systems were used in order to investigate some of the factors that modify the reaction rate in micelles. The rate of S to N acyl transfer of S-octanoyl-β- mercaptoethylamine (OMA) is enhanced by hexadecyl trimethylammonium bromide (CTAB) micelles by 4.6 fold and slightly inhibited by the non ionic detergent Brij-35. The rate of S to N transfer of S-acetyl-β-mercaptoethylamine (AMA) is unaffected by CTAB or Brij-35. Micelles of a negative detergent, sodium dodecyl sulfate inhibit the rate of S to N transfer of AMA by 100 fold, the inhibition in the case of OMA is 1.7 x 103 fold. An increase in the apparent pK of the ammonium ion and a decrease in the conformational mobility of OMA is proposed to account for the observed results. CTAB increases the rate of thiolysis of p-nitrophenyl acetate by substituted thiophenols by approximately 50 fold. The calculated rate constant in the micellar phase (k2m) is identical to that in the aqueous phase (k2w) for thiophenol, p-methoxithiophenol and p-metilthiophenol. k2m is 40% less than k2w in the case of p-clorothiophenol. The observed rate acceleration can be attributed, exclusively, to substrate concentration in the micellar phase.

We now report an in depth analysis of the successful in vitro enzymatic synthesis of PHB utilizing the three-enzyme system from the bacteria Cupriavidus necator. Using HPLC methodology developed in this laboratory, and by adding each enzyme in a step-wise manner, we follow each individual stage in the three-enzyme route for PHB synthesis and delineate all stoichiometric relationships. We report the construction of the first metabolic model developed specifically for analyzing in vitro enzymatic PHB synthesis. We developed a hands-on student laboratory for culturing, producing, isolating, and purifying the bacterial biopolyesters PHB. We now report the first structural characterizations of iso-CoA, acetyl-iso-CoA, acetoacetyl-iso-CoA, and beta-hydroxybutyryl-iso-CoA using MS, MS/MS, and homo- and hetero-nuclear NMR analyses.We describe HPLC methodology to separate the isomers of several iso-CoA-containing compounds and report the first examples of iso-CoA-containing compounds acting as substrates in enzymatic acyl-transfer reactions. We describe a simple regioselective synthesis of iso-CoA from CoA. We also demonstrate a plausible mechanism, which accounts for the existence of iso-CoA isomers in commercial preparations of CoA-containing compounds. Herein we report that phenylaminoethyl selenide compounds protect DNA from peroxynitrite-mediated single-strand breaks. The mechanism of protection against peroxynitrite mediated DNA damage was investigated by HPLC. The chemistry of the reaction between peroxynitrite and HOMePAES was investigated using HPLC and HPLC/MS. The unique chemistry of the reaction between peroxynitrite and HOMePAES was investigated using HPLC and HPLC/MS. We report the development of novel CDB derivatives, which are selective COX-II inhibitors. A series of compounds were assayed with an in vitro colorimetric inhibitor screening and with a whole blood ELISA screening and the results indicate that MST is a selective inhibitor of COX-II.