Abstract This thesis entitled “Synthesis of New Glycosubstances, attempted synthesis of Isoavenaciolide and New Reagents for the conversion of alcohols into p-methoxybenzyl ethers” is divided into three chapters. Chapter 1: Synthesis of New Glycosubstances This chapter is divided into two sections. Section A describes the synthesis of carbon-carbon linked disaccharides using furan as masked sugar synthon and new furyl sugars as intermediates for ‘new glycosubstances’. Section B deals with the description on the synthesis of acetylenic new glycosubstances, which are useful intermediates for the synthesis of New Chemical Entities of therapeutic value. Section A: This section is further divided into two parts. Part I: Synthesis of C(4)-C(5) linked (L)- and (D)-disaccharides from ‘diacetone glucose’ The role of carbohydrates in nature goes under the broad heading of “Glycobiology”1, an eye-opening subject encompassing many areas of interest particularly to the synthetic organic chemist and more recently receiving attention from a therapeutic drug development aspect2. OMe OMe AcO OMe AcO O AcO O O AcO O O H OAc MeO 1 O O AcO O O AcO H OAc MeO 2 O O H OAc MeO 3 O The C-glycosides3, where a methylene group replaces the interglycosidic oxygen atom, are non-metabolisable analogues of natural disaccharides and represent an interesting class of compounds for therapeutic studies. Synthetic C-glycosyl compounds are starting chiral synthons, suitable for the synthesis of complex molecules, as they contain a large number of chiral centres and functional groups. In a broader context, this subclass also includes examples in which the monosaccharide units are connected either directly or by way of more extended as well as substituted carbon spacers. 1 Abstract In the present study, addition of 2-furyl lithium to the enantiopure aldehyde template 4 obtained from DAG and further transformations was identified in offering a direct access to the disaccharides 1, 2 and 3, where the new sugar unit has been constructed from the furan moiety, while chirality was induced from the parent sugar template. Accordingly, addition of 2-furyl lithium to the known aldehyde 4 (Scheme 1) afforded the derivatives 5a and 5b as a diastereomeric mixture separable by column chromatography. However, this mixture was successively converted into the major diastereomer 5a by a two step synthetic sequence viz a) oxidation of the diastereomeric mixture under Swern oxidation conditions and b) subsequent reduction of the ketone 6 with NaBH4. Scheme 1 OHC O OM e O 4 OH O OH O O OM e O H 5a O a O + H 5b O OM e O b 6 O c O O O OM e O H O Reagents: a) 2-furyl lithium, THF, -780C; b) (COCl)2, DMSO, Et3N, CH2Cl2, -780C; c) NaBH4, MeOH, 00C. Oxidative unmasking of furan4 with Br2-pyridine in aqueous acetone gave the lactols 7 (Scheme 2), which on reaction with Ag2O-MeI, was subsequently converted into an inseparable mixture of -O-methyl pyranosides 8. Scheme 2 OR 5a OM e O a, b OM e O O c O O O H OH M eO 9 O H O M eO 7 R = H; 8 R = Me OM e OM e O + O O + O O O H OH M eO O 10 H OH M eO O O 11 OM e RO 10 d O O H OAc M eO 12 O e, d O O RO O H OAc O M eO 13 R = H; 1 R = Ac O Reagents: a) Br2, pyridine, aqueous acetone; b) Ag2O, MeI; c) NaBH4, MeOH, 00C; d) Ac2O, pyridine; e) OsO4, t-BuOH: THF. 2 Abstract Stereoselective reduction of 8 using NaBH4 in MeOH afforded after chromatographic purification, the two -glycosides 9 (minor) and 10 (major) in 3:5 ratio while the -anomers 11 were not separable. The major isomer 10 was subjected to acetylation (Ac2O, pyridine) to give the acetate 12, which on selective5 cis dihydroxylation of the double bond using OsO4-NMO in t-BuOH-THF gave the