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)

Unsaturated sugars constitute as an important category of carbohydrate precursors in synthesis. Specifically, 1,2- and 2,3-unsaturated glycosides are excellent intermediates to derivatize monosaccharides and as building blocks in organic synthesis. For example, a major utility of 1,2-unsaturated sugars, namely glycals, is the addition reactions to afford 2-deoxy glycosides under acidic conditions and rearrangement reactions to produce 2,3-unsaturated glycosides. Lewis acids favour the formation of 2,3-unsaturated glycosides, whereas, Brønsted acids lead to normal addition products. A mixture of both the product is obtained often, depending on the nucleophiles and the stereochemistry of glycal. Chapter 1 of the thesis describes (i) reactivities of glycals under acidic condition and (ii) a general survey of reactions involving on C2-C3 carbons of monosaccharides. Glycals are useful precursors to derive a number of functionalized monosaccharide derivatives. A well-known acid catalyzed reaction of glycals is their conversion to 2,3¬unsaturated glycosides, known as the Ferrier products. In a research programme, reactivity switching and selective activation of C-1 or C-3 of 2,3-unsaturated thioglycosides under acid catalyzed condition was undertaken. Thioglycosides are excellent glycosyl donors and can be activated easily. In identifying the reactivities of 2,3-unsaturated thioglycosides, obtained through Ce(IV)-mediated reaction of a glycal, it was intended to study the glycosylation reaction and also the reactivity control of C1-C3 carbons during a glycosylation reaction. Experiments showed that a reactivity switching was possible through activation of either C-1 or C-3. Thus, C-1 glycosylation with alcohol acceptors occurred in the presence of NIS/TfOH, without the acceptors reacting at C-3. On the other hand, reaction of 2,3-unsaturated thioglycosides with alcohols mediated by triflic acid alone led to a transposition of C-1 ethylthio-moiety to C-3 intramolecularly, to form 3-ethylthio-glycals. Resulting glycals underwent glycosylation with alcohols to afford 3-ethylthio-2-deoxy glycosides. However, when thiol was used as an acceptor, only a stereoselective addition at C-3 resulted, so as to form C-1, C-3 dithio-substituted 2-deoxypyranosides. Oxocarbenium ion is the reactive intermediate during activation of a glycosyl donor, and in the case of a 2,3-unsaturated thioglycosides, the oxocarbenium ion may stabilize further by the presence of a C2-C3 unsaturation. Reaction of a nucleophile with allylic oxocarbenium ion may lead to two regio-isomers. Initially, NIS/TfOH was attempted on 2,3–unsaturated sugar with various alcohols and it was found that C-1 was the preferred reactive centre (Scheme 1) Scheme 1 In order to optimize the reaction for selective nucleophilic attack at C-3, further study was continued by using stoichiometric TfOH, in presence of acceptors alcohols with the intension to activate the double bond. The reaction led to the formation of 2-deoxy O-glycosides with the concomitant transposition of C-1 ethylthio-moiety to C-3 (Scheme 2). Scheme 2 An important observation was that the transposition of thioethyl group from C-1 to C-3 was highly regioselective. For example, with thiocresol as the nucleophile, there was an addition across the C-2-C-3 double bond to afford C-1, C-3-dithio derivative (Scheme 2). Thus, hard-soft nature of the nucleophiles, as well as, carbon centres helped to rationalize the reactivites. It was also observed that the intramolecular transposition of thioethyl group is highly stereo-controlled by equatorial C-4 acetoxy group. Thus, thioethyl nucleophile approached selectively at C-3 and afforded trans-diequatorial products. This rationalization was further confirmed through (i) reaction of benzyl protected 2,3-unsaturated thioglycoside, wherein a C-3 epimeric mixture was observed in 1:1 ratio; (ii) galactosyl derivative under similar reaction condition afforded anomeric mixture of 3-(4-methylphenylthio)-O-glycosides, with trans-diaxial orientation of substituent at C-3 (Scheme 3). Scheme 3 These reactions confirmed the role of C-4 substituent on the carbocation at C-3, through the presence or absence of a neighbouring group participation. In summary, in Chapter 2 the selective activation of either anomeric carbon or C-3 with proper choice of activation and reactivity control at each carbon will be described. Thioglycosides are excellent glyosyl donor and their glycosylation reactions were well explored. Upon indentifying the intramolecular transposition of thioalkyl/aryl functionality from C-1 to C-3, further investigations was undertaken to utilize the newly formed carbon sulfur bonds at C-3. Realizing a potential for such 3-alkyl/aryl thio 2-deoxy sugar, the Pummerer rearrangement was investigated. For this purpose, the thioalkyl/aryl moiety at C-3 was oxidized first to a sulfoxide. The resulting sulfoxide was allowed to undergo Pummerer rearrangement to afford vinyl sulfide (Scheme 4), resulting from the elimination of HOAc in the thioacetal formed in situ. Having implemented Pummerer rearrangement on a sugar substrate, synthetic utility of the rearrangement product, namely vinyl sulfide was undertaken. An effort to implement conjugate addition reaction was undertaken, which required the conversion of vinyl sulfide to vinyl sulfoxide in the first step. The conjugate addition reactions were first conducted with