The oxidation of simple benzene derivatives by a mutant of Pseudomonas putida, called 39-D, produces cis-arenediols (1). The diols are enantiomerically pure and can be used as synthons for the preparation of a variety of interesting compounds because of their stereochemistry and the special array of functional groups. See: Figure 1 cis -Toluenedio] (2) served as a chiral intermediate in an efficient synthesis of enone (3). which has been used to attain prostaglandin Fra and Neplanocin A. The same diol (2) was transformed into both enantiomers of a terpene synthon (4). See: Figures 2, 3, 4 Oxidative functionalization of cis-chlorobenzenediol (5) afforded intermediates suitable for transformation into L-erythrose (6), conduritol C (7), dihydroconduritol C (8) and aminoconduntol F-4 (9). See: Figures 5, 6, 7, 8 The application of this versatile synthetic protocol culminated in an approach to kifunensine (10), an important glycosidase inhibitor, which was approached according to the following retrosynthetic analysis: See: Figures 10, 11, 12, 5, 14, 13 A detailed study of the nucleophilic opening of epoxide 13 was carried out in order to better understand the parameters of the diastereoselective functionalization of arenediols. Details are provided for the oxidative functionalization of chlorobenzenediol (5), the key compound in all of the projects discussed. / Ph. D.

Carbohydrates are a family of polyfunctional natural products and can be chemically modified in numerous ways. The primary significance of carbohydrates rests in their importance in biological functions. A particular class of sugars, namely, 2-deoxy or C-2 modified sugars has received a special attention, due to their importance in biological functions. These sugars are defined as carbohydrates carrying a hetero-atom, other than the hydroxyl group, and their derivatives. There is an ever-leading requirement to synthesize various carbohydrates-containing natural and un-natural products, such as, oligonucleotides, glycopeptides, antitumor drugs and cardiac glycosides, having C-2 modified sugars. Chapter 1 describes various synthetic modifications, particularly at the C-2 of a monosaccharide, as relevant to the work presented in this Thesis. 1, 2-Unsaturated glycopyranosides, namely, glycals, are versatile synthetic intermediates for the elaboration to a number of functionalized glycosyl derivatives. A major utility of the glycals is their conversion to the 2-deoxy glycosyl derivatives. In a programme, it was desired to identify a synthetic method to prepare 2-deoxy sugar derivatives that are endowed with an anomeric activation. In particular, a thioglycoside activation was desired. In the event, a methodology was identified, which allowed the synthesis of activated 2-deoxy-1-thioglycosides.The method involved reaction of a glycal with EtSH, in the presence of ceric ammonium nitrate (CAN) as the catalyst. The reaction was applicable to different epimeric glycals. Apart from the 2-deoxy-1-thioglycosides, formation of the 2, 3-unsaturated enoses, corresponding to the Ferrier product, also observed. Optimal conditions for the formation of the 2-deoxy-1-thioglycosides were identified (Scheme 1) and the reaction was proposed to proceed through a radical oxocarbenium ion and a thiolate intermediate. (Fig) Scheme1 Upon synthesis of 2-deoxy-1-thioglycosides, few glycosylation reactions with both aglycosyl and glycosyl acceptors were performed and the α-anomeric 2-deoxy glycosides were obtained exclusively. Chapter 2 summarizes synthesis, characterization of 2-deoxy-1-thioglycosides and their glycosyl donor properties towards several glycosyl acceptors. Many naturally-occurring antibiotic and antitumor drugs contain 2-deoxy glycosides as important structural components. For example, 2,6-dideoxy-hexopyranoses are common structural units of chromomycin A3, olivomycin A and mithramycin. The most common structural features of these molecules are: (i) the presence of 2-deoxy sugar residues and (ii) the sugar residues are connected to the aromatic moiety, through a β-glycosidic linkage. The synthesis of these biologically important 2-deoxy glycosides encounters difficulties, due to the absence of stereoelectronic influences at C-2 of the 2-deoxy glycosyl derivatives. Direct glycosylation of phenols and naphthols with activated 2-deoxy-1-thio-glycosides, in the presence of the thiophilic activator N-iodosuccinimide/triflic acid (NIS/TfOH), lead to the formation of the α-anomer, as the major glycosylated product (Scheme 2). (Fig) An effort was under taken to identify methods to prepare the 2-deoxy aryl glycosides, in the β-anomeric configuration. A nucleophilic substitution reaction was anticipated to lead to the formation of β-anomeric glycosides. A