Compound 34 was synthesized following the procedure describe for compound 30
N- Benzyloxycarbonyl- D -alanyl -(O-monomethoxytrityl)- D -serine methyl ester (47)
4. NMR Spectra
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135
4. NMR Spectra
NMR Compound 28. CDCl3 250 MHz
NMR Compound 29. CDCl3 250 MHz
4. NMR Spectra
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136
NMR Compound 34. CDCl3 250 MHz
NMR Compound 35. CDCl3 250 MHz
4. NMR Spectra
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137
NMR Compound 36. CDCl3 250 MHz
NMR Compound 37. CDCl3 600 MHz
4. NMR Spectra
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138
NMR Compound 38. CDCl3 250 MHz
NMR Compound 39. CDCl3 250 MHz
4. NMR Spectra
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139
NMR Compound 40. CDCl3 250 MHz
NMR Compound 41. CDCl3 600 MHz
4. NMR Spectra
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140
NMR Compound 42. CDCl3 250 MHz
NMR Compound 43. CDCl3 250 MHz
4. NMR Spectra
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141
NMR Compound 44. CDCl3 250 MHz
NMR Compound 45. CDCl3 600 MHz
4. NMR Spectra
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142
NMR Compound 46. CDCl3 250 MHz
NMR Compound 47. CDCl3 250 MHz
4. NMR Spectra
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143
NMR Compound 48. CDCl3 250 MHz
NMR Compound 49. CDCl3 250 MHz
4. NMR Spectra
___________________________________________________________________________
144
NMR Compound 50. CDCl3 250 MHz
NMR Compound 51. CDCl3 250 MHz
4. NMR Spectra
___________________________________________________________________________
145
NMR Compound 52. CDCl3 250 MHz
NMR Compound 53. CDCl3 250 MHz
4. NMR Spectra
___________________________________________________________________________
146
NMR Compound 54. CDCl3 250 MHz
NMR Compound 55. CDCl3 250 MHz
4. NMR Spectra
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147
NMR Compound 56. CDCl3 250 MHz
NMR Compound 57. CDCl3 250 MHz
4. NMR Spectra
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148
NMR Compound 58. CDCl3 250 MHz
NMR Compound 59. CDCl3 250 MHz
4. NMR Spectra
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149
NMR Compound 60. CDCl3 250 MHz
NMR Compound 61. CDCl3 250 MHz
4. NMR Spectra
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150
NMR Compound 62. CDCl3 250 MHz
NMR Compound 63. CDCl3 600 MHz
4. NMR Spectra
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151
NMR Compound 72. CDCl3 250 MHz
NMR of Compound 73 CDCl3 250 MHz
4. NMR Spectra
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152
NMR of Compound 74 CDCl3 250 MHz
NMR of Compound 75 CDCl3 250 MHz
4. NMR Spectra
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153
NMR of Compound 76 CDCl3 250 MHz
NMR of Compound 77 CDCl3 250 MHz
4. NMR Spectra
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154
NMR of Compound 78 CDCl3 250 MHz
NMR of Compound 79 CDCl3 250 MHz
4. NMR Spectra
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155
NMR of Compound 85 CDCl3 250 MHz
NMR of Compound 86 CDCl3 250 MHz
4. NMR Spectra
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156
NMR of Compound 87 CDCl3 250 MHz
NMR of Compound 88 CDCl3 250 MHz
4. NMR Spectra
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157
NMR of Compound 89 CDCl3 250 MHz
NMR of Compound 90 CDCl3 250 MHz
4. NMR Spectra
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158
NMR of Compound 91 CDCl3 250 MHz
NMR of Compound 92 CDCl3 250 MHz
4. NMR Spectra
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159
NMR of Compound 93 CDCl3 250 MHz
NMR of Compound 94 CDCl3 250 MHz
4. NMR Spectra
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160
NMR of Compound 95 CDCl3 250 MHz
NMR of Compound 96 CDCl3 250 MHz
4. NMR Spectra
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161
NMR of Compound 97 CDCl3 250 MHz
NMR of Compound 98 CDCl3 250 MHz
4. NMR Spectra
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162
NMR of Compound 99 CDCl3 250 MHz
NMR of Compound 100 CDCl3 250 MHz
4. NMR Spectra
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163
NMR of Compound 101 CDCl3 250 MHz
NMR of Compound 102 CDCl3 250 MHz
4. NMR Spectra
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164
NMR of Compound 103 CDCl3 250 MHz
NMR of Compound 104 CDCl3 250 MHz
4. NMR Spectra
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165
NMR of Compound 116 CDCl3 250 MHz
NMR of Compound 117 CDCl3 250 MHz
4. NMR Spectra
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166
NMR of Compound 118 CDCl3 250 MHz
NMR of Compound 126 CDCl3 600 MHz
4. NMR Spectra
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167
NMR of Compound 126 CDCl3 600 MHz
13C NMR of Compound 126 CDCl3 150.9 MHz
4. NMR Spectra
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168
NMR of Compound 127 CDCl3 250 MHz
NMR of Compound 128 CDCl3 250 MHz
4. NMR Spectra
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169
NMR of Compound 129 CDCl3 250 MHz
NMR of Compound 130 CDCl3 250 MHz
4. NMR Spectra
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170
NMR of Compound 131 CDCl3 250 MHz
NMR of Compound 132 CDCl3 250 MHz
4. NMR Spectra
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171
13C NMR of Compound 132 CDCl3 63.5 MHz
NMR of Compound 133 CDCl3 600 MHz
4. NMR Spectra
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172