diol 13. Finally, acetylation of the diol 13 (Ac2O, pyridine) gave the tri-acetate 1. Similar functional group transformations performed on the minor isomer 5b resulted in obtaining 2, the antipode of 1 and 3. Accordingly, oxidative ring opening of 5b gave the lactols 7a (Scheme 3), which were subsequently converted into the methyl glycosides 8a. Reduction of the enones 8a with NaBH4 and chromatographic separation gave the allylic alcohols 9a (major) and 10a (minor) in 2:1 ratio. Acetylation of 9a and chromatographic purification afforded 11a (major) and 11b (minor). These were subsequently submitted to catalytic osmylation to afford the diols 12a and 12b, which on acetylation furnished the respective tri–acetates 2 and 3. Scheme 3 OR 5b O a, b OM e OM e O O c O H O + O O H OH M eO O M eO 7a R = H; 8a R = Me O O H OH M eO O 9a OM e O O 10a OM e RO O O O 9a d OAc M eO O e, d O OAc O M eO 12a R = H; 2 R =Ac O 11a OM e O RO + OM e RO O O OAc M eO O e, d O O RO O OAc O M eO 12b R = H; 3 R =Ac O 11b Reagents: a) Br2, pyridine, aqueous acetone; b) Ag2O, MeI; c) NaBH4, MeOH, 00C; d) Ac2O, pyridine; e) OsO4, t-BuOH: THF. 3 Abstract Part II: Synthesis of furyl sugars – intermediates for ‘new glycosubstances’ In the preceding section, D-glucose was efficiently converted into furyl sugars (Scheme 1). Scheme 1 OH OH O O OHC O O O O a H O MeO 1 MeO 2a O O O + O H O MeO 2b O b O H O MeO 3 O Reagents: a) 2-furyl lithium, THF, -780C; b) (COCl)2, DMSO, Et3N, CH2Cl2, -780C. Similarly, galactose diacetonide 4 was subjected to oxidation to give 5, which on reaction with 2-furyl lithium gave 6 (Scheme 2) as an inseparable mixture of isomers. Further oxidation of 6 under Swern conditions gave the keto derivative 7. Scheme 2 O OH O HO O O O 4 OHC O a O O O O O b O O O O5 O O H O 6 a O O H O O O 7 Reagents: a) (COCl)2, DMSO, Et3N, CH2Cl2, -780C; b) 2-furyl lithium, THF, -780C. In a further study, aldehyde 5 (Scheme 3) was converted into acetylene 9 through 8. Reaction of 9 with 2-furaldehyde gave the furyl sugar 10. Scheme 3 Reagents: a) PPh3, CBr4, CH2Cl2, 00C; b) n-butyl lithium, THF, -780C; c) n-butyl lithium, 2-furaldehyde, THF, -780C. Likewise, the known olefin 11 (Scheme 4) was subjected to 1, 3-dipolar cycloaddition reaction with the oxime derived from furaldehyde to give the adduct 12, which on reduction using LAH afforded the furyl derivative 13. 4 Abstract Scheme 4 HO HO O OMe O O OMe H a NHR OR N O 12 O 11 O O b O O OMe c O OMe H O O O 13 R = H O O 0 Reagents: a) PPh3, I2, Imidazole, Toluene, 110 C; b) furaldoxime, NCS, Et3N, CH2Cl3, RT; c) LAH, ether, 00C. In a similar study, the known alcohol 14 (Scheme 5) on oxidation with DMSO(COCl)2 gave the aldehyde 15, which on reaction with 2-furyl lithium afforded 16a and 16b. Further oxidation of the isomeric mixture furnished the keto derivative 17. Scheme 5 O O O OH O O O a O O OH O O 14 O b O CHO O O c O OH O O H O O + O OH O O OH 16a b O OH H O H O O OH 16b 15 O O O d O O 17 Reagents: a) TMSOI, t-BuOK, DMSO; b) (COCl)2, DMSO, Et3N, CH2Cl2, -780C; c) 2furyl lithium, THF, -780C; d) NaBH4, MeOH. The thus prepared furyl sugars are very useful intermediates for the synthesis of Cdisaccharides, glycosyl hydroxy, keto and amino acids, aza-C-disaccharides and others. 