Chapter 1. An Overview of Bile Acid Science This chapter deals with an overview of bile acid science (cholanology) compiling elevant literature review, covering bile acid chemistry, biosynthesis, bile salt evolution, physiology and medicinal values. Figure 1. (a) Digestive system; (b) enterohepatic circulation and (c) cholic acid Bile acids are the end products of cholesterol metabolism, secreted in the liver and stored in the gall bladder (Figure 1). They are normally conjugated with glycine (75%) or taurine (25%). Because of their facially amphiphilic nature, bile salts tend to form micellar aggregates in aqueous solution. They have remarkable ability to transform lamellar array of lipids into mixed micelles. All primary bile acids seem to have three features in common: (1) They are major products of cholesterol metabolism; (ii) they are secreted into the bile largely in a conjugated form and (iii) the conjugates are membrane impermeable, water soluble, amphiphilic molecules. Recent advances in molecular biology have greatly accelerated the knowledge relating to the significance of bile salts in a number of physiological functions. The new role of bile salts as pheromones and ligands for nuclear hormone receptors has been discussed. Chapter 2. Pythocholic Acid: A Major Constituent of Python’s Bile and 16α-Hydroxycholic Acid: A Minor Constituent of Avian’s Bile The first chemical synthesis of pythocholic acid (major constituent of python’s bile) and 16α-Hydroxycholic acid (a minor constituent of avian’s bile) were accomplished starting from cholic acid with overall yields of 5.0% and 5.5%, respectively. A biomimetic remote functionalization strategy was utilized as a key step to achieve the selective chlorination at C-17. Dehydrochlorination of 17-chlorosteroid resulted in the Δ16 olefin. Hydroboration-oxidation of the Δ16 olefin followed by the selective oxidation of the pentol under TEMPO mediated oxidation resulted in an ε-lactone. Hydrolysis of the lactone using 5% KOH in MeOH furnished the 16α-Hydroxycholic acid. On the other hand, selective oxidation of 7-OH of the lactone was achieved using N-bromosuccinimide in acetone/H2O to yield the 7-keto lactone. The ketolactone when subjected to the Huang-Minlon modification of the Wolf-Kishner reduction furnished pythocholic acid. Pythocholic acid showed unusual aggregation behavior and high cholesterol solubilization ability, compared to other trihydroxy bile acids. Chapter 3. 16-Epi-pythocholic acid: An Unnatural Analogue of Pythocholic Acid The synthesis of 16-epi-pythocholic acid, an unnatural analogue of pythocholic acid, was accomplished starting from cholic acid. Cholic acid was converted to Δ8-14) olefin using ZnCl2 in refluxing acetone. Methylation followed by isomerization in CHCl3 by passing dry. HCl at -78 oC resulted in the Δ14 olefin. Allylic oxidation using Na2Cr2O7.2H2O in the presence of N-hydroxysuccinimide in acetone furnished the enone. Selective reduction of the olefin using Pd/C-H2 resulted in 16-Epi-pythocholic acid the 16-keto steroid. NaBH4 reduction of this ketone in MeOH/THF (2:1 v/v) followed by hydrolysis produced the 16-OH bile acid. Analysis of spectral data confirmed that it is a 16β-epimer of pythocholic acid (3α,12α,16β-trihydroxy-5β-cholan-24-oic acid). Critical micellar concentration and cholesterol solubilization properties were studied. Chapter 4. Low Molecular Mass Organogelators Derived from Simple Esters of Cholic Acid This chapter begins with an introduction to low molecular mass organogelators and highlights their applications. Serendipitous gelation of a number of organic solvents by allyl cholate and the design of related simple esters of cholic acid are discussed. A series of simple and easily accessible esters of bile acids were prepared. Ethyl cholate and propyl cholate were found to immobilize a variety of organic solvents like benzene, toluene, xylene, mesitylene, 1,2-dichlorbenzene (DCB) and chlorobenzene (Figure 2). The morphology of the xerogels was well characterized using SEM, AFM and polarizing optical microscopy (POM) techniques, Which