L’objectif de ce travail est le développement de nouvelles voies d’accès à des dérivés de l’acide L-iduronique à partir d’un sucre abondant et peu couteux, le méthyl a-D-glucopyranoside. Plusieurs approches de synthèse ont été envisagées. Tout d’abord, l’obtention d’un composé 1,6-anhydro-5-ulose a été réalisée avec fixation de la configuration L-ido en C-5 et une fonctionnalisation adéquate en C-4. Par la suite, la désoxygénation de ce composé a fait l’objet d’une étude approfondie en employant diverses méthodes (radicalaires, ioniques…). Dans la troisième partie, la chimie (formation et réactivité) des septanosides a été également explorée comme une nouvelle stratégie vers les dérivés L-ido. Enfin, la quatrième partie concerne l’étude de trois voies annexes potentielles qui utilisent des intermédiaires précédemment obtenus afin de préparer des dérivés du L-idose. / This work deals with the development of new routes to L-iduronic acid derivatives from a cheap and abundant sugar, the methyl a-D-glucopyranoside. Many approaches were studied. First, the 1,6-anhydro-5-ulose compound preparation was achieved with the right configuration L-ido at C-5 and the adequat protection at C-4. Then, a large study of its deoxygenation was made by using different methods (radicals, ions…). The third part is focused on the septanoside chemistry (preparation and reactivity) as a new strategy to the L-ido compound derivatives. To finish, three auxiliary routes are tested from different molecules obtained previously in order to prepare L-idose derivatives.

Synopsis The thesis entitled “Synthesis of Glyco-amino-acids, Glycosyl-amino-acids, and α-Amino γ-Lactams from Carbohydrate Derived Donor-Acceptor Cyclopropanes” is divided into five chapters. Chapter 1: Introduction and Background: Carbohydrate Derived Cyclopropanes and Glycoconjugates of Amino Acids and Peptides In this chapter, introduction and background on cyclopropanes, carbohydrate derived DA-cyclopropanes, glycopeptides and its mimetics is discussed Chapter 2: Efficient Synthesis of Glycosyl Esters of Amino Acids from Carbohydrate Derived Cyclopropanecarboxylates In this chapter, the N-iodosuccinimide (NIS) mediated ring opening of carbohydrate derived donor-acceptor (DA) cyclopropanes with carboxylic group of various N-protected amino acids is discussed. Under mild conditions, glucosyl esters of amino acids have been synthesized in moderate to good yields. This methodology has also been applied to galactose derived DA-cyclopropanes for the synthesis of galactosyl-amino-acid derivative. Among three N-protected valine derivatives (–Fmoc, –Boc, and –Cbz), the reaction of N-Fmoc protected valine derivative of glycosyl-amino-acid has not been successful due to the steric hindrance of bulky Fmoc group. Chapter 3: Synthesis of O–Linked Glycosyl-amino-acids & C–Linked Glyco-amino-acids. In this chapter, the synthesis of glycosyl-amino-acids and glyco-amino-acids by the NIS mediated ring opening of carbohydrate derived DA-cyclopropanes is reported. To synthesize the precursors of glycopeptides, deprotection of NHBoc has been performed with trifluoroacetic acid (TFA) and trimethylsilyl chloride (TMSCl). Trimethylsilyl chloride is found to be a better reagent than trifluoroacetic acid for this reaction. The synthesis of both O–linked glycosyl-amino acids and C–linked glycopeptides from single starting material using the orthogonal strategy at amine groups has been achieved. In these glycoconjugates of amino acids, the azide group (–N3) has been used as a masked amine (–NH2) which circumvents the protection and deprotection steps. Chapter 4: Synthesis of Carbohydrate Fused α-Amino γ-Lactams. In this chapter a flexible protocol for the synthesis of carbohydrate fused α-Amino γ-Lactams from carbohydrate derived cyclopropanecarboxylates has been disclosed. Also, the synthesis of carbohydrate fused γ-Lactams in a single-step from the iodo-azide by reductive cyclization has been reported. The formation of -lactam is achieved in low yield using both methods (A & B). The utility of the carbohydrate fused α-Amino γ-Lactams in the synthesis of Agl-bridged glycopeptide conjugates in a