The elimination reaction of (III) with sodium ethoxide in DMF gives 2',3'-dideoxy-2',3'-didehydroadenosine (V), which is hydrogenated with H2 over Pd/C in ethanol.
The reaction of 5'-triphenylmethyl-2'-deoxyadenosine (I) with p-toluenesulfonyl chloride in pyridine gives 5'-triphenylmethyl-3'-(p-toluenesulfonyl)-2'-deoxyadenosine (II), which by partial hydrolysis with acetic acid yields 3'-p-toluenesulfonyl)-2'-deoxyadenosine (III). The reaction of (III) with ethylmercaptane (A) by means of sodium ethoxide affords 3'-ethylthio-2',3'-dideoxyadenosine (IV), which is finally desulfurized by treatment with Raney-Ni in refluxing methyl cellosolve - ethanol (100 C).
The reaction of 2',3'-dideoxy-2'chloro-3'-ethylthioadenosine (VI) with potassium thiocyanate gives 2',3'-dideoxy-2'-thiocyanato-3'-ethylthioadenosine (VII), which by treatment with Ni sponge in DMF at 100 C under H2 atmosphere is converted into compound (IV), which is finally treated with Raney-Ni in refluxing methyl cellosolve-ethanol (100 C).
The bromination of 2'-deoxyadenosine (VIII) with Br2 in dioxane - water by means of CaCO3 or sodium acetate gives 8-bromo-2'-deoxyadenosine (IX), which by reaction with triphenylmethyl chloride in pyridine - DMF is converted into 8-bromo-2'-deoxy-5'-O-triphenylmethyladenosine (X). The reaction of (X) with p-toluenesulfonyl chloride in pyridine affords 8-bromo-5'-O-triphenylmethyl-3'-O-(p-toluenesulfonyl)-2'-deoxyadenosine (XI), which by reaction with thiourea (A) in refluxing butanol and treatment with propanol-ammonia-water is converted into 2',3'-dideoxy-8-mercapto-8,3'-anhydroadenosine (XII). Finally, this compound is desulfurized by treatment with Raney-Ni in refluxing water.
The reaction of adenosine (XIII) with 2-acetoxyisobutyryl bromide (XIV) in acetonitrile gives 3'-deoxy-3'-bromo-2'-O-acetyl-5'-(2,5,5-trimethyl-1,3-dioxolan-4-on-2-yl)adenosine (XV), which is submitted to hydrogenolysis with H2 over Pd/C in methanol containing triethylamine.
A new synthesis of 2',3'-dideoxyadenosine has been described: The reaction of uridine (I) with methyl orthoformate and p-toluenesulfonic acid gives the cyclic orthoester (II), which is acetylated with acetic anhydride at 100 C to the acetate (III). The reaction of (III) with acetic anhydride at temperatures over 120 C yields 5'-O-acetyl-2',3'-dideoxy-2',3'-didehydrouridine (IV), which is hydrogenated to 5'-O-acetyl-2',3'-dideoxyuridine (V).
The hydrolysis of (V) affords 2',3'-dideoxyuridine (VI), which is finally submitted to transdeoxyribosilation with adenine (VII) by means of Escherichia coli AJ-2595 microorganisms.
2) The reaction of uridine (I) with methyl orthoformate and p-toluenesulfonic acid gives the cyclic orthoester (II), which is acetylated with acetic anhydride at 100 C, yielding the 5'-acetoxy derivative (III). The reaction of (III) with acetic anhydride at temperatures over 120 C affords 5'-O-acetyl-2',3'-dideoxy-2',3'-didehydrouridine (IV), which is hydrogenated to 5'-O-acetyl-2',3'-dideoxyuridine (V). Hydrolysis of (V) affords 2',3'-dideoxyuridine (VI), which is finally submitted to a transdideoxyribosylation with hypoxanthine (VII) by incubation in an appropriate medium with Escherichia coli AJ 2595 resting cells.
