Antiviral carbocyclic nucleosides

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]. 

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 enantiomer of 154 can be made by using the corresponding L-alanine derivative as the chiral auxiliary. Compound 154 is also a precursor to the antiviral carbocyclic nucleoside, neplanodn A, and the antitumour agent, 5 -noraristeromycin. ... 

Racemic diol 157, derived from 128, is also used in the synthesis of the antiviral carbocyclic nucleoside, 9-(c-5-hydroxy-c-4-hydroxymethylcyclo-pent-2-en-r-l-yl)-9//-adenine (Epinor-BCA) [49]. Diol 157 is elaborated to... 

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. 

Agrofoglio, L. et al. Synthesis of a New Exocyclic Amino Carbocyclic Nucleoside with Potential Antiviral Activity. 2.4 1993 [103]... 

Brothwick, A. D., Evans, D. N., Kirk, B. E., et al. (1990) Fluoro carbocyclic nucleosides synthesis and antiviral activity of 2 -and 6 -(luoro carbocyclic pyrimidine nucleosides including carbocyclic l-(2-deoxy-2-fluoro-P-d-arabinofuranosyl)-5-methyluracil and carbocyclic l-(2 -deoxy-2-fluoro-P-d-arabinofuranosyl)5-iodouracil. J. Med. Chem., 33, 179-186. 

Carbocyclic nucleoside analogues have also attracted considerable attention because of their antiviral and antitumor activities. Of particular interest are cyclohexenyl nucleosides, whose conformation resembles that of natural nucleosides. They can hybridize with nucleic acids and may therefore hold promise as components of antisense oligonucleotides.46-52... 

Neplanocins. Neplanocins A—D and F (37—41) are carbocyclic nucleoside antibiotic products of Ampullariella regularis (1,4) that are structurally related to (36) in that they contain either a cyclopentene or epoxy cyclopentane ring (121,122). The chemical syntheses of (37—41) and the 3-deazaneplanocins have been reported (123—126). Compound (37), which is converted to its 5 -triphosphate, has potent antitumor and antiviral activities (127—129). It strongly inhibits SAM in cells and viruses (128—131) and is converted to the 3 -keto derivative by Tadenosylhomocysteine hydrolase (132,133). 

A review has discussed selective biocatalytic modifications of conventional nucleosides, carbocyclic nucleosides and C-nucleosides, including such topics as selective acylation of nucleosides, regioselective deacylation, and enzymic resolution of precursors of carbocyclic and C-nucleosides. The enzymatic synthesis of antiviral nucleosides has also been reviewed, in Chinese. A survey has been given of synthetic approaches to nucleosides in the unnatural L-series, and their potential use as antiviral and anticancer agents. ... 

In the area of carbocyclic nucleoside antibiotics, a full account of syntheses of (—)-aristeromycin and (—)-neplanocin A (see Vol. 31, p. 261) was mentioned above. " The known intermediate 174, prepared from D-ribose, has been used for the first synthesis of neplanocin C (175), a minor component of the neplanocin family. The diastereomeric epoxide was also obtained. In efforts to prepare prodrugs, the oxetanocin analogue 176, an antiviral agent (lobucavir), has been selectively aminoacylated with l-valine on either of the hydroxymethyl groups using enzymic methods. A synthesis of the cyclohexenyl nucleoside antibiotic pyralomycin Ic is mentioned in Chapter 18. 

Ohno has reviewed the work of his group on the enantioselective synthesis of, inter alia, nucleosides, C-nucleosides and carbocyclic nucleoside analogues using chiral synthons derived by asymmetric hydrolysis of meso-diesters with pig liver esterase. Although acyclonucleosldes are not discussed in detail in these volximes, we note an extensive review of the chemistry and antiviral activity of such compounds. ... 

Resolution of an Af-acetylaminocyclopentene carboxylate shown in Scheme 2.34 was used to access optically pure starting material for the synthesis of carbocyclic nucleoside analogs with promising antiviral activity [241]. The bulky tricyclic monoester was required for natural product synthesis [242]. 

Bicyclic haloketones, which were used for the synthesis of antiviral 6 -fluoro-carbocyclic nucleoside analogs, were resolved by using the same technique [1222] (Scheme 2.163). Both enantiomers were obtained with >95% optical purity. The exquisite enantioselectivity of the microbial oxidation is due to the presence of the halogen atoms since the dehalogenated bicyclo[2.2.1]heptan-2-one was... 

Carbocyclic nucleosides are structural analogues of natural and synthetic nucleosides, which often exhibit powerful antitumor and antiviral activities. In the course of synthesising chiral members of this family of compounds, Castillon et al. have developed the DKR of a 3-hydroxymethyl-cyclopentanol intermediate as key step, providing the corresponding acetate which constituted the key intermediate of this synthesis. This DKR process was... 

In the area of carbocyclic nucleoside antibiotics, hydrolysis of the racemic esters 40 (R= n-Bu or ii-CeHis) by the lipase from Candida rugosa proceeds with very high enantiomeric selectivity, and from the resolved materials both enantiomers of aristeromydn were made by an established route. The authors report that a previous similar method (Vol.21, p. 182) is not as enantioselective. In a new synthesis of neplanocin A (43), the alcohol 41, derived from D-ribose, was converted to the cyclopentene 42 using an intramolecular insertion reaction of an alkylidene carbene. The new stereocentre in 42 was mostly of the wrong P-configuration, but could be corrected by a process of desilylation, oxidation and borohydride reduction. The biosynthesis of neplanocin A (43) and aristero-mycin has been reinvestigated, and the cyclopentenone 44 has been proposed as an intermediate, which is converted to aristeromycin via neplanocin A without any bifurcation. The 3-deaza-analogue 45 of 5 - or-aristeromydn has been prepared, and the antiviral activity of it and of the 7-deaza-compound (Vol.27, p. 235) are reported. ... 

The intermediate (51), in racemic form, was used for the synthesis of various 2 -fluoro-carbocyclic nucleosides the analogue (52) of the important antiviral FMAU was prepared by introducing fluoride with inversion of configuration, whilst the compound of... 

Unsaturated and carbocyclic nucleoside analogues Synthesis, antitumor, and antiviral activity, J. Med. Chem. 34 421 (1991). 

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. ... 

The naturally occurring oxetanocin A (18) and synthetic oxetanocin G (19) represent a novel class of nucleosides possessing antiviral propmies. Modification of die unique oxetanosyl-lV-glycoside structural feature of 18 and 19 into the carbocyclic nucleoside framework led to the synthesis of 20 and 21 as racemates and enantiomers, which have shown activity against herpesviruses and HIV.22b,c,24,25 in view of the potent and selective anti-HCMV properties of the l -enantiomer of 21, the synthesis of the R sto eoisomer 22 was undertaken and accomplished. 

Carbocyclic analogues of nucleosides have attracted much attention as potential antiviral and antitumor therapeutic agents. Carbovir 72 is one of the most famous derivatives of this series, but its closely related analogue 1592U89 73 also holds remarkable promise for the treatment of AIDS and is currently in phase II clinical trials. 

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