Aristeromycin synthesis

Kitagawa and coworkers have used this strategy for the preparation of pseudo-nucleosides exhibiting various biological activities. The synthesis of (-)-aristeromycin from D-glucose is demonstrated in Scheme 7.17.90... 

Borchardt and coworkers (265) have employed the chiral cyclopenten-ones derived from aldonolactones for the synthesis of the analogue 302a of neplanocin A. Neplanocin A (302b) and aristeromycin (303), carbocyclic analogs of adenosine having antiviral and antitumor activities, have also been synthesized (277,278). 

Very recently, there have been reports of the utility of TASF for the synthesis of 2 -deoxy-2 -fluoroinosine ( ) and of the p-6 -fluoro analog of ( )-aristeromycin (A8). 

The interesting homochiral diol derivative (-)-259 (Scheme 52) has been prepared and used by Trost and co-workers in the synthesis of the antiviral agents (-)-carbovir [(-)-256] and (-)-aristeromycin [(-)-262] (92JA8745). 

The rather low reactivity of the 3-p-tolylsulfinyl acrylates (they do not react with furan even under forcing conditions) prompted the search for more reactive dienophiles. In this context, pyridylsulfinyl derivatives proved to be more efficient than the arylsulfinyl ones. Thus, menthyl-3-(2-pyridylsulfinyl)propenoates 14a and 14b were prepared from (+)-menthyl propiolate in low yields [34]. Their reactions with cyclopentadiene proceed smoothly in the presence of Et2AlCl at -70°C to afford just one endo diastereoisomer 15a or 15b [35] (in the absence of the catalyst the 7r-facial selectivity for the endo approach was lower than that observed for the p-tolylsulfmyl derivatives [10c]). These compounds were transformed into 16a or 16b [36] respectively (Scheme 8), both allowing the synthesis of the bicyclic lactone 17 (known as Ohno s lactone), a key intermediate in Ohno s synthesis of (-)-aristeromycin and (-)-neplanocin A [37]. 

In 1988 Koizumi et al. reported the first sulfoxide used as a chiral synthetic equivalent of dimethyl acetylene dicarboxylate [86a]. The synthesis of dimethyl (R)s-2-(10-isobornylsulfmyl) maleate (88), its reaction with cyclopentadiene catalyzed by ZnCl2, and the further transformation of the major adduct 89 into a half-ester 90 (which had been used as the starting material for the synthesis of carbocyclic nucleosides (-)-aristeromycin and (-)-neplanomicin) are described (Scheme 46). 

Boyer, S.J. et al. Carbocyclic Nucleoside Analogs. I. Concise Enantioselec-tive Synthesis of Functionalized Cyclopentanes and Formal Total Synthesis of Aristeromycin. 2.4 1997 [109]... 

Trost and his group have used both of these palladium-catalysed alkylations in a synthesis of aristeromycin from epoxycycl ope nta diene. The cis stereochemistry of this carbocyclic nucleotide analogue is of paramount importance and was completely controlled by retention of configuration in both substitutions. 

An intermolecular reaction, again with overall syn Sn substitution, was successfully applied in a synthesis of the carbocyclic nucleoside analog aristeromycin to introduce the nitrogen base stereoselectively (equation 21), although with heteronucleophiles, unlike the case of carbon nucleophiles, a lower propensity for attack distal to oxygen to give the 1,4-product with vinyloxiranes exists. 

A synthesis of the antibiotic aristeromycin " makes use of the displacement of a pyrimidine 4-chloride to allow introduction of the amine and the generation of the 4,5-diamino-pyrimidine for subsequent closure of the flve-membered ring. 

One of the best examples of an enzymatic dephosphorylation for a synthetic purpose is shown in the entry 5 ofTable 13-6. A 5 -ribonucleotide phosphohydrolase was used in the synthesis of (-)-aristeromycin, a carbocyclic analog of adenosine. The (-)-enantiomer of aristeromycin shows some cytostatic and antiviral activity, while the (+)-enantiomer is inactive. The racemate ( )-5 -phosphorylated aristeromycin was resolved by selective hydrolysis of the (-)-enantiomer with the hydrolase. The (-)-alcohol and the (+)-5 -phosphate derivative were separated easily on a silica gel column. Hydrolysis of the (-t-)-enantiomer with calf intestinal phosphatase yielded pure (+)-alcohol. 

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