This compound is prepared by two related ways: 1) The partial silylation of adenosine (I) with tert-butyldimethylsilyl chloride and imidazole gives 5'-O-(tert-butyldimethylsilyl)adenosine (II), which by reaction with 1,1'-thiocarbonyldiimidazole (III) in hot DMF is converted into 5'-O-(tert-butyldimethylsilyl)-2',3'-O-thionocarbonyladenosine (IV). The desulfurization of (IV) with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (V) or triethyl phosphite in THF yields 5'-O-(tert-butyldimethylsilyl)-2',3'-didehydro-2',3'-dideoxyadenosine (VI), which is deprotected with tetrabutylammonium fluoride in THF affording 2',3'-didehydro-2',3'-dideoxyadenosine (VII). Finally, this compound is hydrogenated with H2 over Pd/C in methanol. 2) The reaction of silylated adenosine (II) with CS2 and NaOH in DMSO, followed by methylation with methyl iodide gives 5'-O-(tert-butyldimethylsilyl)-2',3'-bis-O-[(methylthio)thiocarbonyl]ad enosine (VIII), which is desulfurized with tributyltin hydride and AIBN in refluxing toluene to yield the dideoxy-didehydroadenosine (VI), already obtained.
3) The reaction of inosine (I) with tert-butyldimethylsilyl chloride by means of imidazole in DMF gives the 5'-O-silyl derivative (II), which by reaction with CS2 and 3-bromopropionitrile by means of NaOH in DMSO is converted into 5'-O-(tert-butyldimethylsilyl)-2',3'-bis-O-(2-cyanoethyldithiocarbonyl)inosine (III). The reaction of (III) with tri-n-butyltin hydride and AIBN in refluxing toluene affords 5'-O-(tert-butyldimethylsilyl-2',3'-dideoxy-2',3'-didehydroinosine (IV), which is deprotected with tetrabutylammonium fluoride in THF to 2',3'-dideoxy-2',3'-didehydroinosine (V). Finally, this compound is hydrogenated with H2 over Pd/C in ethanol - water. 4) The reaction of (II) with 1,1'-thiocarbonyldiimidazole (DTI) in DMF gives 5'-O-(tert-butyldimethylsilyl)-2',3'-O-(thionocarbonyl)inosine (VI), which by reaction with refluxing triethyl phosphite is converted into the didehydro derivative (IV), already obtained (5).
A new synthesis of 2',3'-dideoxyadenosine has been described: The stereospecific deamination - lactonization of L-glutamic acid (I) with NaNO2 - HCl in water gives (S)-(+)-gamma-carboxy-gamma-butyrolactone (II), which is esterified with ethanol - p-toluenesulfonic acid to the ester (III). The selective reduction of (III) with NaBH4 in ethanol yields (S)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (IV), which is benzoylated with benzoyl chloride as usual, affording the benzoate (V). The selective reduction of (V) with disiamyl borane in THF gives the alcohol (VI), which is acetylated with acetic anhydride in pyridine to the acetate (VII). The reaction of (VII) with trimethylsilyl bromide in dichloromethane yields the tetrahydrofuryl bromide (VIII), which is condensed with the silylated adenine (IX) to afford 5'-O-benzoyl-2',3'-dideoxyadenosine (X). Finally, this compound is deprotected with NH3 in methanol.
1) The stereospecific deamination - lactonization of L-glutamic acid (I) with NaNO2 - HCl in water gives (S)-(+)-gamma-carboxy-gamma-butyrolactone (II), which is esterified with ethanol and p-toluenesulfonic acid in the usual way, yielding the ethyl ester (III). The selective reduction of (III) with NaBH4 in ethanol affords (S)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (IV), which is benzoylated with benzoyl chloride to the benzoate (V). The selective reduction of (V) with disiamyl borane in THF yields the alcohol (VI), which is acetylated with acetic anhydride in pyridine to the acetate (VII). The reaction of (VII) with trimethylsilyl bromide in dichloromethane affords the tetrahydrofuryl bromide (VIII), which is then condensed with the adenine (IX), giving 5'-O-benzoyl-2',3'-dideoxyadenosine (X). The deprotection of (X) with NH3 in methanol yields 2',3'-dideoxyadenosine, which is finally deaminated enzymatically with the enzyme adenosine deaminase.
A new method for the synthesis of title compound has been reported: The reaction of 5'-O-triphenylmethyl-2'-deoxyadenosine (I) with CS2, methyl iodide and NaH gives the corresponding xanthate (II), which is reduced with tributyl hydrogen stannide to 5'-O-triphenylmethyl-2',3'-dideoxyadenosine (III). Finally, this compound is deprotected in the usual way.