This book describes two different projects associated with the chemical (de novo) synthesis of rare and unnatural carbohydrates from readily available starting materials. After a comprehensive introduction to indium chemistry and stereoselective aldol reactions, two new methodologies are presented which complement the synthetic arsenal available to the carbohydrate chemist. The indium mediated allylation of unprotected carbohydrates was applied in the synthesis of acetamido-heptoses and octoses which are constituents of the aminoglycoside antibiotics Apramycin and Destomycin. Furthermore, a new approach for the incorporation of fluorine into carbohydrates is described. Amino acid building blocks were chain-elongated via a titanium mediated aldol addition, finally furnishing amino-, fluoro-functionalised pentoses and hexoses. These compounds are of high interest not only concerning their potential antimicrobial activity but also their usefulness in elucidating fundamental biological processes such as antigen-antibody aggregation.

List of abbreviations 5

1 Introduction 9

1.1Barbier-rype indium reagents in organic synthesis 10

      1.1.2 Indium mediated carbonyl allylation 12

      1.1.2 Propargylation and allenylation 15

      1.1.3 Indium mediated alkylation 18

1.2 Tilanium mediated aldol-rype reactions in organic synthesis 19

      1.2.1The Mukaiyama aldol reaction 19

      1.2.2 The Evans aldol reaction 25

      1.2.3 Garner's aldehyde 33

      1.2.4 Aldol additions in carbohydrate synthesis 34

2 Results and discussion 40

2.1 Aim and background of the projecls 40

2.2 Motivalion for the Drojecls 43

      2.2.1 Motivation for the synthesis of higher amino sugars 43

      2.2.2 Motivation for the synthesis of fluorinated amino sugars 45

2.3 Synthesis of higher amino sugars 49

      2.3.1 Indium mediated allylation of unprotected carbohydrates 49

      2.3.2 Epoxidation of unsaturated aldehydes 51

      2.3.3 Nucleophilic azide opening of epoxides 53

      2.3.4 Deprotection protocol 55

2.4 Synthesis of Juorinated amino sugars 63

      2.4.1 Epoxidation/fluoride opening approach 63

      2.4.2 Allylation/ozonolysis/α-fluorination approach 66

      2.4.3 Stereoselective aldol addition approach 69

      2.4.4 Further elaboration on the aldol addition approach 81

3 Experimental part 94

3.1General methods 94

3.2 General procedures 96

      Method A: Acidic deacetylation, ozonolysis. Synthesis of 6a-c 96

      Method B: Azide reduction. Synthesis of 7a-7c 96

      Method C:Zempléen saponification. Synthesis of 8a-c,28-31 97

      Method D:Aldol addition, Synthesis of 15-19,32-33,42 97

      Method E: Oxazolidinone,acetonide cleavage. Synthesis of 20-23 98

      Method F:DIBAL reduction,Boc cleavage.Synthesis of 24-27 98

      Method G: Reductive auxiliary cleavage. Synthesis of 34-35 99

      Method H: Pummerer rearrangement,acidic deprotection. Synthesis of 40-41 99

      Procedure for the preparation of the Roush reagent 100

      Procedure for the preparation of flouroacetyl chloride 101

      Procedure for epimerization of L-threonine to D-allo-threonine 101

3.4 Experimental procedures and datajor key intermediares and final producs1.2 102

      2-azido-2-deoxy-D-glycero-D-ido-heptose(6a) 102

      2-azido-2-deoxy-D-threo-L-galacto-octose(6b) 102

      2-azido-2-deoxy-D-erythro-L-galacto-octose(6c) 103

      2-acetamido-1,3.4,6,7-penta-O-acetyl-2-deoxy-D-glycero-D-ido-heptose (7a) 104

      2-acetamido-1,3.4,6,7,8-hexa-O-acetyl-2-deoxy-D-threo-L-galacto-octose (7b) 106

      2-acetamido-1,3,4,6.7,8-hexa-O-acetyl-2-deoxy-D-erythro-L-galacto-octose (7c) 107