5 Abstract SECTION B: Synthesis fluorophenoxymethyl)-3, of (2R, 5R)-5-Ethynyl-2-(p- 4-O-isopropylidinetetrahydrofuran from mannose diacetonide: Chiral tetrahydrofuran based compounds such as A and several 2, 5-disubstituted tetrahydrofurans with biological activity were found in nature6. The research for the development of new drugs based on such chiral tetrahydrofurans resulted in several analogues having anti-inflammatory activity. Such a research resulted in a therapeutically interesting tetrahydrofuran A and its stereoisomers as potent 5-LO inhibitors7. In furthering the research on the development of new chiral furans with potent activity, synthesis of 1 was reported starting from ‘mannose diacetonide’. OH HO O O O F O R R F A R = CH2CH2N(OH)CONH2 1 R = CH2CH2N(OH)CONH2 1, is a tetrahydrofuran derivative related to A, with a dihydroxy group. The synthesis of acetylene 2 would serve as a key intermediate for the synthesis of NCEs and radio labelled compounds for the metabolic studies. As seen from the Scheme 1, it was envisaged that 2 could be made from ‘mannose diacetonide’ 3 by the transformations as indicated. Scheme 1 F introduce CH2OAr O O O H O OH O O convert to acetylene O O O 3 2 Accordingly, the known alcohol 4 (Scheme 2) was subjected to tosylation using pTsCl and Et3N in CH2Cl2 to give 5, which on etherification with p-fluorophenol using NaH in dry DMF gave 6 in 53% yield. Deprotection of isopropylidene functionality in 6 with catalytic Conc. HCl in MeOH at room temperature afforded the diol 7, which on oxidative cleavage with NaIO4 in the presence of aqueous NaHCO3 in CH2Cl2 gave the corresponding aldehyde 8 (79%). Finally, aldehyde 8 on treatment with CBr4 and Ph3P 6 Abstract in CH2Cl2 at room temperature afforded dibromo compound 9, which on further reaction with n-BuLi gave 2 in 77% yield. Scheme 2 O O O O O O OH 3 OR O b, c a O F HO HO d O O O O O 5 R = Ts 4 OHC 7 6 R = 4-F-Ph Br F Br F O O e f O O O g O H O O 8 2 O 9 Reagents: a) TMSOI, t-BuOK, DMSO, 0ºC to RT, 1 h; b) p-TsCl, Et3N, CH2Cl2, RT, 4 h; c) 4-F-C6H4OH, NaH, DMF, 80ºC, 5 h; d) Conc. HCl, MeOH, RT, 2 h; e) NaIO4, saturated aqueous NaHCO3, CH2Cl2, RT, 6 h; f) CBr4, Ph3P, CH2Cl2, 0ºC to RT, 30 min; g) n-BuLi, THF, -78ºC to RT, 2 h. Thus, in the present study, the acetylene 2 was prepared by the introduction of hydroxymethylene substituent at C-1 of mannose diacetonide while C-5 was converted to acetylene moiety. In a further study, the change of the sequence, i.e., introduction of -CH2OAr group at C-5 position and acetylenic substituent at C-1 position results in a different isomer of 2. Accordingly, 3 (Scheme 3) was treated with diphenyldisulphide and TBP in dichloromethane to afford the thioglycoside 10. 10 was hydrolysed with catalytic Conc. HCl in MeOH for 2 h, to afford the diol 11, which on oxidative cleavage with NaIO4 in aqueous dichloromethane afforded the aldehyde 12. Scheme 3 O O O OH O O b O O 10 O SPh O O 11 d O 12 O O O SPh g O O OHC SPh c HO O RO SPh e, f HO 13 SPh O O O O O a O 3 HO O O SO 2Ph O F 16 14 R = Ts 15 R = 4-F-C4H4 O O F O O R 17 R = -CH2CH2OMPM Reagents: a) PhSSPh, Bu3P, CH2Cl2; b) H+, MeOH; c) NaIO4, aqueous CH3CN; d) NaBH4, MeOH; e) p-TsCl, Et3N, CH2Cl2; f) 4-F-PhOH, NaH, DMF, 80ºC; g) Ammonium molybdate, H2O2, EtOH. 7 Abstract Reduction of 12 with NaBH4 in MeOH gave the hydroxy compound 13. Tosylation of the hydroxyl group in 13 using TsCl and Et3N in CH2Cl2 afforded 14, which on reaction with 4-F-C6H4OH using NaH in DMF gave 15. The next step was to oxidise thiophenyl substituent to sulfone funtionality, which can be substituted with the required R-group through zinc mediated coupling. Oxidation of thiophenyl substituent in 15 was achieved with ammonium molybdate and H2O2 in ethanol affording the sulfone 16. However, efforts to substitute sulfone moiety in 16 with zinc mediated alkynyl bromide coupling met with failure in offering 17. CHAPTER 2: New reagents for the conversion of alcohols into pmethoxybenzyl ethers This chapter is dealt with the description of development of new methodologies for the conversion of alcohols into