Carbocyclic nucleosides carbovir

The (1, 45) enantiomer ((-)- ) has been used for the preparation of the carbocyclic nucleoside (-)-carbovir (3) (eq 2) which has been shown to have similar activity against HIV (RF strain) as AZT (Zidovudine). 

Full details have been reported (see Vol. 27, p. 213, ref 78 for preliminary account) on the preparation of the diacetate of racemic cydopentenol 83. The same group has also reported the synthesis of both enantiomers of 83 by reaction of meso-epoxyalcohol 84 with two equivalents of butyllithium in the presence of (1<, 2R ) or (l/ ,25)-norephedrine. Compound 83 is an important intermediate for preparing the carbocyclic nucleoside, carbovir. 

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 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). 

Carbovir, a dideoxy didehydro carbocyclic nucleoside, has been shown to be a potent inhibitor of HIV-I replication. For a review on carbocyclic nucleosides as well as other purine nucleosides with altered glyconic moieties see ref 218. 

Enzymic desymmetrization was used to develop an enantiospecific synthesis of ( —)-BCA (168), and the same approach was also used to make (—)-carbovir. The carbocyclic nucleoside analogues 169 and have been synthesized as racemates. 

Work on the synthesis of 2, 3 -didehydro-2, 3 -dideoxy carbocyclic nucleosides has led to the emergence of the guanosine analogue carbovir (105, B=Gua) as a potent and selective anti-HIV agent. 154 The precursor (106) of the bioactive (-)-isomer of carbovir can be resolved by the enantioselective hydrolysis of the unwanted isomer by a Pseudomonas... 

J. G. Mayo, R. H. Shoemaker and M. R. Boyd, Potent and selective activity of a new carbocyclic nucleoside analog (carbovir NSC 614846) against human immunodeficiency virus in vitro, Biochem. Biophys. Res. Common. 156 1046 (1988). 

K. A. Shoberu, and A.G. Sutherland, Potential use of carbocyclic nucleosides for the treatment of AIDS chemo-enzymatic syntheses of the enantiomers of carbovir, J. Chem. Soc., Perkin Trans. 1 589 (1992). 

Further work on griseolic acid analogues has been reported (see Vol. 25, p. 232), giving guanosine analogues, e.g. 28, instead of adenine derivatives and its 3, 4 -stereoisomers together with carbocyclic analogues. Other carbocyclic nucleoside derivatives of aristeromycin and a synthesis of carbovir are mentioned in Chapter 20, and a synthesis of the carbocyclic nucleoside precursor, Ohno s lactone, is referred to in Cluster 18. 

Scheme 13.43. The five-membered bicarbonate 160 was alkylated to give compound 161 in 97% chemical yield and 98% ee. Subsequently, the asymmetric allylic substitution of cyclopentene 161 with TMSN3 furnished azide 162 as a single diastereomer in 99% yield. A series of additional synthetic transformations was required to transform 162 to compound 163, a known intermediate in the synthesis of many bioactive carbocyclic nucleosides (e.g., carbovir, an anti-HIV drug).

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. 

The importance of the carbafuranoses stems from the interest in having access to carbocyclic analogues of nucleosides [88], which have attracted particular attention as anti-tumor and anti-viral agents, (-)-carbovir being one of the more popular synthetic target molecules [89]. (Fig. 1)... 

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