Nucleoside carbocyclic

A review has appeared covering the chemistry of carbocyclic nucleosides published over the period 1994-1998, discussing compounds with ring sizes from three to six, and also bicyclic systems.  

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.  

There has been a further report on the synthesis of racemic 2, 3 -dideoxy-2, 3 -methanoadenosine (see Vol. 33, p. 297). 4 -Hydroxymethyl-carbocyclic nucleosides 162 (B = Ade, Thy) have been made as racemates, along with their 3 -epimers, and the compounds 163 (B = Ade, Hx) have been described. References to the carbocyclic analogues of oxanosine and oxetanocin are mentioned in the next section. 

Ribosylation of isopropylideneuridine and subsequent manipulations led to the synthesis of 170 (R = H), which constitutes a part-structure of the liposidomycin class of antibiotics. The two isomers of 170 (R = CH2OH) were also prepared in synthetic sequences that involved ribosylation of D-allofuranose and L-talofuranose derivatives at 0-5, with introduction of uracil at a late stage. Molecular modelling was carried out of both liposidomycins and tunicamycin with the UDP-iV-acetylmuramic acid-pentapeptide that is the substrate for the enzyme (translocase) in bacterial cell wall biosynthesis that the antibiotics inhibit, and, in accordance with the predictions, only the 5-isomer of 170 (R = CH2OH) was a good inhibitor.  

A number of nikkomycin analogues of type 171 have been prepared by acylation of uracil polyoxin C with aminoacid units, using iV-hydroxysuc-cinimidyl esters as intermediates. The best inhibitory activity against fungal chitin synthase was found for cases in which the aminoacid was an 5-arylmethyl derivative of L-cysteine or penicillamine.  

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Regioselective 1,4-azidohydroxylation to give 309 takes place by the reaction of the vinyloxirane 308 with sodium azide[188]. The reaction of the cyclopen-tadiene monoepoxide 310 with sodium azide or purine base offers a good synthetic method for the carbocyclic nucleoside 311(189-191]... 

A similar rearrangement takes place with A,A-dibenzyl-L-serme benzyl ester [UO (equation 68) and with partially protected carbocyclic nucleosides, such as l-hydroxymethyl-4-(2,4-dinitroanilino)cyclopentane-2,3-diol [133]... 

New developments in the selective synthesis of cyclopentyl carbocyclic nucleosides 98T9229. 

Keywords Diels-Alder reactions of chiral polyfunctional carbocyclic nucleosides and cyclopropane amino acids... 

Azabicyclo[2.2.1]hept-5-en-3-one, a bicyclic y-lactam, is an intermediate for the synthesis of antiviral carbocyclic nucleosides (Figure 6.41). This compound was resolved using a cloned lactamase in an industrial-scale process [106,107]. 

Wang J, Jin Y, Rapp KL, Schinazi RF, Chu CK (2007) D- and L-2, 3 -didehydro-2, 3 -dideoxy-3 -fluoro-carbocyclic nucleosides synthesis, anti-HIV activity and mechanism of resistance. J Med Chem 50 1828-1839... 

Deoxy-5 -fluoroadenosine (911) and the analogs 910, 912, 913 were prepared by coupling of 5-deoxy-5-fluoro-D-ribofuranose and 6-chloro-purine. 2, 5 -Dideoxy-5 -fluoroadenosine (914) was prepared through a displacement reaction of the corresponding 5 -0-tosyl precursor with fluoride (BU4NF in DMF). The carbocyclic nucleosides 915 and 916 have been prepared and their antiviral activities evaluated. 

A rapid access to carbocyclic nucleosides, containing a fused isoxazoline ring has been proposed, starting from cyclopentadiene. The route involves a het-ero Diels-Alder cycloaddition reaction of nitrosocarbonylbenzene followed by a 1,3-dipolar cycloaddition of nitrile oxides, cleavage of the N-0 tether and transformation of the heterocyclic aminols into nucleosides via construction of purine and pyrimidine heterocycles (457). 

The resulting derivatives (269) can be considered as strategically important intermediates in the synthesis of glycosidase inhibitors and carbocyclic nucleosides (150). A new approach to the stereoselective synthesis of the piperidine ring with the use of [4+ 2] [3+ 2]-cycloaddition from specially prepared substrates is also very interesting (431)b, c. In the context of this problem, the conditions for the formation of systems containing quaternary vicinal stereocenters were found. 

