Acyclonucleosides: Part 2. diseco-Nucleosides.

This chapter is the second of a sequence of three chapters that appears in successive volumes of this series dealing with the chemistry of acyclonucleosides. The first chapter appeared in the previous volume [97AHC391] and dealt with seco-nucleosides (one bond disconnection). This chapter deals with diseco-nucleosides (two bond disconnections). The final chapter of this series will deal with tri-, tetra-, and pentaseco-nucleosides, as well as contain an appendix of the literature that appeared after the three chapters were prepared.

diseco-Nucleosides from Two Bond Disconnections

Acyclonucleosides that are considered under this type of disconnection are those resulting from omitting any two bonds from the pentose. There are seven such types.

1′,2′- and 2′,3′-diseco-Nucleosides (Type 2.1)

The most important member is the guanine analog. There are various modifications under this type of acyclic nucleoside.

General Methods for Construction

Most of these methods involve the alkylation of the heterocyclic ring by a suitable alkoxy alkyl halide. Further modification on the heterocyclic rings may sometimes be used on a preformed acyclonucleoside. Thus, the chloromethyl ether 266 was prepared from epichlorohydrin (264) by treatment with benzyl alcohol and aqueous NaOH to give 1,3-di-O-benzylglycerol 265 (83JMC759). Alternatively, 265 was prepared from 1,3-dichloro-2-hydroxypropane 268 (84CJC241). Chloromethylation of 265 gave 266, whose treatment with potassium acetate gave 2-O-(acetoxymethyl)-1, 3-di-O-benzylglycerol (267) (83JMC759). The choice of the hydroxy protecting groups must be made to avoid difficulties encountered with the removal of the benzyl groups during the subsequent steps, particularly in the cytosine series. Thus, the requisite acyclic chain 272 was prepared by commencing with 1,3-dichloro-2-propanol 268. Methoxymethylation of 268 gave 269, where this group served a dual purpose. It protected that position from a trans-acylation process in the subsequent step and furnished the backbone methyleneoxy unit whose methoxy group could be converted into the most suitable leaving group. Treatment of 269 with the desired acid salt in DMF gave 270, whose acetolysis gave 271, which converted it to the bromomethylester 272 (88JMC144).

Scheme 55

The synthesis was started by condensing the persilylated base with chloromethylether 266 79JMC21, 82CJC3005, 84CJC16, 85JMC358, 85JMC971, 85USP4508898, 87MI4, 88MI2, 89MI8, 90GEP3906357. Both mercuric cyanide and tetra-n-butylammonium iodide (TBAI) were frequently used as catalysts in the coupling reactions. The latter catalyst has the advantages that it is less toxic, is required in smaller quantities, and involves reactions that are generally easier to manipulate during workup. Lithium bromide/ TFA/MeCN was also used (88MI2). In the case of triazine derivatives, in addition to the major product, a minor quantity of the 4-alkylated isomer was obtained (91MI5). Direct or phase catalytic, hydrogenation of 273 gave 274, except in the presence of a halogen or nitro group when boron trichloride was used 84CJC16, 84CJC241, 85JMC358, 85JMC971, 87MI2, 93MI1. Attempted debenzylation with BBr3 gave a 2-methoxymethyl derivative because of complex formation between BBr3 and the C-2 oxygen. Nucleophilic substitution may have occurred at C-1′ (N — CH2 — O) when the complex was quenched by the addition of MeOH (91MI5). However, the chlorine atom in position 6 of 6-chloro-Pu and 6-chloro-Gu could be hydrogenolyzed without any significant loss of the benzyl groups (84-CJC241).

In the case of purine derivatives, the N-7 isomers were obtained, in addition to the N-9 isomers; the N-7 isomers rearranged to the N-9 on heating (84CJC2702). The 6-chloropurines could be converted to the corresponding methoxy or hydroxy derivatives by NaOH/MeOH/H2O at room temperature and on heating, respectively. The 2-amino-6-chloropurines were converted to the 2-amino-6-methoxypurines and to the guanine analogs by reaction with NaOMe and NaOH/MeOH/H2O, respectively (84CJC2702). In 2,6-dichloropurine, substitution of the 6-chlorine atom takes place preferentially, by which means another substituent can be introduced later at the 2-position [86IJC(B)823].

