Cytosine benzylation

B-i = Benzylated Adenine, B2 = Thymine Bi = Benzylated Cytosine, B2 = Thymine Z = Dimethyl Triptophan, B- = B2 = Thymine... 

SCHEME 2.4 Competing reaction pathways in the benzylation of cytosine (R = H) and 1-methyl cytosine (R = Me) explored by computational DFT means. 

The data in Table 2.1 suggest that the O-benzylated adduct cannot be isolated since it is less stable than reactants. The N3-benzylated adduct should be generated faster, but it should also decompose under mild conditions into free reactants, because the activation free energy in aqueous solution for the decomposition into free QM and methylcytosine is only 21.4 kcal/mol.14 In other words, these data suggested that the QM-N3-cytosine conjugate could act as QM-carrier, few years before the experimental data related to the stability of QM-conjugates became available.4... 

The data on reported cases of neurological disorders after intrathecal chemotherapy with methotrexate or cytosine arabinoside that could be attributed to benzyl alcohol or to other preservatives have been reviewed in the context of a case of flaccid paraplegia after intrathecal administration of cytosine arabinoside diluted in bacteriostatic water containing 1.5% benzyl alcohol (1). Most commonly, flaccid paraparesis, with absent reflexes, developed rapidly, often with pain and anesthesia. Very often there was full recovery. The prognosis depended mainly on the concentration of the preservative and on the time of exposure. In some cases, the paralysis ascended to cause respiratory distress, cardiac arrest, and death. Only preservative-free sterile CSF substitute or saline, or preferably the patient s own CSF, should be used to dilute chemotherapeutic agents (SEDA-11, 475). 

This new sugar had the formula C5Hio04- In other words, it possesses one atom of oxygen less than does a pentose. Analysis of its benzyl-phenylhydrazone, of its guanine and hypoxanthine nucleosides, and of its thymine and cytosine nucleosides, confirmed this composition. It therefore appeared probable that the sugar might be a desoxypentose. 

Numerous syntheses have also been reported for arabinofuranosyl nucleoside analogues, prepared either conventionally from arabinofuranosyl derivatives or via 2,2-anhydro-nucleosides obtained from appropriate ribonucleosides. 5-Aza-cytosine-D-arabinoside has been synthesized and found to show similar antiviral activity to Ara-C(arabinosyl-cytosine). 7-a-, 7-<3-, 9-0 -, and 9- 3-arabino-furanosyl derivatives of 3-deazaguanine have also been prepared, but none showed any anti-tumour activity. 9-(o -D-Arabinofuranosyl)-8-aza[2- C]-adenine, 7-(/3-D-arabinofuranosyl)-pyrrolo[2,3-d]pyrimidine-4(3//)-one (15)," l-(a-D-arabinofuranosyl)- and l-(/3-D-xylofuranosyl)-4-nitropyrazole, and Ot-arabino-nucleosides of 5-fluoro-cytosine and -uracil derivatives have also been prepared. An improved synthesis of 9-(/3-D-arabinofuranosyl)-2-fluoro-adenine has been reported. The ratio of o to 3 anomers obtained by phase-transfer reaction of 2,3,5-tri-O-benzyl-D-arabinofuranosyl bromide with 6-chloro-2-thiomethyl-7-deazapurine varied with the quaternary ammonium salt used as a catalyst, although the jU-anomer predominated in every case. 2,2-Anhydro-nucleosides have been used to prepare l-j3-D-arabinofiiranosyl derivatives of 5-alkylthio-uracils, 5-ethyl-cytosine, and 5-ethyl-uracil, 8-alkylamino-purines, and 2-aralkylamino-l,4-dihydro-4-imino-pyrimidine hydrochlorides (16). ... 

Similarly Klotzer [24-26] has used the same two ethers of hydroxyurea for the preparation of iV-alkoxy and A-hydroxy derivatives of uracil, barbituric acid, cytosine, thymine, and 5-fluorouracil by condensation reactions catalyzed with sodium ethoxide. Thus, for example, the reaction of N-benzyloxyurea with ethyl cyanacetate gave l-benzyloxy-6-aminouracil which was debenzylated by heating it with hydrogen bromide in acetic acid [24]. In syntheses of 1- and 3-hydroxycytosine [24] and of l-hydroxy-5-fluorouracil the O-benzyl protective group was removed by hydrogenolysis in presence of palladium [25, 26]. 

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