The hydrolysis of racemic non-natural amides has led to useful products and intermediates for the fine chemical industry. Thus hydrolysis of the racemic amide (2) with an acylase in Rhodococcus erythrolpolis furnished the (S)-acid (the anti-inflammatory agent Naproxen) in 42 % yield and > 99 % enantiomeric excess1201. Obtaining the 7-lactam (—)-(3) has been the subject of much research and development effort, since the compound is a very versatile synthon for the production of carbocyclic nucleosides. An acylase from Comamonas acidovor-ans has been isolated, cloned and overexpressed. The acylase tolerates a 500 g/ litre input of racemic lactam, hydrolyses only the (+)-enantiomer leaving the desired intermediate essentially optically pure (E > 400)[211. 

Extending the aforementioned methodology from imidazole to adenine, the Tsuji-Trost reaction between the sodium salt of adenine and allylic acetate 66 gave 67 as a 82 18 mixture of cis trans isomers. Carbocyclic nucleoside 67 was advantageous over normal nucleosides as a drug candidate because it was not susceptible to degradation in vivo by nucleosidases and phosphorylases [52],... 

D-Ribonolactone is a convenient source of chiral cyclopentenones, acyclic structures, and oxacyclic systems, useful intermediates for the synthesis of biologically important molecules. Cyclopentenones derived from ribono-lactone have been employed for the synthesis of prostanoids and carbocyclic nucleosides. The cyclopentenone 280 was synthesized (265) from 2,3-0-cyclohexylidene-D-ribono-1,4-lactone (16b) by a threestep synthesis that involves successive periodate oxidation, glycosylation of the lactol with 2-propanol to give 279, and treatment of 279 with lithium dimethyl methyl-phosphonate. The enantiomer of 280 was prepared from D-mannose by converting it to the corresponding lactone, which was selectively protected at HO-2, HO-3 by acetalization. Likewise, the isopropylidene derivative 282 was obtained (266) via the intermediate unsaturated lactone 281, prepared from 16a. Reduction of 281 with di-tert-butoxy lithium aluminum hydride, followed by mesylation, gave 282. 

Ferrero, M. and Gotor, V., Biocatal3ttic selective modifications of conventional nucleosides, carbocyclic nucleosides, and C-nucleosides. Chem. Rev., 2000,100, 43194-347 and references cited therein. 

Taylor, S.J.C., Sutherland, A.G., Lee, C., Wisdom, R., Thomas, S., Roberts, S.M. and Evans, C., Chemoenzymatic synthesis of (—)-carhovir utilizing a whole cell catalysed resolution of 2-azabicyclo[2.2.1 ]hept-5-en-3-one. J. Chem. Soc. Chem. Commun., 1990, 1120-1121 Evans, C.T., Roberts, S.M., Shoheru, K.A. and Sutherland, A.G., Potential use of carbocyclic nucleosides for the treatment of AIDS chemo-enzymatic syntheses of the enantiomers of carbovir. J. Chem. Soc. Perkin Trans. 1,1992, 589-592. 

A cyclic ring sulfite (with an -O-SO-0- ring in a carbocyclic nucleoside) was oxidised by RuClj/aq. Na(lO )/CCl -CH3CN/0°C as a synthon for the convergent synthesis of carbocyclic nucleosides (Fig. 5.17) [116]. 

A number of workers have described the synthesis and cycloaddition reactions of oxazoline nitrone dipoles, (e.g., 361 and 362, Scheme 1.80) (413 17). A homochiral oxazoline nitrone derived from camphor has been used to great effect by Langlois and co-workers (418,419), from which they have prepared a number of natural targets through enantioselective cycloaddition reactions, including the antiviral carbocyclic nucleoside analogue (+)-carbovir (48) (Fig. 1.1, Section 1.3). 

The preparation of compound 175, a structurally diverse analogue of the carbocyclic nucleoside ribavarine 176, was reported using an intermolecular 1,3-dipolar cycloaddition of the cyclopentyl azide 174 with methyl propiolate (37) (Scheme 9.37). 

The Tsuji-Trost reaction, more commonly applied to carbocyclic nucleoside synthesis, has been used in the synthesis of famciclovir 21 (Scheme 5) <2000T4589>. Reaction of 2-amino-6-chloropurine with allylic carbonate 22 in the presence of Pd2DBA3 and bis(diphenylphosphino)ethane (DPPE) gave a 1 1 ratio of 23 to 24 after 1 h (DBA = dibenzylideneacetone). However, a ratio of >95 5 in favor of the thermodynamically favored N-9 isomer 23 was subsequently obtained upon further stirring, highlighting the reversibility of the reaction in this specific instance. 

In conjunction with this, Jeong reported the cycloadditions of bis(allyl) and bis(homoallyl) acetals of alkynals leading to bicyclic lactols. Smaltz extended its utility to the synthesis of carbocyclic nucleoside by coupling with nucleophilic substitution of a 7r-allylic palladium complex (Equation (46)). ... 

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