halide substitution at C-1 for an effective nucleophilic substitution was adopted. Thus, conversion of the activated 2-deoxy-1-thioglycosides with Br2 in the first step, followed by reaction of the resulting bromide with aryloxy anions, led to the facile conversion to 2-deoxy glycosides in a nearly quantitative f-anomeric configuration at C-1(Scheme 3). Scheme 3 (Fig) Chapter 3 presents details of the methodologies that allow a facile preparation of each of the anomers of aryl 2-deoxy-D-glycosides from a common precursor, namely, 2-deoxy-1-thio-glycosides. An easy access to activated 2-deoxy-1-thioglycosides from the 1, 2-unsaturated sugar and their synthetic utility towards various glycosyl and aglycosyl acceptors led towards synthesis of 2-deoxy disaccharides. Synthesis of six new 2-deoxy-arabino-hexopyranosyl and 2-deoxy-lyxo-hexopyranosyl sugar containing disaccharides were accomplished. These are: (i) 2-deoxy-α-D-arabino-hexopyranosyl-(1→4)-D-glucopyranose (2'-deoxy maltose); (ii) 2-deoxy-α-D-lyxo-hexopyranosyl-(1→4)-D-glucopyranose; (iii) 2-deoxy-α-D-arabino-hexopyranosyl-(1→4)-2-deoxy-D-arabino-hexopyranose (2,2'-dideoxy maltose); (iv) 2-deoxy-α-D-lyxo- hexopyranosyl-(1→4)-2-deoxy-D-arabino-hexopyranose; (v) α-D-glucopyranosyl-(1→4)-2 deoxy-D-arabino-hexopyranose (2-deoxy maltose) and (vi) β-D-galactopyranosyl-(1→4)- deoxy-D-arabino-hexopyranoside (2-deoxy lactose). The 2'-deoxy and 2, 2'-dideoxydisaccharides were synthesized using a 2-deoxy glycosyl donor and a normal glycosyl acceptor (in case of 2'-deoxy disaccharides) and a 2-deoxy glycosyl acceptor (in case of 2, 2'-dideoxy disaccharides) with a free OH group at C-4, while the remaining hydroxyl groups protected suitably (Scheme 4). Scheme 4 (Fig) On the other hand, the syntheses of 2-deoxy disaccharides were initiated from a D-maltose and D-lactose, respectively. The conversion of these disaccharides to a disaccharide glycals was targeted first and conversion of these glycals to a 2-deoxy-1-thioglycosides or a 2-deoxy-1-acetates, followed by a hydrolysis of the thiol moiety or the acetate group, afforded the 2-deoxy disaccharides (Scheme 5). (Fig) Chapter 4 describes synthesis, characterization of 2-deoxy, 2,2'-dideoxy and 2'-deoxy disaccharides. Continuing the efforts to establish the utility of 2-deoxy-1-thioglycosides as potential glycosyl donor, synthesis of 2-deoxy cyclic and linear oligosaccharides was undertaken. Prominent among cyclic oligosaccharides are the cyclodextrins. Due to their unique structural and physical properties, cyclodextrins find manifold applications. Known methods to synthesize cyclic oligosaccharides are (i) the cyclization of linear oligosaccharides to produce the cyclic oligosaccharides and (ii) the synthesis of designed monomers and subjecting them to cyclooligomerization protocols. The cyclooligomerization was adopted to synthesize new types of 2-deoxy cyclic-and linear oligosaccharides. After a series of trials, a disaccharide monomer, namely, ethyl 4-O-(6-O-benzoyl-2,3-di-O-methyl-α-D-glucopyranosyl)-2-deoxy-3,6-di-O-methyl-arabino-hexopyranoside (1), was identified as a suitable monomer for thecyclooligomerization protocol. For an effective oligomerization, the concentration of the monomer and the choice of the reagents are important. The reaction was conducted at three different monomer concentrations, 2 mM, 10 mM and 25 mM, using two thiophilic activators, namely, (i) NIS/TfOH and (ii) NIS/AgOTf. Better yields of the cyclic oligosaccharides, namely, the cyclic tetrasaccharide (2) (40 %) and cyclic hexasaccharide (3) (25 %), were isolated when the monomer (1) concentration was 25 mM and NIS/TfOH acid was used as the promoter (Scheme 6). The formation of linear disaccharide (4) (10 %) and tetrasaccharide (5) (18 %) was also observed at this concentration. On the other hand, when the reaction of the monomer was performed in the presence of NIS/AgOTf, the oligomerization reaction led to the formation of linear oligosaccharides, consisting of di-to eicosa-saccharides. Synthesis of different monomers, their characterization and oligomerization reaction using these monomers through a polycondensation protocol are discussed in Chapter 5. Scheme 6(fig) In summary, the Thesis establishes the chemistry of 2-deoxy sugars, formation of activated 2-deoxy sugars, formation of alkyl and aryl glycosides, 2-deoxy disaccharides, 2-deoxy cyclic and linear oligosaccharides. Routine physical methods were used to characterize the newly formed 2-deoxy sugars and the oligosaccharides. Single crystal X-ray structural determination was performed for an aryl 2-deoxyglycosides, which provided the solid state configurational features of the 2-deoxy pyranose. (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.