revealed the presence of highly entangled self-assembled 3D-fibrillar network (SAFINs). The fiber diameter was found to vary between 300-500 nm. Direct imaging of the collapse of this fibrillar network and direct observation of the evolution of nanofibers was achieved for the first time using variable temperature POM techniques. FT-IR studies, X-ray powder diffraction and variable temperature POM studies revealed the resemblance of SAFINs to the bulk solid. Formation of helical fibrillar network was observed in SEM images and the existence of chiral aggregates was confirmed by induced circular dichroism experiment using achiral Reichardt’s dye as the chromophore. Chapter 5. Ambidextrous Gelators Derived from Spacer Linked Bile Acid Derivatives Based on our observation of simple esters of cholic acid as organogelators a rational design of a series of spacer linked dimers and tripodal derivatives were carried out. Some of these molecules formed highly transparent gels in solvents like haloarenes, anisole, xylene and dibromoalkanes. These molecules also showed rapid gelation in DMF/H2O and DMSO/H2O mixtures in varying proportions of water and the co-solvent. These types of gelators are known as ambidextrous gelators. The xerogels were characterized using SEM, TEM and POM techniques and the presence of highly entangled 3D-fibrillar network (Figure 3) was observed. XRPD showed crystalline nature of bulk solid, whereas the xerogels were shown to lose their crystalline nature. (For figures and structural formula pl see the pdf file.)

Des matériaux hybrides de classe II ont été préparés à partir de précurseurs bis(tripropynylstannylés). Deux familles de précurseurs sol-gel incluant des espaceurs hydrocarbonés et thiophénique ont été obtenues et conduisent à des matériaux hybrides auto-organisés où les plans d’oxyde sont séparés par les espaceurs organiques. Ainsi l’espaceur rigide a donné lieu à une structure pseudo-lamellaire montrant une bande d’émission monomère avec un assez faible décalage vers le rouge par rapport à l'émission des précurseurs en solution. En revanche, alors que les xérogels thiényle plus désordonnés conduisent à une large émission caractéristique de la formation d’excimères ou de dimères. Par ailleurs, des films minces contenant les espaceurs alkylène et arylalkylène ont été préparés et ont montré une morphologie "pseudoparticulaire" poreuse et un ordre à courte distance contenant des réseaux SnOx. De façon inattendue, ces films minces hybrides détectent le dihydrogène dès une température de 50 °C dans la gamme 200-10000 ppm. A partir de ces films hybrides minces, le dioxyde d'étain cristallin (SnO2) a été préparé par un post-traitement thermique. Comme prévu, ces films SnO2 cassitérite détectent le dihydrogène et, dans une moindre mesure le monoxyde de carbone avec une température optimale de fonctionnement comprise entre 300 et 350 °C. / Class II hybrid materials were prepared from ditin hexaalkynides. Two families of precursors, including either hydrocarbon or oligothiophene-based spacers, were obtained and led by the sol-gel process to self-assembled organotin-based hybrid materials made of planes of oxide separated by organic bridges. Thus, the rigid thienyl spacer gave rise to a “pseudo-lamellar” structure that showed a monomer emission band with a rather small red-shift compared with to the emission of the precursor in solution. However more disordered thienyl xerogels led to broad emission features assigned to excimer or dimer formation. Moreover, thin films containing alkylene- and arylalkylene bridged have been prepared and showed a “pseudoparticulate” porous morphology and a short-range hierarchical order in the organic-inorganic SnOx pseudoparticles. Unexpectedly these hybrid thin films detect hydrogen gas at a temperature as low as 50 °C at the 200-10000 ppm level. From these hybrid thin films, crystalline tin dioxide (SnO2) were prepared by a thermal post-treatment. As expected, cassiterite SnO2 films detected H2 and to a less extent CO with a best operating temperature comprised between 300 and 350 °C.