single-step with high efficiency has been demonstrated. Chapter 5: Studies on the Synthesis of Septanosides from Carbohydrate Derived DA-Cyclopropanes In carbohydrate derived DA 1,2-cyclopropanes, generally, the electron withdrawing group is attached at C-7 (type-I), C-2 (type-II), or C-3 (type-III). In this chapter, studies on the synthesis and use of carbohydrate derived DA-cyclopropanes of type-II & -III to form the the septanoside derivatives have been described. Attempts at the synthesis of 3,4,6-tri-O-methyl-D-glucal derived cyclopropanecarboxylates of type-II have not been successful. The failure of the cyclopropanation reactions might be due to presence of the carbmethoxy group at C-2 causing steric hindrance on the olefinic bond of 3,4,6-tri-O-tri-methyl-D-glucal methyl ester. It was then speculated that replacement of the of the carboxylate group in tri-O-methyl-glucal with hydroxymethyl group can promote the cyclopropanation reaction. Cyclopropanation of benzyl protected corresponding alcohol furnished the desired cyclopropane derivative in moderate yield (48%) as an inseparable mixture of diastereomers (1:1). Hence the synthesis of cyclopropanecarboxylates of type-II has not been achieved using this methodology. Glucose derived 3-oxo-1,2-cyclopropanes is synthesized from 3,4,6-tri-O-acetyl-D-glucal in good yield. This glucose derived cyclopropane of type-III did not furnish the septanoside derivative under different conditions. The synthesis of 3-oxo-1,2-cyclopropanated galactose derivative has been achieved in reasonably good yield from D-galactal with in three steps. When the galactose derived DA-cyclopropane is reacted with NIS and MeOH in the presence of catalytic amount of TMSOTf, it furnished the desired septanoside along with many side-products. The attempts at separation and identification of the septanoside in pure form have not been successful.

Seven-membered cyclic sugars, namely, septanoses and septanosides, are less commonly known sugar homologues. Synthesis of septanoses arise an interest due to their configurational and conformational features and the attendant possibilities to explore their chemical and biological properties. Septanosides derivatives, mostly, deoxy-septanosides were synthesized, by many synthetic methodologies, such as, Knoevengal condensation, ring-closing metathesis, Bayer-Villeger oxidation and ring-expansion of 1,2-cyclopropanted glycals as key steps. Apart from septanosyl monosaccharides, septanoside containing di- and tri-saccharides were also performed using glycosylation and ring expansions. Another area of sustained interest is the studies of the stabilities of glycosidic bonds. Acid- and enzyme-catalyzed hydrolysis of glycosidic bond were investigated intensely in the case of pyranosides and furanosides. The explanation of the hydrolysis of such stereomeric sugars were rationalized on the basis of stereoelectronic effects, such as, (i) antiperiplanarity; (ii) synperiplanarity of lone-pair of electrons involed in the hydrolysis process; (iii) steric effects; (iv) field and hyperconjugative effects; (v) conformational effects; (vi) disarming torsional effects and (vii) substituent effects. Chapter 1 of the thesis describes a survey of (i) synthesis of deoxy-septanosides and septanoside-containing di-and tri-saccharides and (ii) acid-catalyzed hydrolysis of glycopyranosides. In a programme, it was desired to identify a new methodology for the synthesis of 2-deoxy-2-C-septanosides. Synthesis of various septanosides from 2-hydroxy glycals, namely, oxyglycals, involves intermediates, such as, vinyl halide (III) and diketone (IV) (Scheme 1). These intermediates were identified as precursors for the synthesis of desired 2-deoxy-2-C-septanosides. Scheme 1 reactions, namely, Heck, Suzuki and Sonogashira reaction for the formation of hither-to unknown septanoside, branching out at C-2. Heck coupling and Suzuki coupling reaction of bromo-oxepine was performed using activated alkenes, acrylates and substituted boronic acid, respectively, in presence of Pd(OAc)2, to furnish 2-deoxy-2-C-alkyl/aryl septanoside derivatives (Scheme 2). Scheme 2 2-deoxy-2-C-alkynyl