Aminocyclitols have attracted a great deal of attention in recent years because of diverse biological activities exhibited by them and also synthetic usefulness in the synthesis of other natural compounds or pharmaceuticals. In this study, novel synthetic strategies leading to aminocyclitol derivatives were investigated and the synthesis of aminotetrol derivative (113) was achieved successfully. Moreover, by the use of singlet oxygen reactions having considerable synthetic utilities in organic chemistry we developed new synthetic methodologies for the aminoquercitol and aminoconduritol derivatives (114 and 115). 3a,4,7,7a-tetrahydro-isobenzofuran-1,3- dione (111) and 3a,7a-dihydro-isobenzofuran-1,3-dione (112) were synthesized from easily available starting materials in order to be used as key compounds. The anhydride moiety in key compounds provided us to obtain hydroxymethyl and amine groups in target molecules by performing Curtius rearrangement. The introduction of iii hydroxyl groups into the molecules was achieved by both singlet oxygen and cisdihydroxylation of osmium tetroxide. As a result of this, we were able to synthesize aminotetrol derivative and we had considerable advance in the synthesis of aminoconduritol and aminoquercitol derivatives.

Cyclitols are cyclic compounds having hydroxyl groups which attached to different carbons on the ring. Cyclitols have attracted a great deal of attention for having diverse biological activities. Cyclic alcohols play an important role in biological processes such as inhibition of glycosidase, cellular recognition, and signal transduction. In addition to this, these compounds are very important molecules due to being capable of using while synthesizing natural products or pharmaceuticals. In this study, development of new methodology for the synthesis of bis-aminoinositol derivatives was aimed. The starting material, cis-diester, was synthesized from the Diels-Alder reaction of furan and maleic anhydride followed by reaction with MeOH. As a second key compound, trans-diester was obtained from the Diels-Alder reaction of furan and fumaryl chloride followed by esterification. The diester functionality in these two compounds was planned to be converted into the hydrazide upon treatment with hydrazine monohydrate. Before this reaction, double bond was protected via stereo selective oxidation reaction with m-CPBA due to preventing retro Diels-Alder reaction. Then, hydrazide functionality was converted into acyl azide through &beta / -nitroso hydrazide intermediate. Subsequent Curtius rearrangement reaction resulted in the formation of the isocyanate which was converted to the corresponding bis-urethane by treatment with MeOH. Attempt to cleave the oxa-bridge in urethane with sulfamic acid provided the unexpected tricyclic product 148. Furthermore, hydrolysis of isocyanate with aqueous HCl formed the diamine 156. However, O-bridge could not be opened with any reagents used for that of urethane derivative as described above. Then,the cis-diol 157 was synthesized to prevent the neighboring group participitation during the epoxide-opening reaction. Further ring-opening reactions are under investigation.

Aminocyclitols are cyclitols in which at least one of the hydroxyl groups is exchanged with an amino functional group. In turn, they constitute a wide group of natural products with interesting biological properties and are widely distributed throughout. In particular, antibiotics containing an aminocyclitol unit have stimulated the development of synthetic methodologies in the search for analogues with enhanced pharmacological profiles. In this study, three different methods were applied to synthesize diaminoconduritol derivative 202. In the first method, 1,2,3,6-tetraphthalic anhydrate (196), derived from Diels-Alder reaction between of maleic anhydride and 3-sulfolene, was used as a starting compound. Starting with the opening of anhydride group with trimethyl silylazide, tetrazolinone derivative 205 instead of bisamino cyclohexane derivative 201 was obtained. v In the second method, we started the synthesis of target compound 202 by the Birch reduction of benzene. Lactame 218 was synthesized as a key compound. Functionalization of lactame 218 was started with the cleavage of bond between nitrogen and carbonyl group in 218. At the end of the method, imidazole derivative 215 was obtained instead of target compound 202. Diaminoconduritol 242 was synthesized successfully by bishydrazide method. In this strategy, 1,2,3,6-tetraphthalic anhydrate (196) was used as a starting material. After conversion of bisurethane 223 to acylazide derivative 230, Curtius degradation and phtooxygenation reactions were used to introduce the amine and oxygen functionalities into the cyclohexene ring.

Cyclitols are of great importance due to their biological activities playing a crucial role in living organisms as well as their synthetic usefulness in the synthesis of other natural compounds or pharmaceuticals. In this study, new synthetic strategies leading to the aminocyclitols were investigated. The synthesis of aminoconduritol and aminoinositol derivatives (173 and 174) were achieved starting from easily available compound, 7-oxa-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (166) obtained from the Diels-Alder reaction of furan and maleic anhydride. The anhydride functionality in 166 was converted into the half-ester 169 by desymmetrization in methanol. The carboxylic acid moiety in the molecule was used to obtain urethane functionality by making use of Curtius rearrangement. After the cleavage of oxa-bridge with the help of a Lewis acid the aminoconduritol derivative 173 was synthesized. The cis-dihydroxylation of 173 with osmium tetroxide resulted in the formation of inositol derivative 174. Consequently, we developed a new methodology for the synthesis of aminocyclitol derivatives.