alkoxide nucleophiles. The reaction showed that addition of nucleophiles occurred from axial face to furnish manno-configured derivatives as a single diastereomer at sulfinyl sulfur in a moderate yield along with O-deacetylated product. It was also found that O-benzyl protected sugar vinyl sulfoxide was totally resistant to the conjugate addition reaction (Scheme 4). Scheme 4 In order to find the influence of the substituents in sulfoxide moiety in the addition of nucleophiles, additional study was conducted in which a less hindered thioethyl moiety was installed in place of p-tolylthio moiety. To install ethylthio moiety, a similar sequence of reaction was undertaken as described previously in Scheme 4. Conjugate addition reaction with alkoxide nucleophiles was conducted and analysis of the reaction showed that the addition of alkoxides remained similar, leading to the formation of manno-configuration of substituents (Scheme 5). Scheme 5 The configuration of the Michael adducts were ascertained from 1H NMR, as well as 2D NMR spectroscopies. H-1 of all adducts appeared as an apparent singlet, consistent with very small J1,2 values. Aryl vinyl sulfoxide afforded conjugate addition product at much higher ratio than corresponding alkyl vinyl sulfoxide. Thus, among aryl and alkyl vinyl sulfoxides, conjugate addition occurred better with the aryl vinyl sulfoxide, indicating a strong electronic effect of aryl group in stabilizing the conjugate anion which would form in situ during nucleophilic addition with vinyl sulfoxide. Therefore, p-tolylthio substituted vinyl sulfoxide served as a more efficient Michael acceptor when compared to the thioethyl substituted vinyl sulfoxide. Asymmetric environment of vinyl sulfoxides play a vital role during the reaction. Vinyl sulfoxides can exist in two stereochemically distinct conformation which makes the vinyl group electronically dissimilar. In one of the conformer S-O and C-C bonds are coplanar, whereas in the other conformation, these two bonds are opposite to each other. It is agreed generally that vinyl sulfoxides generally try to adopt the most reactive conformer during the reaction in which the C-C and S-O bonds are syn to each other. Thus, the preference for an axial attack would originate from a face anti to the lone pair of electrons on the sulfur of sulfoxide functionality, leading to the formation of the product with manno-configuration. As O-deacetylated vinyl sulfoxide was obtained along with the Michael adducts, it was assumed that one of the epimers of vinyl sulfoxide appeared to be more reactive when compared to the other. Chapter 3 describes implementation of a Pummerer rearrangement in order to synthesize a sugar vinyl sulfoxide and its conjugate addition reactions with alkoxide nucleophiles. The nucleophilic addition reactions of vinyl sulfoxide with other nucleophiles were studied further. The effect of the substituents of chiral sulfoxides in conjugate addition reactions was also incorporated in the course of reactions. Reactions of amines, carbon and sulfur nucleophiles were undertaken with p-tolylthio-substituted vinyl sulfoxides. The reactions showed formation of the addition-elimination products (Scheme 6). All primary amines, carbon and sulfur nucleophiles afforded C-2 axial epimer, namely, threo-epimer exclusively, wherein secondary amines furnished the equatorial vs axial epimer in 3:1 ratio. Scheme 6 In order to assess the course of the reaction, vinyl sulfoxide presenting a p-cumenethio¬moiety was installed in place of p-tolylthio moiety. Conjugate addition reactions were performed with both primary as well as secondary amines that showed formation of the C-2 epimeric mixtures. With both the primary and secondary amines C-2 equatorial epimer was found to be as the major product (Scheme 7). Scheme 7 In conjugate addition of vinyl sulfoxides, nucleophiles approach the olefinic face preferentially, which is anti to the electron rich sulfur lone pair of electrons and syn to the bulky aryl group. Therefore, C-2 axial epimer was observed as most favourable product. However, secondary amines remarkably influenced the pattern as well as selectivity of the reaction. Steric considerations were likely to dictate the overall reactivity with secondary amines which was even more pronounced when using p-cumenethio-substituted vinyl sulfoxide. Chapter 4 describes the conjugate additions as well as remote effect of aryl substituent on the selectivity of addition of amines on sugar sulfoxide In summary, the Thesis establishes: A new reactivity of switching and a selective activation of 2,3-unsaturated thioglycoside; A Pummerer rearrangement route in order to synthesize sugar vinyl sulfide for the first time, which on selective oxidation furnish a sugar vinyl sulfoxide, a useful precursor for conjugate addition reactions; An assessment of the stereoelectronic, as well as, steric effect of the chiral vinyl sulfoxide with various nucleophiles in conjugate addition reactions; Influence of the protecting groups were also studied in conjugate addition reactions. Overall the study presented in the Thesis provides a new insight to unsaturated sugars. The salient features of the present findings also showed that the intermediates such as C-3 substituted thioalkyl/aryl glycosides, vinyl sulfides, a variety of new C-2 substituted vinyl sulfoxides are also the potential sites for many types of modifications in monosaccharides. (For structural formula pl see the pdf file)