Carbocyclic Nucleoside Analogues

The homologue 157 of neplanocin A, and several other analogues with different bases, have been synthesized from a known chiral cyclopentenone unit (Vol. 24, 

The or-analogue 159 has been made by a Pd-catalysed reaction involving an allylic phosphate as reactant, whilst others have also described routes to 159, its hydrogenated analogue, and the enantiomer and diastereoisomers of this, using enzymic desymmetrization to introduce chirality the products were evaluated for their ability to inhibit tumour necrosis factor-a. A chemo-enzymatic approach has also been used to make the cyclopropane-fused analogue 160 and 

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. 

Some references to cyclopropyl analogues are mentioned in Section 14, and some phosphates and phosphonates of carbocyclic nucleosides are discussed in the next Section. Some papers concerned with carbocyclic nucleoside antibiotics and their close analogues are mentioned in Chapter 19. 

The carbocyclic analogue 118 of AICAR, an intermediate in purine nucleoside biosynthesis, has been prepared in a sequence which involved elaboration of the imidazole ring from a cyclopentylamine a similar sequence was used to make the later biosynthetic intermediate SAICAR. 

Various 2 -C -alkylated derivatives of carbocyclic 5-methyluridine have been prepared, as have 6 -alkoxy and -acyloxy-derivatives of carbocyclic thymidine (119), in order to test the effect of the structural alterations on DNA/RNA duplex stability. A short and high-yielding synthesis of carbocyclic bromo-vinyl-deoxyuridine (BVDU) has been described, involving a cyclopentylamine derivative as an intermediate. Carbocyclic BVDU and carbocyclic 2 -deoxy-guanosine have been made by a modification of an earlier route to carbocyclic 2 -deoxynucleosides, involving a microbiological reduction. Racemic difluoro-carbocyclic nucleosides of type 120 have been made via the fluorination of ( )-JV-Boc-2-azabicyclo[2.2.1]hept-5-en-3-one (see Vol.28, p.284), and the (+)-enan-tiomer of 2-azabicyclo[2.2.1]hept-5-en-3-one has been converted into the (—)-enomtiomer, which is of considerable use in the synthesis of carbocyclic nucleosides in the o-series.  

A new asymmetric synthesis of the unnatural (+)-form of carbovir has been described, involving the cycloaddition of a camphor-derived nitrone with cyclo-pentadiene, and racemic rranj-carbovir has been made using a Ramberg-Backlund reaction to prepare the cyclopentene unit. ( )-2, 3 -Didehydro-2, 3 - 

An alternative route has been developed in Marquez laboratory to prepare the methano-carbocyclic thymidine 127 (see Vol.28, p.286). A key step involved the highly stereoselective formation of 126 by addition of diazomethane to the a,P unsaturated nitrile, itself accessible from a known intermediate in two steps. Photochemical loss of nitrogen from 126 was followed by a Curtius sequence to establish an amine from which the thymine ring was formed. The aristeromycin analogue 128 has also been prepared, using chemistry reminiscent of earlier work on analogues of this type (Vol.28, p.285-6), and bicyclic compounds of type 129 have been prepared as racemates.  

A series of cyclohexenyl nucleoside analogues such as 130, which can be regarded as a carbovir analogue with an extra methylene group inserted, have been described, as have nucleoside phosphonates of type 131 and the compounds 132 and 133 (B = Gua, Ade, Ura), where the base units were added to the cyclohexyl ring by nucleophilic opening of epoxides.  

---

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 reaction of an epoxide containing molecule with a nucleophile is typically an excellent manner in which to open the epoxide ring. A recent synthesis of carbocyclic nucleoside analogues provides an excellent example of reaction conditions that epoxides can sometimes withstand <07T5050>. Treatment of epoxide 18 with chloropurine under Mitsunobu conditions provides a good yield of epoxy purine derivative 19. This derivative was then converted to adenine derivative 20 by ester hydrolysis and subsequent chloride displacement with cyclopropylamine. 

Some triphosphate derivatives (128 129) of carbocyclic nucleoside analogues containing hydrolytically-stable phosphonate modifications have also been synthesised and shown to be potent substrates for terminal deoxynucleotidyl-transferase and HIV reverse transcriptase. ... 

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... 

Uracils can be prepared via reaction of primary amines with 3-ethoxyacryloyl isocyanate this method is particularly suitable for complex amines and has found much use in recent years in the synthesis of, for example, carbocyclic nucleoside analogues as potential anti-viral agents. The immediate product of amine/ isocyanate interaction can be cyclised under either acidic or basic conditions and the method can also be applied to thiouracil synthesis. 

MHz H n.m.r. spectra of various oligoarablnonuclgotldes has been achieved and their conformations thus determined. The conformations adopted by some carbocyclic nucleoside analogues of tubercldln... 

Carbocyclic Nucleoside Analogues Nucleoside Phosphates and Phosphonates Ether, Acetal, and Ester Derivatives Miscellaneous Nucleoside Analogues Reactions... 

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. ... 

Carbocyclic nucleoside analogues Classification, target enzymes, mechanisms of action and synthesis 12UK729. 

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... 

More recently, Jacobsen and coworkers have found that epoxides undergo a highly enantioselective ring-opening with TMS-azide when catalysed by (salen)Cr(III) complexes such as (5,5)-4. This asymmetric ring opening shows a second-order rate dependence on catalyst concentration . Applications of the process have included kinetic resolution of terminal epoxides , an efficient synthesis of (/ )-4-(trimethylsilyloxy)cyclopent-2-enone, the dynamic kinetic resolution (equation 11) of epichlorohydrin, an enantioselective route to carbocyclic nucleoside analogues and a formal synthesis (equation 12) of the protein kinase inhibitor 5. 

Nucleoside Antibiotics Ribofuranosyl Analogues Oxetanocin and its Analogues Carbocyclic Nucleoside Analogues... 

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... 

Some phosphonates of carbocyclic dideoxynucleosides, such as (162), have been prepared. 1 9 Some carbocyclic nucleoside analogues have been made by using a modified Mitsunobu reaction to link the base and the carbocycle, and there has been a second report of carbocyclic clitocine (see Vol, 24, p. 241), along with a guanosine-type analogue.l 2... 

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

---