Les glycosidases sont des enzymes impliquées dans un grand nombre de processus biologiques. Leurs inhibiteurs présentent un potentiel thérapeutique en tant qu'agents antidiabétiques, agents antiviraux ou agents pour traiter des maladies génétiques. Au cours de ce travail, nous nous sommes attachés à développer une voie de synthèse chimioenzymatique permettant d'accéder à des analogues de la valiolamine, puissant inhibiteurs d'alpha-glucosidases. Les aminocyclitols que nous avions pour objectif de préparer diffèrent de la valiolamine par la position du groupement amino et des stéréochimies des hydroxyles. Nous avons synthétisé ces aminocyclitols selon une méthode originale, basée sur un procédé en un seul pot mettant en jeu deux enzymes et trois réactions : une aldolisation catalysée par la fructose-1,6- biphosphate aldolase, une déphosphorylation catalysée par une phytase et une nitroaldolisation intramoléculaire. Ainsi deux liaisons C-C sont formées de façon hautement stéréosélective en une seule étape. Nous avons synthétisé neuf nouveaux aminocyclitols et deux nouveaux zwitterions et dérivé N-alkylé. Quelque aminocyclitols se sont révélés des inhibiteurs sélectifs de la béta-glucosidase d'amandes douces et de la béta-galactosidase d'Aspergillus oryzae.

Carbohydrates are ubiquitous and important biomolecules. Initially thought to be dull, energy storing moieties, the importance of carbohydrates and their conjugates, glycoproteins and glycopilids, in cellular communication and various related processes has been well established. Carbohydrate recognition events are involved in the progression of various diseases, as the binding of pathogens to the host cells is carbohydrate mediated. Also the malfunctioning of carbohydrate processing enzymes has been implicated in life-threatening diseases. Thus there is tremendous interest in the design of molecules which can mimic the carbohydrates and provide insights into the mechanisms of action of carbohydrate processing enzymes. Such designer glycomimics possess several advantages over the parent molecules. In this regard the synthesis of small molecules based on the polyhydroxylated cyclohexane framework has gained vital importance. Some of the efforts of several research groups actively working on the design and synthesis of glycomimics have culminated in therapeutics and resulted in the development of many synthetic routes to polyoxygenated cyclohexanoids emanating from either the chiral pool or from aromatics and other non-carbohydrate sources. Nevertheless, the design of a general and variable strategy to access these cyclohexitols is essential. Our quest for a general and more versatile strategy for accessing several of the polyoxygenated cyclohexanoids led to the development of a new norbornyl based approach. The important feature of our approach involves extraction of the inherent cyclohexanoid from the norbornyl scaffold. The present thesis entitled “Norbornyl system revisited: Exploring a versatile building block for the syntheses of natural products and analogues” delineates our synthetic endeavors. The thesis is represented in two parts “Part 1: Synthesis of polyoxygenated cyclohexanoids and azepanes” is subdivided into Introduction, Results and Discussion, Summary, Experimental, Spectra and References sections and describes our synthetic efforts towards various polyoxygenated cyclohexanoids and azepanes. Introduction deals briefly about the importance of glycomimics and synthetic approaches from the literature towards these polyhydroxylated cyclohexanoids. Our findings constitute the Results and Discussion section wherein we delineate the synthesis of a versatile cyclohexanoid building block through a Grob like Wharton fragmentation on an suitably crafted norbornyl scaffold. The synthetic utililty and versatility of this building block are explored in subsections titled Carbasugars, Cyclitols, Gabosines, Aminocyclitols and Azepanes. The synthesis of several polyhydroxylated cyclohexanoid natural products and analogues is discussed. “Part 2: Synthetic studies towards the novel diterpenoid rameswaralide” deals with the elaboration of the versatile norbornyl building block towards the synthesis of a novel 5-7-6 fused diterpenoid rameswaralide. This part is again divided into Introduction, Results and Discussion, Summary, Experimental, Spectra and References sections. The Introduction briefs the relevance and importance of total synthesis of natural products, with a mention of terpenoids. The structure and biological significance of rameswaralide and related molecules is discussed. In the Results and Discussion our synthetic studies towards rameswaralide are delineated. Restructuring the norbornyl framework to a 5,5 fused all cis Corey lactone and its further amplification through ring closing metathesis and Diels-Alder protocols are described.