septanoside derivatives (Scheme 3). Scheme 3 BnO OOMe BnO OOMePd(PPh3)2Cl2,CuIBr BnO R BnO DMF:THF:Et3N(3:2:1)BnO OBn 98 oC, 72 h BnO OBn R=Ph,SiMe3,C6H13 One of the 2-deoxy-2-C-alkyl septanoside derivative was converted to the corresponding protecting-group free 2-deoxy-2-C-alkyl septanoside, using hydrogenolysis (Pd/C, H2) and NaBH4-mediated reduction. Chapter 2 presents details of the synthesis of 2-deoxy-2-C-alkyl/aryl/alkynyl septanoside derivatives from a bromo-oxepine. Continuing the efforts to extend the ring-opening of oxyglycal derived gem-dihalo-1,2¬cyclopropanted sugar, a Lewis acid-catalyzed ring-opening was considered important. The presence of an additional substituent in C-2 of oxyglycal switches reactivity as compared to glycals. For example, ring-opening of glycal derived gem-dihalo-1,2-cyclopropane generates 2-C-branched pyranoside, whereas corresponding oxyglycal generates oxepines even when both the reactions were performed under a mild basic condition, illustrating a sufficient reactivity difference between a glycal and an oxyglycal. Thus, ring-opening reaction of gem-dichloro-1,2-cyclopropanted oxyglycal in the presence of a Lewis acid, hither-to unknown, was examined. In this event, it was found that ring-opening reaction led to chloro-oxepine derivatives in the presence of AgOAc, using alcohol as nucleophiles. Primary, secondary, unsaturated and aromatic alcohols were used in the ring-opening reaction. The ring-opening reaction was stereoselective and only α-anomer was obtained in a good yield in each case (Scheme 5). The counter-anion also reacted in an instance, so as to furnish O-acetyl chloro-oxepine during the ring-opening reaction. Scheme 5 The course of the reaction in the absence of alcohol led to afford only the O-acetyl chloro-oxepine (Scheme 6). Scheme 6 It became pertinent to compare the result this work with that of AgOAc-catalyzed ring-opening of glycal derived gem-dihalo-1,2-cyclopropanated sugar, which led to C-furanoside derivative, as reported by Harvey and co-workers. The sequence of reactions involved were protonation of the endo-cyclic oxygen, followed by ring-opening to generate resonance stabilized allylic ion, which rearranged to C-furanoside. In contrast, oxyglycal derived gem-dihalo-1,2-cyclopropane studied herein led to chloro-oxepine exclusively, without subsequent rearrangement. Ring-opening of glucal derived gem-dihalo-1,2-cyclopropanated sugars, followed by cyclization to C-furanoside were likely to have occurred, due to isomerisation of less-substituted endo-cyclic double bond at C2-C3 of oxepine to C1-C2 unsaturated vinyl ether. Such a reaction was related closely to the acid-catalyzed rearrangement in less-substituted oxepine systems. On the other hand, gem-dichloro-1,2¬cyclopropanated oxyglycal derived chloro-oxepine did not undergo such an isomerisation, possibly due to unsaturation being present at highly substituted C2-C3 carbons (Scheme 7). Thus, the presence of an additional oxy-substituent at C-2 in oxyglycal derived cyclopropane derivative plays a major role to control the reactivity, as compared to glycal derived cyclopropane derivatives. Scheme 7 without undergoing further reactions, was confirmed further by the following reactions: (i) RuCl3¬NaIO4 mediated oxidation; (ii) NaBH4 reduction and (iii) Pd/C mediated hydrogenolysis (Scheme 8). Scheme 8 1,2-cyclopropane to exclusive formation of chloro-oxepine in the presence of AgOAc. It was planned further to synthesize a 1,7-linked-α-D-diseptanoside, through the oxyglycal route. Ring-opening of oxyglycal derived gem-dihalo-1,2-cyclopropanated derivative with 6¬hydroxy glycal led to 1,7-α-linked disaccharide unit. The following reactions were performed in order to synthesize 1,7-linked-α-diseptanoside 2: (i) cyclopropanation of the glycal double bond; (ii) ring opening of the gem-dihalo cyclopropane; (iii) RuO4 mediated oxidation; (iv) NaBH4 reduction and (v) hydrogenolysis using Pd/C, H2 (Scheme 9). Similar methodology was used for the synthesis of monoseptanoside, namely, n-pentyl-D-glycero-D-galacto-septanoside. Scheme 9 1 Oxyglycal route was also used for the synthesis of 2-chloro-2-deoxy