p-methoxybenzyl ethers using the lanthanide triflates such as Yb(OTf)3 and Y(OTf)3 as Lewis acid catalysts and with newly developed reagents. This chapter is further divided into two sections. SECTION A: p-Methoxybenzyl acetate (PMBA)- A new reagent for the conversion of alcohols into p-methoxybenzyl ethers through Yb(OTf)3 catalysis The p-methoxybenzyl group is frequently used for the protection of alcohols, which is introduced by NaH and p-methoxybenzyl bromide in the conventional method where base sensitive groups are not compatable. Herein, simpler method for the preparation of PMB-ethers is described employing milder conditions wherein acid and base sensitive groups do survive the reaction conditions. A new reagent, p-methoxybenzyl acetate (PMBA) was prepared and developed as a new and facile reagent for PMB protection. p-Methoxybenzyl alcohol was treated with Ac2O in pyridine to give PMBA. Alcohol was subjected to reaction with PMBA and 5 mol% Yb(OTf)3 in dichloromethane at room temperature to give the PMB-ethers, where both acid and base sensitive groups survive under the reaction conditions. 8 Abstract ROH Yb(OTf)3 MPMOAc CH2Cl2, RT ROMPM eq (1) R = alkyl, terpenoidal, sugar etc. The generality of the reaction was established by studying the protection of a wide variety of alcohols such as aliphatic, terpenoidal and sugar derivatives. SECTION B: Y(OTf)3 mediated conversion of alcohols into pmethoxybenzyl ethers with PMBA and PMB-silyl ethers Two new reagents, t-butyldimethylsilyl p-methoxybenzyl ether (PMB-OTBS) and t-butyldiphenylsilyl p-methoxybenzyl ether (PMB-OTPS) were prepared and used for the preparation of PMB-ethers. p-Methoxybenzyl alcohol was treated with TBS-Cl and imidazole in CH2Cl2 to give PMB-OTBS, while treating PMB-OH with TPS-Cl under same conditions furnished PMB-OTPS. PMB protection of a variety of alcohols was performed using the rare earth triflate Y(OTf)3 in catalytic quantity employing the newly developed reagents PMBA, PMBOTBS and PMB-OTPS, in an extension to the protocol developed in our group8, wherein PMB-OH was employed as a reagent for the formation of PMB-ethers. Comparative studies for better choice of the reagents and catalysts are recorded. ROH Y(OTf)3 MPMOR' CH2Cl2, RT ROMPM eq (2) R = alkyl, terpenoidal, sugar etc. R' = Ac, TBS, TPS The generality of the reaction was established by studying the protection of a wide variety of alcohols such as aliphatic, terpenoidal and sugar derivatives. 9 Abstract CHAPTER 3: Radical mediated approaches for the attempted synthesis of isoavenaciolide This chapter describes the synthetic efforts towards the synthesis of isoavenaciolide and is further divided into two sections. SECTION A: Attempted synthesis of isoavenaciolide starting from ‘Diacetone glucose’ (DAG) Isoavenaciolide9 1, avenaciolide10 2 and ethisolide9 3 (Figure 1) are secondary metabolites isolated fro Asperigillus and Pencillium fermentation broths, which inhibit fungal growth. Carbohydrates are appropriate starting materials and intermediates for the synthesis of enantiomerically pure compounds (chiron approach)11. Figure 1. Metabolites isolated from Asperigillus and Pencillium fermentation broths The apparent structural similarity of 1 to DAG and the presence of exo methylene group in the unique bis-butyrolactone skeleton prompted us to evolve a strategy using radical route for its synthesis. The utility of radical12 reactions on carbohydrate13 derived ‘chiral templates’, a fascinating protocol, particularly for the creation of cisfused bicyclic systems has been well documented in our group earlier, where the syntheses14-16 of avenaciolide, discosiolide, 4-epi-ethisolide, sporothriolide