NMR of Compound 133 CDCl3 600 MHz
13C NMR of Compound 133 CDCl3 150.9 MHz
4. NMR Spectra
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173
NMR of Compound 134 CDCl3 600 MHz
NMR of Compound 134 CDCl3 600 MHz
4. NMR Spectra
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174
13C NMR of Compound 134 CDCl3 150.9 MHz
NMR of Compound 135 CDCl3 250 MHz
4. NMR Spectra
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175
NMR of Compound 136 CDCl3 600 MHz
NMR of Compound 137 CDCl3 600 MHz
4. NMR Spectra
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176
NMR of Compound 137 CDCl3 600 MHz
13C NMR of Compound 137 CDCl3 150.9 MHz
4. NMR Spectra
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177
NMR of Compound 138 CDCl3 600 MHz
NMR of Compound 138 CDCl3 600 MHz
4. NMR Spectra
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178
13C NMR of Compound 138 CDCl3 150.9 MHz
NMR of Compound 139 CDCl3 600 MHz
4. NMR Spectra
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179
NMR of Compound 139 CDCl3 600 MHz
HSQC of Compound 139 (CDCl3)
4. NMR Spectra
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180
13C NMR of Compound 139 CDCl3 150.9 MHz
NMR of Compound 140 CDCl3 600 MHz
4. NMR Spectra
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181
13C NMR of Compound 140 CDCl3 150.9 MHz
NMR of Compound 141 CDCl3 600 MHz
4. NMR Spectra
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182
13C NMR of Compound 141 CDCl3 150.9 MHz
NMR of Compound 142 CDCl3 600 MHz
4. NMR Spectra
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183
13C NMR of Compound 142 CDCl3 150.9 MHz
NMR of Compound 143 CDCl3 600 MHz
4. NMR Spectra
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184
13C NMR of Compound 143 CDCl3 150.9 MHz
NMR of Compound 144 CDCl3 600 MHz
4. NMR Spectra
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185
13C NMR of Compound 144 CDCl3 150.9 MHz
NMR of Compound 145 CDCl3 600 MHz
4. NMR Spectra
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186
13C NMR of Compound 145 CDCl3 150.9 MHz
NMR of Compound 146 CDCl3 600 MHz
4. NMR Spectra
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187
NMR of Compound 146 CDCl3 150.9 MHz
5. Summary
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188
5. Summary.
Strains from several bacteria like Staphylococcus aureus and Streptococcus Pneumoniae, which might cause severe infections, are becoming resistant to many of the existing antibiotics112. Antibiotic resistance in S. aureus was almost unknown when penicillin was first introduced in 1943; indeed, the original Petri dish on which Alexander Fleming observed the antibacterial activity of the penicillium mould was growing a culture of S. aureus. By 1950, 40% of hospital S. aureus isolates were penicillin resistant; and by 1960, this had risen to 80%113.Some strains from S. aureus can be handle only with Vancomycin, but has been found some strains with increasing resistance to it114.
Until 2000, S. pneumoniae infections caused 100,000-135,000 hospitalizations for pneumonia, 6 million cases of otitis media, and 60,000 cases of invasive disease, including 3300 cases of meningitis115. Incidence of sterile-site infections showed geographic variation from 21 to 33 cases per 100,000 population. Disease figures are now changing due to conjugate vaccine introduction; in 2002, the rate of invasive disease was 13 cases per 100,000 in the United States.
In order to find new alternative therapies and develop new medicaments against these bacteria it is mandatory to obtain substances with exact molecular structures and decisive functions in the activation of our immunosystem.
In order to contribute to find a solution for all these challenges, is reported in this dissertation the synthesis of important cell wall components of Gram-positive bacteria; LTA´s of S.aureus and S. pneumoniae.
With the synthesis of some fragments and analogues of S. aureus LTA it could be elucidated the minimal structure which is able to activate the immunosystem. It was also demonstrated in this work that, some structural changes made to the natural compound, didn t affected the activation of cytokine released in human blood.
5. Summary
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189
5.1 Synthesis of S. aureus LTA fragments.
All the glycerol moieties used in this work, 14, 15 and 19, were obtained from 1,2-O-isopropylidene-sn-glycerol49. Using the phosphoramidite approach were obtained the different backbone fragments. Starting with the reaction between 14 and 19, with tetrazole as catalyst and tBuOOH as oxidant agent, could be obtained the fragment with n=1 (20) (Scheme 40).
BnO OH
Scheme 40: Obtaining of the fragments.
5. Summary
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190
Desilylation and successive repetitions of this process yielded the different fragments 21, 23, 25, 27. These fragments were a 2n complex mixture of diasteromers, due to the chirality of the triesterphosphate which disappears only after the final deprotection. This mixture complicated any monitoring and purification of the reactions, due to the large number of spots.
The reaction of the fragments with the gentiobiose phosphite 13 yielded, in good yields, the protected fragments with the desired sequence of glycerophosphate backbones 30, 34, 38 and 42.
CAN, CH3CN/Toluene/H2O -10°, 72-87%