Carbocyclic adenosine

Aristeromycin (carbocyclic adenosine) has been converted to its 2 -deoxy-2 -fluoro-ara-analogue using DAST together with a 3,5-dibenzoate, the product being a potent antiviral agent.Epimeric 6 -fluoro-analogues of aristeromycin as well as its 6 -methylene... 

Nucleosides in which the ribofiiranosyl oxygen is replaced by a methylene to result in a cyclopentane ring are referred to as carbocyclic nucleosides. The first such conopound was carbocyclic adenosine (1, aristeromycin), which was synthesized in its racemic form prior to isolation of the (-)-enantiomer from Streptomyces citricolor. The antiviral activity of has stimulated the search for other carbocyclic nucleosides that would display a more favorable therapeutic index. ... 

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). 

The 5 -alkynyl(cyano) derivatives of adenosine 274 and its carbocyclic analog derivatives 231 and 232 were examined as inhibitors of S-adenosyl-L-homocysteine and S-adenosyl-L-methionine hydrolase (89EUP334361). 

A C2 symmetric bis(amidophosphine) ligand was used by Trost to prepare the natural nucleoside adenosine (see Chapter 49 for nucleosides) in similar fashion to the carbocyclic analogue described above. The key enantioselective step was the first allylic alkylation that selected between two cnan-tiotopic benzoates in the meso dihydrofuran derivative to give one enantiomer the expected cis product. 

Carbocyclic nucleosides are nucleoside analogs in which the furanose ring is replaeed by a eyclopentane ring. Two earbocyclie adenosine analogs, e.g. aristeromycin and neplanocin A have been isolated from natural sources. ... 

Nucleoside Cyclic Pyrophosphates. Extensive work has been carried out by Matsuda et al. in their efforts to synthesise chemically stable cyclic adenosine diphosphate ribose (cADPR) analogues. The carbocyclic inosine analogue (83) was first prepared through an efficient cyclisation of an 8-bromo-A-1 -[5"-(phosphoryl)carbocyclic-ribosyl]inosine 5 -phenylthiophos-... 

A carbocyclic NAD(+) analogue (91) incorporating a methylenebisphospho-nate linkage in place of the natural pyrophosphate has been prepared as an inhibitor of ADP-ribosyl cyclase which is resistant to non-specific phosphatase degradation.The analogue 91 was obtained in 25% yield following a Poulter coupling of the precursor 92 with adenosine 5 -methylenebisphosphonate. 

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. 

Cyclic vinyl epoxides are versatile building blocks (Table 11) which have been used in palladium-assisted routes to carbocyclic nucleosides. A formal synthesis of ( )-aris-teromycin101, the carbocyclic analog of adenosine, has been accomplished employing ni-tromethane as the nucleophile which serves as an acyl anion equivalent (Table 11. entry 2). The aldehyde is released by subsequent basic potassium permanganate oxidation. If nitromethane is used diluted in tetrahydrofuran, then a mixture of mono- and bis-alkylated product is formed. Whereas the alkylation of cyclohexenoxide with dimethyl malonate proceeds in a 1,4-crs fashion under palladium(O) catalysis, the 1.2-/ra/i.v-product is formed under basic conditions in the absence of the palladium(O) catalyst. 

We note further studies concerning the ethanolysis of l-chloro-2-aza-adamantanes, the rearrangement " of iV-chloro-tropanes, the dealkylation " of (76) with PhSeH, the formation of a stable adduct between (77) and sulphur dioxide " and also between aaa-trifluoroacetophenone and 1,4-diazabicyclo-octane, "" and the use of (78) as an intermediate " in the synthesis of the antifungal antibiotic aristeromycin (79), which is a carbocyclic analogue of adenosine. The acid-catalysed cyclization "" of (80) gave (81) the structure of the product was determined by X-ray analysis. 

Aristeromycin and neplanocin A (Figure 1) are naturally occurring carbocyclic nucleosides produced by Streptomyces citricolor (reviewed in [2]). Both molecules have a close structural similarity to adenosine and possess potent biological activity, including inhibition of 5-adenosylhomocysteine hydrolase [3]. Neplanocin A also exhibits anti-tumour... 

The 4 -acyl nucleosides 77, 78, 4 -C-branched nucleosides such as 79, and l-A -[(2 -deoxy-P-D-n7>o-pentofuranosyl)methyl] thymine, cytosine and adenosine. A number of carbocyclic nucleosides cis-l-[(2-hydroxymethyl)cyclo-pentyl]uridine, 4,4-dihydroxymethyl-(l-thymin-l-yl)cyclohexane, and the cyclopropyl-fused carbocylic analogue 81. ... 

An intermediate prepared from isopropylidene-D-glyceraldehyde via a Claisen rearrangement and previously used for the synthesis of some branched-chain fluorinated nucleosides (Vol. 32, p. 272-273), has now been used to make a fluorinated cyclopentane unit, to which was linked 6-chloropurine, thus leading to carbocyclic 2, 3 -dideoxy-4 -fluoro-L-adenosine (161). The same synthetic sequence could be modified to generate, via a metathesis step, an enantiomeric cyclopentane unit, and hence the enantiomer of 161, and equivalent structures with the other nucleobases. ... 

Secrist JA, Montgomery JA, Shealy YF, O Dell A, Clayton SJ. Resolution of racemic carbocyclic analogues of purine nucleosides through the action of adenosine deaminase. Antiviral activity of the carbocyclic 2 -deoxyguanosine enantiomers. J Med Chem 1987 30 746-749. 

In a new approach to carbocyclic 2 -deoxyribonucleosides, intermediate 159, produced in chiral form by enzymic resolution, was converted to its bicyclic sulfate by interaction with SOCI2 followed by oxidation the sulfate was then linked with an appropriate base unit to give the analogues 160 of 2 -deoxy-adenosine and -guanosine together with the 2,6-diaminopurine... 

The carbocyclic analogue of 3-deazaadenosine Is a promising antiviral agent, and a number of 5 -substituted analogues of it have been prepared. Carbocyclic uronamldes of type (105) have also been reported these incorporate features which give hypotensive effects in adenosine analogues. 

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