The synthesis of chiral acyclic nucleosides 276 utilizes the readily available protected acetoxymethyl ether of glycerol 275, which reacted with silylated nucleobases under phase transfer conditions using dibenzo-18-crown-6 to give N-9 purinyl and N-1 pyrimidinyl acyclonucleosides. Removal of the benzoyl groups by methanolic ammonia gave 277 88JMC144, 89TL6165.

Scheme 57

The bis-chloromethyl ether 280 could also be used for alkylation. Thus, isopropylidenation of glycerol (278) followed by benzoylation and deisopropylidenation gave 279, whose chloromethylation gave 280. Coupling of the latter with silyl derivatives of bases gave 281, whose deprotection gave 282, whereas the use of sodium hydroxide led to a cleavage of one of the methyl ether linkages to give 283 and 284. The former belongs to nucleoside analogs of type 2.2. Mixed derivatives of 282 were also prepared (86MI2).

Scheme 58

Another preparation of analogs 287 was by reacting the purine bases with acetal 286 prepared from 285 (92GEP4020481).

Scheme 59

The synthesis could be achieved via a transpurination process by reaction of tetraacetylguanosine 288 with the acetoxymethyl ether 271 using chlorobenzene as a solvent, or with 2-(acetoxymethoxy)-1,3-dibenzyloxypropane (267) by fusion to give a separable 9- and 7-isomeric mixture of 289 and 290 82BBR1716, 89MI5. Heating 290 gave a mixture of 290 and 289. The reaction of 267 with diacetylguanine gave a similar mixture (83JMC759). The tetraacetyladenosine did not undergo such a transpurination process.

Scheme 60

Modification on the Heterocyclic Rings

Some modifications on the heterocyclic rings are shown in Scheme 56 , in particular the use of 6-chloropurine in coupling reactions, followed by substitution of the chlorine by an amino group. Moreover, the preferential substitution of one of the chlorine atoms in 2,6-dichloropurines introduces two different substituents at these two positions.

Scheme 56

Because of the susceptibility of cytidine derivatives to overreduction on hydrogenolysis of the benzyl ether groups, acyclic analogs were prepared from the uridine analogs by acetylation (Ac2O/Py) to give 291; P4S10 treatment gave 294, whose reaction with NH3/MeOH gave 296. In contrast, the fluorocytidine 297 was prepared from 292 via 295 by phosphorodichloridate and triazole followed by ammonia. Bromination (Br2/Ac2O/AcOH) of 291 gave 293, which could be deacetylated with NH3/MeOH (85JMC358).

Scheme 61

The synthesis of the 5-allyl and 5-n-propyl derivatives used organopalladium intermediates. The uracil derivative 299 first was treated with mercuric acetate, then was condensed with allyl chloride in the presence of Li2PdCl4 to give the 5-allyl derivatives 300 whose reduction gave 301. Treatment of 298 with iodine monochloride led to the 5-iodo derivative 302. Compound 302 also served as the starting point for the introduction of the bromovinyl side chain at C-5 by the conversion of the 5-iodo to the 5-methyl propenoate 303. The ester groups in 303 were hydrolyzed, and the bromine atom was introduced using N-bromosuccinimide to give 304 (84CJC16). None of the compounds tested showed significant activity.

Scheme 62

Coupling base 305 with 266 gave 306. Selective replacement of the amino group by halogens via treatment of 306 with t-butyl nitrite in 60% HF/pyridine gave the 2-fluoro derivative. The reaction conditions also resulted in the partial loss of benzyl groups to form 309–311. The 2-amino group in 306 could also be selectively diazotized to an oxygen function, giving rise to the isoguanine structure. Removal of the benzyl groups gave the isoguanine derivative 307, which is isomeric with BIOLF-62. The 2,6-diaminopurine derivative was treated with an excess of adenosine deaminase, which was quantitatively converted into BIOLF-62 (308) (84CJC241). The dimethylaminomethylene acyclonucleosides were prepared by reactions of the amine group with N,N-dimethylformamide dimethyl acetal in DMF/MeOH (85MI5).