      2-acetamido-2-deoxy-D-glycero-D-ido-heptose (8a) 108

      2-acetamido-2-deoxy-D-threo-L-galacto-octose (8b) 109

      2-acetamido-2-deoxy-D-erythro-L-galacto-octose (8c) 110

      (R,E)-methyl 4-(dibenzylamino)-5-((4-methoxybenzyl)oxy)pent-2-enoate (9a) 111

      (R,E-methyl 5-(tert-butyldiphenylsilyloxy)-4-(dibenzylaminopent-2-enoate (9b) 112

      (R,E-methyl 4-(dibenzylamino)-5-(pivaloyloxy)pent-2-enoate(9c) 112

      ((2S.3S)-3-((S)-1-(dibenzylamino)-2-(4-methoxybenzyl)oxy)ethyDoxiran-2-yD)methanol(10) 113

      (2R.3S)-methyl 3-(S)-2-(ter-butyldiphenylsilyboxy)-1-(dibenzylamino)ethyD)oxirane-2-carboxylate(11) 114

      (S)-tert-butyl 4-(R))-1-(benzyloxy)-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate(12) 115

      (R)-tert-butyl 4-((1R,2S.,E)-1-(benzyloxy)-5-ethoxy-2-fuoro-5-oxopent-3-en-1-yl)-2,2-dimethyloxazolidine-3-carboxylate(13) 116

      (4S.5R)-3-(2-fluoroacetyl)-4-methyl-5-phenyloxazolidin-2-one(14) 117

      (S)-tert-butyl-4-((S,2R))-2-fluoro-1-hydroxy-3-((4S.5R)-4-methyl-2-oxo-5-phenyloxazolidin-3-yl)-3- oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate (15) 118

      (S)-tert-butyl-4-((IR,2S)-2-fluoro-1-hydroxy-3-((4S,5R)-4-methy-2-oxo-5-phenyloxazolidin-3-yl)-3- oxopropyl-2,2-dimethyloxazolidine-3-carboxylate (16) 119

      4R.5R)-tert-butyl-4-((IR,2S)-2-Nuoro-1-hydroxy-3-((4S.5R)-4-methyl-2-oxo-5-phenyloxazolidin-3-yl)-3- oxopropyl)-2.2,5-trimethyloxazolidine-3-carboxylate(17)120

      (4S.5S)-tert-butyl 4-(IR,2S)-2-fluoro-1-hydroxy-3-((4S,5R)-4-methyl-2-oxo-5-phenyloxazolidin-3-yl))-3- oxopropyl)-2,2,5-trimethyloxazolidine-3-carboxylate (18) 121

      (4S.5R)-tert-butyl-4-((IR,2S)-2-fluoro-1-hydroxy-3-((4S.5R)-4-methyl-2-oxo-5-phenyloxazolidin-3-y)-3- oxopropyl)-2,2.5-trimethyloxazolidine-3-carboxylate(19) 122

      (2S.3R,4S)-methyl-4-(ter-butoxycarbonylamino)-2-fluoro-3.5-dihydroxypentanoate (20) 122

      (2S.3R,4R)-methyl-4-((tert-butoxycarbonyl)amino)-2-fluoro-3,5-dihydroxypentanoate (21) 123

      (2S.3R.4S.5R)-methyl-4-((tert-butoxycarbonyl)amino)-2-fluoro-3.5-dihydroxyhexanoate (22) 124

      (2S.3R,4R,5S)-methyl-4-((tert-butoxycarbonyl)amino)-2-fluoro-3,5-dihydroxyhexanoate(23)125

      4-acetamido-1,3-di-O-acetyl-2,4-dideoxy-2-fluoro-D-xylose (24) 125

      4-acetamido-1-O-acetyl-2,4-dideoxy-2-fluoro-D-arabinose (25) 126

      4-acetamido-1,3-di-O-acetyl-2,4.6-trideoxy-2-fluoro-D-idose (26) 127

      4-acetamido-1-O-acetyl-2.4,6-trideoxy-2-fluoro-L-galactose (27) 128

      4-acetamido-2,4-dideoxy-2-fluoro-D-xylose (28) 129

      4-acetamido-2,4-dideoxy-2-fluoro-D-arabinose (29) 130

      4-acetamido-2,4,6-trideoxy-2-luoro-D-idose (30) 131

      4-acetamido-2,4,6-trideoxy-2-fluoro-D-galactose (31) 132

      (S)-tert-butyl 4-((1R.2S)-2-fluoro-1-hydroxy-3-(4S,5R)-4-methyl-2-oxo-5-phenyloxazolidin-3-yl)-3- oxopropyl)-2,2-dimethylthiazolidine-3-carboxylate (32) 133