septanoside 3, using hydrogenolysis (Pd/C, H2) and NaBH4 mediated reduction of chloro-oxepine (Scheme 10). Scheme 10 A kinetic study of the hydrolytic stabilities of mono-and diseptanoside was undertaken using an acid-catalysis, in a subsequent investigation. In the course of studies, it was observed that glycosidic bond in the reducing-end hydrolyzed twice faster than that at the non-reducing end, whereas glycosidic bond in monosaccharide 1 hydrolyzed 1.5 times faster than of reducing-end glycosidic bond in diseptanoside 2. Further, it was found that the replacement of the C-2 hydroxyl group by a chloride group reduced the rate of hydrolysis (Table 1). Table 1. First order rate constants and thermodynamic parameters for the acid-catalyzed hydrolysis of glycosidic bond in septanosides 1, 2 and 3. Compound Rate of hydrolysis ΔH# ΔS# ΔG# (kobs) (104 s-1) (kcal/mol) (cal/mol K) (kcal/mol) 35 oC 45 oC 85 oC 90 oC a non-reducing end of 2. A computational study was conducted, in order to gain further insight into the hydrolysis, using B3LYP/6-311G* level theory in the Gaussian 09 program packages. Calculations using the PCM solvent model with water as the solvent showed that the orientation of hydroxylmethyl group plays an important role. In the case of 1, the gg conformer was calculated stable by 2.12 kcal/mol, as compared, to tg-conformer. In the gg conformation, the optimal positioning of the dipole C7-O7 stabilized the oxo-carbonium ion in the transition state (Figure 1). Also, hydroxyl group at C4 stabilized the transition state, through non-covalent interaction (Figure 1). The transition state for the hydrolysis of 1 was found to present activation barrier (∆G#) of 19.9 kcal/mol, which was in good agreement with value for 1 (∆G# = 23.26 kcal/mol), as calculated from Erying plot (Table 1). On the other hand, inductive effect of the chloride group, as well as, the tg-orientation of the hydroxymethyl group appeared to contribute to the slower rate of the hydrolysis. Figure 1. gg- and tg-conformations in the ground state of 1. Chapter 4 describes synthesis of 1,7-linked-α-D-diseptanoside, 2-chloro-2-deoxy septanoside and their acid-catalyzed hydrolysis studies. Solid-state and solution phase conformation of septanosides are rare at present even when solid-state structures of pyranoside and furanosides are known commonly, that provide rich information of covalent and non-covalent interactions. In this context, single crystal X-ray structural analysis of septanosides, namely, n-pentyl-2-chloro-2-deoxy-α-D-manno-sept-3-uloside 4 and p-bromo phenyl 4,5,7-tri-O-benzyl-β-D-glycero-D-talo-septanoside 5 were analyzed. It was observed that the solid-state structure of 4 adopted twist-chair conformation, namely, 5,6TC3,4, whereas 5 adopted O,1TC2,3 conformation (Figure 2). An analysis of non-covalent interactions revealed that a dense network of O−H···O and C−H···O stabilized the crystal lattice of 4, whereas O−H···O and C−H···π stabilized the crystal lattice of 5. Chapter 5 describes the detailed analysis of X-ray crystal structure of two septanoside derivatives including non-covalent interactions responsible for the stabilization of crystal lattice. Figure 2. ORTEP of 4 and 5 with displacement ellipsoids, at a 10 % and 50 % probability level. In summary, the thesis established the following major results: (i) synthesis of 2-deoxy-2-C¬alkyl/aryl septanoside from a bromo-oxepine, using organometallic C-C bond forming reactions; (ii) the ring-opening reaction of oxyglycal derived gem-dihalo-1,2-cyclopropane in the presence of AgOAc and the effect of additional C-2 oxy-substituent in the reactivity, in comparison to glycal; (iii) an oxyglycal route for the synthesis of 1,7-linked-α-D-diseptanoside, 2-chloro-2-deoxy septanoside and their acid-catalyzed hydrolysis studies and (iv) solid-state X-ray crystal structural analysis and computational analysis of the conformation and non-covalent interactions associated with the stabilization of crystal lattice. Overall, the studies presented in the thesis provide a new insight into the synthesis, acid-catalyzed hydrolysis and solid-state structural analysis of septanoside derivatives.