Scheme 63

The synthesis of the 7-deazapurine and 5-aza-7-deazapurine analogs of DHPG were prepared by the alkylation of the respective heterocycles 312 and 316 with 266 and 267, respectively. A mixture resulting from the alkylation of N-3 and N-9 was obtained. Deprotection of 313 and 317 gave 315 in the former case, whereas in the latter case the product 318 was contaminated with the dihydro derivative; isolation was done by silylation, purification by chromatography, and then desilylation (85JHC1137). The 4-substituted analogs 314 were prepared via the 4-chloro derivative and then amination (89MI1). Compounds 315 were inactive against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) in cell culture, whereas 318 had moderate antiviral activity. Compound 314 showed poor antiviral activity against Cox B6 virus.

Scheme 64

The analogs of tubercidin, toyocamycin, and sangivamycin were prepared by treatment of the sodium salt of 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidines with 266, followed by debromination, and then debenzylation with BCl3. Conventional functional group transformation of the cyano group to CONH2, CSNH2, and C(NOH)NH2 was also done. 4-Chloro-2-methylthiopyrrolo[2,3-d]pyrimidine was aminated, desulfurized, and then debenzylated to give the tubercidin analog (89JMC402).

The synthesis of acyclic 7-deazapurine nucleosides involving a pyrrole nucleoside intermediate as a common synthon to both the 7-deazaadenosine and the 7-deazaguanosine analogs was achieved. The construction of these key intermediates (320) involves the treatment of the Na salt of the pyrrole derivative 319 with the electrophile 266 in DMF. Desulfurization of 320 (R = SMe) using Raney nickel afforded 320 (R = H). Dehydration of the carboxamide functionalities of 320 gave the corresponding dinitrile 322. Treatment of 320 with carbon disulfide followed by direct oxidation and then treatment with ammonia afforded 321. The amide was transformed to the nitrile and then deprotected to give 326. The 7-deazaadenine analogs were prepared by reacting the aminopyrrole 322 with triethyl ortho-formate followed by displacement of the ethoxy group by ammonia and subsequent cyclization and deprotection to afford the 7-deazapurine ring system 324, which could also be prepared from 323. The nitrile was transformed to the amide 325. The 7-deazaadenine analogs show activity against HIV 90JMC2162, 92MI7.

Scheme 65

The synthesis of 8-azapurine analog 330 was done by the chloroalkylation of the alcohols 265 followed by replacement of chlorine with azide to give 327. Cyclization with cyanoacetamide gave the 1,2,3-triazoline 328. Deprotection formed 329, and cyclization of 328 with ethyl formate and deprotection gave 330 (88S879). The same strategy was used to prepare analogs of types 2.2 and 3.1.

Scheme 66

Scheme 79

Analogs with a sulfur instead of an oxygen atom in the side chain were also prepared. Thus, the starting synthon 332 was prepared from 265 via 331 in four steps. Alkylation of 332 with the silyl derivative of 2-amino-6-chloro-9H-purine gave a mixture of 334 and its N-7 isomer that could be separated, whereas the use of the respective guanine led to a mixture that could not be isolated. Acetolysis of 334 with ferric chloride in Ac2O and then deacetylation gave 335. The cytosine analog 333 was similarly prepared from 332 by reaction with a fivefold excess of the cytosine followed by debenzylation to give 333 (89MI3). Tautomeric purine derivatives were prepared 80USP4199574, 85EUP145207, 90EUP349243. The introduction of an amino group at the 8-position was done by bromination with NBS, hydrazinolysis, and reduction. Guanine analogs were also reported.

Scheme 67

The influence of these acyclic nucleosides on the growth of L5178 mouse lymphoma cells and antiherpes activity has been a subject of great interest 83MI1, 83MI2, 84MI2, 84MI3, 85MI3, 90EUP375329, 90USP4968686. The Gu analog (DHPG BIOLF-62) has shown remarkable activity against herpes virus 82CJC3005, 82MI3, 83MI3, 84CJC16, 85EUP161955, 85MI1. In vitro studies indicate that DHPG is a potent and broad-acting (herpes simplex virus types 1 and 2, cytomegalovirus, and Epstein-Barr virus) antiherpetic agent. In vivo studies indicate its lack of toxicity and its superiority over acyclovir (83JMC759). The 6-H2-Pu is active against CMV. The 2-amino-6-isopropyl Pu and its esters with long-chain acyl groups were prepared as prodrugs (89AUP388734). The 6-Cl-Gu derivative is active against HSV-1 (84CJC241) and showed high activity against Coxsackievirus 3 in in vivo testing in mice. The uracil analogs show little activity against herpes viruses (84CJC16). Pyrimidine analogs inhibited the proliferation of P388 mouse leukemia [88JAP(K)63/060929]. None of the triazine derivatives were active against HSV-1 and HSV-2 or inhibited toxic effects in uninfected HFF cells (93MI1). Antiviral testing showed that a cytosine analog was equivalent to the guanine analog in potency against human cytomegalovirus and Epstein–Barr virus (88JMC144). The structure–activity relations among selected purine and pyrimidine nucleosides have been studied (88AF1545).

