Cyclopropanes are strained molecules and undergo reactions, for example, through ring opening and rearrangements. Preparative methods and reactivities of cyclopropanes are known widely in organic synthesis. The high reactivities inherent in cyclopropanes allow them to be valuable building blocks in organic synthesis. The combination of cyclopropanes and carbohydrates has been explored in recent years. Carbohydrates, the naturally-occurring members of chiral pool, are attractive platforms for asymmetric synthesis. Cyclopropanation of, for example, unsaturated sugars affords [4.1.0] bicyclic systems, thereby combining the high reactivities of cyclopropanes together with optical purities of sugars. Chapter 1 of the Thesis describes (i) various types of cyclopropane ring opening reactions in general and (ii) known reactions of cyclopropanes in carbohydrates relevant to the work presented in the Thesis. Seven-membered cyclic sugars, namely, septanoses and septanosides, are less commonly known sugar homologues. Synthesis of septanoses arise interest, due to their configurational and conformational features and the attendant possibilities to explore their chemical, physical and biological properties. In a programme, it was desired to identify a new methodology for synthesis of septanosides. It was envisaged that 2-hydroxy glycals, namely, oxyglycals, would form as suitable substrates for ring expansion, leading to the formation of septanoside derivatives that are retained with hydroxyl groups in each carbon of the septanoside. In the event, a new methodology was identified. A carbene insertion of an oxyglycal substrate, nucleophilic ring opening of the cyclopropyl moiety, oxidation and reduction reactions were identified to expand the six membered pyranoses to seven membered septanosides (Scheme 1). The methodology was established through preparation of two configurationally different septanosides, namely, the methyl α-D-glycero-D-talo-septanoside and methyl α-D-glycero-L-altro-septanoside from D-glucose and D-galactose, respectively. Chapter 2 presents details of the methodology and the preparation of septanosides from precursors oxyglucal and oxygalactal. Scheme 1 Continuing the efforts to extend the methodology, preparation of a variety of septanosides, using phenoxides, sugars and azide were undertaken. It was found that ring opening with sugars were highly stereoselective, leading to an exclusive formation of the -anomer of sugar oxepines, whereas, the phenoxides and azide led to a mixture of anomers of the corresponding oxepines, in a ~1:1 ratio (Scheme 2). Scheme 2 An important observation was -anomer of the oxepine derived intermediates, having diketo-functionalities, underwent NaBH4 mediated conversion to diols with higher diastereoselectivities at the newly generated stereo-centers, whereas the -anomers lacked to retain the diastereoselectivities, in the case of aryl septanosides. This part of work consolidated further the generality of the oxyglycal ring-expansion method to prepare septanosides, possessing different substituents at their reducing ends. Chapter 3 describes the details of syntheses and characterization of various aryl septanosides, septanoside disaccharides and azido-septanoside derivatives. It was planned further to synthesize septanoside containing di-and trisaccharides from naturally-occurring disaccharides, through the oxyglycal route. Oxyglycals, derived from lactose and maltose, were expanded to septanoside-containing trisaccharides through a ring expansion method. Thus septanosides incorporated disaccharides and trisaccharides, with 6-7, 6-7-5 and 6-7-6 ring sizes, were prepared through the ring expansion method. The reaction not only led to a ring expansion, but also, to a concomitant glycoside formation, in a stereoselective manner (Scheme 3). Scheme 3 A conformational analysis of the galacto-septano-glucopyrano-configured 6-7-6 trisaccharide was undertaken with aid of NMR spectroscopy and computational methods. Spatial distances from NMR experiments were utilized while performing molecular dynamics with AMBER* force field and further optimizations using B3LYP/6-31+G* level. The study showed that septanoside ring in the trisaccharide adopted twist-chair conformation O,1TC5,6, as shown in Figure 1. Chapter 4 describes synthesis of septanoside containing di-and trisaccharides and conformational analysis of a 6-7-6 trisaccharide, through solution phase and computational methods. An effort was pursued to prepare septanoside-based amphiphiles with varying alkyl chain lengths, using our newly established methodology and to study their amphiphilicities. A series of septanoside amphiphiles, having C10 to C18 alkyl groups, were prepared as their -anomers as shown in Figure 2. The amphiphilic behavior of the alkyl septanosides was assessed through studies of their liquid crystalline (LC) properties. The LC properties were evaluated using polarizing optical microscopy, differential scanning calorimetry and powder X-ray diffraction methods. All the septanoside amphiphiles exhibited a smectic A phase in general. DSC thermograms showed crystal-crystal and crystal-mesophase phase transitions. Powder X-ray diffraction studies allowed to identify the lamellar structuring of the smectic A phase. Further, two distinct two layer spacings were observed. Such an observation is un-usual in carbohydrate liquid crystals. Chapter 5 details of synthesis and studies of the mesomorphic behavior of septanoside amphiphiles. In summary, the Thesis establishes a new route to synthesize septanoside derivatives, from oxyglycal sugar derivatives. Ring expansion of a pyranoside to a septanoside was achieved through key reactions of a cyclopropanation, ring opening, oxidation and reduction. Methyl α-D-glycero-septanoside derivatives were synthesized, from the corresponding oxyglycals. Cyclopropane ring opening ability of various nucleophiles were studied, it was found that ring-opening reactions with phenols, sugars, and azides are effective, which facilitated the synthesis of various aryl, glycosyl and azido-substituted septanosides. Synthesis of septanosides incorporated with di-and trisaccharides were accomplished. The detailed conformational analysis studies showed that the septanoside adopted twist-chair conformation in a trisaccharide molecule. Preparation and studies of septanoside based amphiphiles and their mesophase behavior were also accomplished. Overall, the studies presented in the Thesis provide a new insight to ring expanded sugars. The salient features of the present method are that the intermediates such as the seven membered vinyl halides, vinyl ethers, the diketones and the diols are potential sites for many other functionalizations. These features can be explored further in functionalizing the newly formed septanosides. (For structural formula pl see the pdf file)

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.