and (-)canadensolide has been successfully achieved. From the antithetic analysis of 1 (Scheme 1), it was envisaged that the bicyclic system 4 would conveniently furnish 1, and 4 in turn could be easily made by radical cyclisation of xanthate 5 that is obtained from DAG. Scheme 1 C8H17 O 1 OM e H H C8H17 O O O C8H17 O O H O 4 OM e C8H17 M eS(S)CO O AcO 5 10 O 6 O 7 O DAG Abstract Accordingly, the aldehyde 9 prepared from the triol 8 was converted to 10 (Scheme 2) through Wittig olefination and hydrogenation. Oxidation of 10 gave 7, which on reaction with Ac2O/pyridine gave the enol acetate 11. Catalytic hydrogenation of 11 afforded the derivative 6. Deacetylation of 6 followed by treatment of 12 with PMB-Br furnished 13. Methanolysis of 13 afforded 14, which on reaction with propargyl bromide gave 15. Treatment of 15 with DDQ and subsequent reaction of 16 with CS2MeI-NaH gave 5. However, attempts to cyclise the xanthate 5 into the fused bicyclic system 4 met with failure. Scheme 2 H HO HO OHC O O H HO O O a HO O C8H17 C8H17 O O d C8H17 e O C8H17 g O PM BO 13 OM e PM BO O C8H17 k h 14 O OH i PM BO O OM e j HO O O 16 OM e O H H O 5 O 12 C8H17 O OM e C8H17 H O HO O 6 O f 15 OM e M eS(S)CO O 10 R = C8H17 C8H17 C8H17 O O HO O AcO O c O O c 11 O H C8H17 O O 7 O 9a AcO O O R O HO O 9 8 b C6H13 O 4 Reagents: a) NaIO4, aqueous CH2Cl2; b) C6H13P+Ph3Br-, n-BuLi, THF; c) H2, 5% Pd/C, EtOAc; d) PDC, NaOAc, Ac2O, CH2Cl2, 40ºC; e) Ac2O, pyridine; f) Na, MeOH; g) NaH, PMB-Br, THF; h) H+resin, MeOH, 40ºC; i) NaH, 1-bromopropyne, THF; j) DDQ, aqueous CH2Cl2; k) NaH, CS2, MeI, THF. SECTION B: Attempted synthesis of isoavenaciolide from ‘xylose monoacetonide’ From the retrosynthetic analysis of 1 (Scheme 1), it was envisaged that a general strategy could be arrived at where the alkyl chain could be incorporated at a later stage on C-1 position i.e., after acquiring the required bicyclic system as in 3, while the C-5 carbon could be converted into lactone moiety. The bicyclic system 3 could be easily 11 Abstract envisaged by radical cyclisation of xanthate 4, as is evidenced by the lack of steric hindrance offered by the existing functional groups. Xanthate 4 could be obtained in usual functional group manipulations of the xylose monoacetonide 5. Scheme 1 OH HO 1 H O C8H17 RO HO H OMe TBSO 2 OMe HO O O H H O O O O OCS2Me 4 3 R = -TBS HO O 5 Accordingly, 5 was monoprotected with trityl group to give 6 (Scheme 2), which on reaction with NaH and 1-bromopropyne in THF gave 7, a crucial unit required for the target molecule. Methanolysis of 7 with catalytic Conc. H2SO4 in MeOH gave the diol 8, which was then selectively alkylated with TBS-Cl and imidazole in dichloromethane to give 9. Further transformation of 9 into xanthate 4 using NaH, CS2 and MeI in THF and radical cyclisation of 4 using n-Bu3SnH and AIBN in benzene at reflux for 24 h afforded 3. Having obtained the bicyclic system 3, next it was aimed at incorporating the alkyl chain by performing Grignard reaction. To achieve this, 3 was treated with aqueous TFA (5:1) to afford the required system 10, which on reaction with C8H17MgBr in THF afforded 2. The triol 2 on oxidative cleavage with NaIO4 in aqueous CH3CN resulted the lactol 11, which on oxidation with CrO3 and pyridine in dichloromethane at 40ºC afforded the mono lactone 12. However, attempts were unsuccessful in further oxidation of 12 to give 1. Scheme 2 Reagents: a) TrCl, Et3N, CH2Cl2; b) NaH, 1-bromopropyne, THF; c) Conc. H2SO4, MeOH, 50ºC, 2 h; d) TBS-Cl, imidazole, CH2Cl2; e) NaH, CS2, MeI, THF; f) n-Bu3SnH4, C6H6, 80ºC; g) aqueous TfOH; h) C8H17MgBr, THF; i) NaIO4, aqueous CH3CN; j) CrO3, pyridine, CH2Cl2, 40ºC. 12