Scheme 75

The acyclic analogs of tubercidin, toyocamycin, and sangivamycin had only slight-growth inhibitory activity against L1210 murine leukemic cells. The corresponding derivative with CSNH2 was more potent in inhibiting HCMV but not HSV-1 (89JMC402).

Virucidal activity of an imidazole analog against entero- and coronavirus is increased by the addition of hydroxyalkyl groups in the side chain 88DOK58, 88KFZ833. Neither this analog 333 nor 335 had significant in vitro activity against human cytomegalovirus (89MI3).

Deoxyhalogeno Analogs

Analogs of DHPG with one of the alcohol functionalities on the side chain replaced by another functionality were also prepared. The chlorodeoxy precursors were prepared from epichlorohydrin by ring opening to give 336, which chloromethylated to give 337 (X = Cl). Alternatively, ring opening of benzyloxy epoxide gave 340, whose chloromethylation and coupling gave 339 86JMC1384, 91MI6. Similarly, the chloro analogs 339 were prepared by reacting bis(trimethylsilyl)adenine and tris(trimethylsilyl) guanine, and bis(trimethylsilyl)uracil after treatment with one equivalent of Bu4NF, which presumably removes the Me3Si from their N-9 or O-2, with 1-chloro-3-benzyloxy-2-propoxymethyl chloride and deblocking 89MI6, 90HCA912. Reaction with 2,9-diacetylguanine and then deprotection gave 338 (86JMC1384).

Scheme 68

Partial protection of DHPG as bis(monomethoxytrityl) derivative followed by mesylation gave 341, whose displacement with a variety of nucleophiles and deprotection gave 342 86JMC1384, 89MI6. An in vitro assay against HSV-1 showed that all compounds were less active than DHPG, though the fluoro analog was a good substrate for the viral thymidine kinase.

Scheme 69

The optically pure fluoro analogs of thymine and adenine were synthesized (93T713). The (2S)-1-fluoro-3-(R)-[(4-methylphenyl) sulfinyl]-2-propanol 343 was used as a starting material, which was converted to methoxymethyl ether 344. Treatment with trifluoroacetic anhydride and 2,4,6-trimethylpyridine in acetonitrile gave, via a Pummerer rearrangement, a geminal trifluoroacetyloxy-tolylthio intermediate as a masked aldehyde, which hydrolyzed in situ with mercuric chloride. Reduction with sodium borohydride followed by benzylation gave 345. Hydrolysis of the methoxy-methylene group gave 346, whose chloromethylation gave 347. Replacement of the chlorine with thymine gave 348, which deprotected to 351. The reaction with 6-chloropurine gave 9-alkylated isomer 349 in addition to a minor amount of N-7 isomer. The major isomer was transformed to the adenine derivative, which deprotected to give 350 (93 T713). The synthesis of enantiomerically pure 1′,2′-seco-nucleosides was almost similarly achieved (92G493).

Scheme 70

The dichlorodideoxy derivative 353 was prepared by reacting 352 with trimethylsilylated thymine in presence of n-Bu4NI. Compound 353 was treated with potassium acetate in DMF to give the acetoxy derivative, which was then treated with methanolic ammonia to give 354 in low yield (89MI4).

Scheme 71

Deoxyazido and Deoxyamino Analogs

The chiral glycerol derivative 355 was prepared by lipase-catalyzed asymmetric trans-esterification. Tosylation of 355 followed by hydrolysis gave 356. Hydrogenolysis of 356 gave 3-tosyloxy-1,2-propanediol (357). After formylation of 357 with trioxane, the resulting 358 was acetylated with acetic anhydride and ZnCl2 to give a mixture of the acetoxymethyl ethers 359 and 360. The former was treated with bis(trimethylsilyl) thymine in presence of a Lewis acid to give the acyclonucleoside 361. Acyclo AZT (362) was synthesized from 361 by deacetylation followed by treatment with sodium azide in DMF. Treatment of acyclo AZT with the sugar chloride in presence of mercuric cyanide and mercuric bromide gave the respective α- and β-glycosides, whose deacetylation afforded the α- and β-anomers of N-acetyl-d-neuraminyl-(2 → 2)-(S)-1-{[2-azido-1-(hydroxymethyl)ethoxy]-methyl}thymine (Neu5Ac-acyclo AZT) 363 90CPB836, 90JAP(K)02/009870.