      (R)-tert-butyl 4-((IR,2S)-2-fluoro-1-hydroxy-3-(4S.5R)-4-methyl-2-oxo-5-phenyloxazolidin-3-yl)-3- oxopropyl)-2.2-dimethylthiazolidine-3-carboxylate (33) 134

      (S)-tert-butyl 4-((IR.2R)-2-fluoro-1,3-dihydroxypropy)-2,2-dimethylthiazolidine-3-carboxylate (34) 135

      (R)-ter-butyl 4-((IR.2R)-2-fluoro-1,3-dihydroxypropyl)-2.2-dimethylthiazolidine-3-carboxylate (35) 135

      (2R.3R.4R)-4-((2,4-dinitrophenyl)amino)-5-((2.4-dinitrophenylthio)-2-Auoropentane-1.3-diol (36) 136

      2-acetamido-2,4-dideoxy-4-fluoro-D-lyxose (40) 137

      2-acetamido-2,4-dideoxy-4-fluoro-D-xylose (41) 138

      (2R.3R,4R.5R,6S)-6-fluoro-5-hydroxy-7-((4S,5R)-4-methyl-2-oxo-5-phenyloxazolidin-3-yl)-7-

      oxoheptane-1,2,3,4-etrayl tetracetate (42) 139

4 NMR Spectra 141

2-azido-2-deoxy-D-glycero-D-ido-heptose(6a) 142

2-azido-2-deoxy-D-threo-1-galaclo-octose (6b) 143

2-azido-2-deoxy-D-erythro-1-galacto-octose(6c) 144

2-aceramido-1,3.4,6.7-pena-O-aceryl-2-deoxy-D-glycero-D-ido-heptose (7a) 145

2-acetamido-1,3.4,6,78-hexa-O-acetyl-2-deoxy-D-threo-1-galacto-octose (7b) 147

2-uceramido-1,3,4.6.7.8-hexa-O-aceryl-2-deoxy-D-erythro-1-galacto-ocose(7c) 148

2-acelamido-2-deoy-D-glycero-D-ido-heptose (8a) 149

2-acetamido-2-deoxy-D-1hreo-1-galaclo-octose(8b) 150

2-acetamido-2-deory-D-eryhro-1-galacto-oclose(8c)151

(R,E)-methyl 4-(dibenzylamino)-5-1(4-methorybenzyl)oxy)pent-2-enoate (9a) 152

(R,E)-methyl 4-(dibenzylamino)-5-(pivaloyloy)pent-2-enoate (9c) 153

(2S.3S)-3-(S)-1-(dibenzylamino)-2-(4-merthoxybenzyl)oxy)erthy)oxiran-2-yl)methanol(10) 154

(2R.3S)-methyl3-1(S)-2-((tert-butyldiphenylsily)ory)-1-(dibenzylamino)ethyloxirane-2-carboxylate(11) 155

(R)-tert-buyl 4-((1R.2S,E)-1-(benzyloy)-5-ethoxy-2-Jluoro-5-oxopen-3-en-1-yl)-2.2-dimethyloxazcolidine-3- carboxylate(13) 156

(4S,5R)-3-(2-Jluoroaceryl)-4-methyl-5-phenyloxazolidin-2-øne(14) 157

(S)-tert-buyl-4-((1S.2R)-2-Jluoro-1-hydroy-3-(4S.SR)-4-mehyl-2-oo-5-phenyloxazolidin-3-yl)-3- oxopropyl))-2,2-dimerhyloxazolidine-3-carboxylate(15) 158

