Carbocyclic nucleosides neplanocin

A variant of the above method is the nitrone-olefin cycloaddition, exploited for the synthesis of shikimic acid [349] and for the synthesis of the carbocyclic nucleoside neplanocin [350]. RCM has been recently exploited in Ziegler s synthesis of cyclophellitol [351]. This synthesis encompasses a number of steps described throughout this chapter, including chain extensions at Cl, at C6 and branching by Michael addition followed by carbocyclization. 

Benzyl 4-methyl (S)-2-(4-tolyl)sulfinyl maleate (18) adds to several dienes with good to excellent selectivity, depending on the type of the Lewis acid and diene used in the cycloaddition105. The adducts are easily eliminated to give the respective 1,4 dienes. (-)-Norbornadiene (28) thus obtained is a key intermediate in the synthesis of carbocyclic nucleosides neplanocin A and aristeromycin106. 

V. E. Marquez, M. Lim, M. S. Khan, and B. Kaskar, (4R,5R)-(-)-3-(Benzyloxymethyl)-4,5-0-iso-propylidene-2-cyclopentenone-4,5-diol. An optically active a-, /1-unsaturated cyclopentenone for the synthesis of neplanocin A and other cyclopentene carbocyclic nucleosides, Nucleic Acid Chem., 4(1991)27-35. 

Carbocyclic nucleoside analogs such as Aristeromycin (380) have also been isolated from natural sources (Table 40) and have antimicrobial activity. The 4, 5 -dehydro derivative of the latter, namely Neplanocin A, also has antitiunouf activity and has been synthesized (81CPB597). 

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. ... 

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). 

Carboacyclic nucleoside analogs modeled on the unsaturated carbocyclic nucleoside analog neplanocin have been synthesized. The key intermediate for this synthesis was 445, which was prepared from the 1,3-bisbenzoxyacet-one 408 by reaction with triethyl phosphonoacetate to give 444, followed... 

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... 

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. 

The endo cycloadducts resulting from the cycloaddition of optically active 3-(2-pyridylsulfinyl)acrylates and simple dienes such as cyclopentadiene and furan have been utilized successfully in the asymmetric synthesis of several natural products [166-170]. For example, cycloadduct (197), synthesized as a single diastereoisomer from the reaction of (5)-3-(2-pyridylsulfinyl)acrylate with cyclopentadiene, was converted to the lactone (198) [166], a key intermediate in the synthesis of the carbocyclic nucleosides (-)-aristeromycin (199) and (-)-neplanocin A (200) (Scheme 5.65) [167]. 

Analogues of cyclic AMP derived from the carbocyclic nucleosides aristeromycin and neplanocin have been prepared by intramolecular phosphodiester bond formation catalysed by divalent lead ions, and studies have been reported on the synthesis and biological activity of nucleoside 3, 5 -cyclic phosphotriesters and phosphoramidates. ... 

Despite several synthetic approaches to the cyciopentane moiety of carbocyclic nucleosides, starting from noncarbohydrate synthons or readily available meso intermediates, no universally applicable methodology is yet available for the asymmetric synthesis of these compounds (28-31). An efficient access to chirality is via enantioselective resolution of a prochiral or a meso intermediate prior to the addition of the purine or pyrimidine base. For example, pig liver esterase (PLE) has been used in a chemoenzymatic approach to the synthesis of optically active (-l-aristeromycin and (-)-neplanocin (32), whereas cyclic y-acetamido esters were resolved to obtain (-)-4 d5-amino-2,3-trflTis-dihy-droxy hydroxymethyl cyciopentane as a key intermediate in the synthesis of carbocyclic nucleosides (33). Although hydrolytic enzymes often display a limited degree of enan-tiospecificity with such unnatural substrates, reaction conditions can in many cases be optimized to improve the enantioselectivity (34). 

Alditols, Cyclitols and Derivatives Thereof,- Meso-D- /ycero-L-a/tro-heptitol and its monohydratc and hcptaacetate, meso-D- /ycero-L-ido-heptitol and its heptaacetate, i,3,4,5-tetra-0-benzyl-p-D-fhictopyranosyl cyanide, 34 le cyclopropane fused carbocyclic nucleoside analogue 63, neplanocin intermediatB 64,the cyclopentane 65, l,3,S,7-tetraoxadecalins 66 and 67... 

The preparation of the carbanucleoside aristeromycin and carbacyclic precursors of neplanocin A are mentioned in Chapter 19. The preparation of intermediates for the synthesis of unsaturated carbocyclic nucleosides is covered in Chapter 20. 

The carbocyclic nucleoside analogues (-) aristeromycin (18) and neplanocin A (19) have been synthesized from the Diels-Alder adduct of cyclopentadiene and dimethyl acetylene dicarboxylate using a... 

The pyridone analogues (160) of neplanocin have been prepared from a previous intermediate (Vol. 23, p.l96),l78 as has psicoplanocin A (161), a carbocyclic nucleoside combining the structural features of neplanocin A and... 

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. ... 

Two papers have reported carbocyclic nucleosides related to clitocine (see Vol. 24, p.241 for carbocyclic clitocine itself). The neplanocin-like analogue 116 has been prepared, and this was converted to 8-aza-neplanocin A and similar inosine and guanosine systems, whilst other workers have described the racemic 3 -deoxycompound 117. ... 

Carbocyclic analogues of nucleosides are also biologically active. Aristeromycin 51 possesses antimicrobial and neplanocin 52 antineoplastic activity [154]. Abacavir 53, one of the most potent synthetic anti-HIV agents, is a selective inhibitor of HIV-1 and HIV-2 replication [155]. 

---