(S)-tert-buryl-4-((IR,2S)-2-luoro-1-hydroxy-3-(4S,5R)-4-methyl-2-øco-5-phenylocaolidin-3-yl)-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate(16) 159

4R.5R)-ter-buryl-4-((1R,2S)-2-Juoro-1-hydroy-3-(4S.5R)-4-methyl-2-oxo-5-phenyloxazolidin-3-yl)-3- oxopropyl)-2,2,5-4rimethyloxazolidine-3-carboxylae(17) 160

(4S.5S)-ter-buryl4-1(1R,2S)-2-luoro-1-hydroxy-3-((4S.5R)-4-methyl-2-øxo-5-phenyloxazolidin-3-yl)-3-oxopropyl)-2,2.5-1rimethyloxazolidine-3-carboxylate(18) 161

(4S,5R)-er-buryl-4-(1R,2S)-2-Jluoro-1-hydroy-3-((4S.5R)-4-methyl-2-oro-5-phenyloxazolidin-3-yl-3- oxopropyl)-2.2,5-rimethyloxazolidine-3-carboxylate(19) 162

(2S.3R.4S)-methyl-4-((tert-buoxycarbonylamino)-2-fluoro-3,5-dihydroxypentanoate((20) 163

(2S.3R,4R)-methyl-4-(tert-buoccarbonylamino)-2-Jluoro-3.5-dihydroxypenanoate(21) 164

(2S.3R.4S.5R)-methyl-4-((tert-buoxycarbony)amino)-2-Jluoro-3.5-dihydroryhexanoate (22) 165

(2S.3R,4R.5S)-meihyl-4-((ter-buoxycarbonylJamino)-2-Juoro-3.5-dihydroryhexanoae (23) 166

4-acetamido-1,3-diO-aceryl-2,4-dideoxy-2-Juoro-D-xylose(24) 167

4-aceiamido-1-O-aceryl-2,4-dideoxry-2-Fluoro-D-arabinose(25) 168

4-aceramido-1,3-di-O-aceryl-2.4,6-1rideoxy-2-Jluoro-D-idose (26) 169

4-acetamido-1-O-aceryl-2,4,6-1rideoxy-2-Juoro-1-galactose(27) 170

4-acetamido-2.4-dideoxy-2-Jluoro-D-xylose (28) 171

4-acetamido-2,4-dideoxy-2-Jluoro-D-arabinose (29) 172

4-aceramido-2,4,6-1rideary-2-Juoro-D-idose (30) 173

4-acetamido-2.4,6-1ridexy-2-Juoro-D-galaclose (31) 174

(S)-tert-buryl4-((1R.2S)-2-fluoro-1-hydrory-3-((4S.5R)-4-methyl-2-oxo-5-phenyloxazolidin-3-y)-3-

oxopropy)-2.2-dimerhytthiazolidine-3-carboylaue(32) 175

(R)-ter-buryl 4-((1R.2S)-2-luoro-1-hydroxy-3-(4S.5R)-4-methyl-2-øxo-5-phenyloxazolidin-3-yl)-3- oxopropyl)-2.2-dimethythiazcolidine-3-carboxylate (33) 176

(S)-ter-buryl4-((IR.2R)-2-Auoro-1,3-dihydroxypropyl)-2.2-dimethylthiazolidine-3-carboylae(34) 177

(R)-ter-buryl4-((IR.2R-2-Fluoro-1,3-dihydroxypropyl)-2.2-dimethylthiacolidine-3-carboxylae (35) 178

(2R,3R.4R)-4-((2.4-dinirophenyamino)-5-1(2.4-dinirophenylmhio)-2-Juoropentane-1.3-diol (36) 179

2-acetamido-2.4-dideoxy-4-Jluoro-D-lyxose (40) 180

2-acelamido-2,4-dideory-4-Jluoro-D-xylose(41) 181

(2R.3R.4R.5R.6S)-6-luoro-5-hydroxy-7-(4S.5R)-4-meihyl-2-oxo-5-phenyloxacolidin-3-yl)-7-øxoheprane-/,2,3.4-1erayl reracerale (42) 182

5 References182

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