Scheme 72

The optically active compound 1-O-benzyl-d-glycerol (364), which was prepared from d-mannitol, was used as the common starting material for the synthesis of the key chiral intermediates, (R)- and (S)-1-benzyloxy-3-azido-2-propanol (368, 370). Partial tosylation of 364 gave the corresponding 3-p-toluenesulfonate 371, which was further reacted with lithium azide to furnish the (R)-azido enantiomer 370. On the other hand, tosylation of 364 gave the 2,3-di-O-p-toluenesulfonate 365, whose treatment with sodium benzoate in DMF gave the benzoate ester 366, selectively. Treatment of compound 366 with sodium methoxide resulted in an internal SN2 displacement reaction, yielding (R)-benzyl-2,3-epoxypropyl ether 367 with inversion of configuration at carbon-2. Ring opening of the epoxide 367 with lithium azide afforded the other desired intermediate (S)-azido enantiomer 368. Treatment of the chiral alcohols 368 and 370 with paraformaldehyde and anhydrous hydrogen chloride gas afforded the corresponding chloromethyl ethers 369 and 372. Each was then coupled with bis(trimethylsilyl)-5-benzyluracil in refluxing toluene under anhydrous conditions to yield the protected azido acyclonucleosides 374 and 373, respectively. Hydrogenation gave the corresponding amino derivatives. The removal of the benzyl protecting group could not be achieved by the same catalytic hydrogenation conditions. However, by converting the amino derivatives first to their corresponding hydrochloric acid salts, and then following the same reduction conditions just mentioned, the respective final deblocked acyclicnucleosides 375 and 376 were obtained. The (R) and (S) enantiomers have the same affinity for binding to uridine phosphorylase and have marked high water solubility (90MI3). Similarly, thymine, uracil, 6-azathymine, 6-azauracil, 5-phenyl-6-azauracil, or 5-benzyl-6-azauracil were prepared; their debenzylation with boron trichloride in dichloromethane afforded the desired products of azido-acyclic nucleosides 377 (91MI6). None of them exhibited significant antiviral activity against human immunodeficiency virus and herpes simplex virus.

Scheme 73

A similar approach utilizing (+)-epichlorohydrin was carried out. Coupling with silylated thymine in the presence of TMSOTf, deprotection, and catalytic hydrogenation gave the amine. O-Thexyldimethylsilylation of the azide followed by reduction and then reaction with cyanogen bromide gave the N-cyano derivative and with 2,4,5-trichlorophenylformate in DMF containing ethyldiisopropylamine gave the N-formyl derivative. Desilylation was done with BU4NF (91TL1447).

The reaction of glycerol 378 with para-formaldehyde catalyzed by p-toluenesulfonic acid has been reported to give a mixture of glycerol formal 379 and 380 that upon tosylation and then separation gave two isomers 381 and 382. Azide salt was reacted with 3-O-tosyl derivative 381 to give 3-azidoglycerol formal and treatment with acetyl bromide resulted in acylative cleavage of the C(2) — O bond to give the two isomers bromomethyl ether acetates 383 and 384. Their coupling with silylated pyrimidines produced a mixture of 385 and 386, which were separated by chromatography. Deacetylation of 386 gave 377 (89MI7).

Scheme 74

Alternatively, the azido functionality was introduced onto an already prepared nucleoside. Thus, silylation of 274 gave 387 and 388. The hydroxy group in the latter was tosylated, and then displaced with azide ion and deprotected to give 391, whose reduction gave 392. The diazide derivative 390 was prepared via the respective ditosylate 389, whose reduction gave 393 (84CJC241). Treatment of 274 with a combination of triphenylphosphine-carbontetrabromide–lithium azide gave 391. In the case of an adenine analog, the diazide 390 was found as a by-product (84CJC241). However, the use of carbon tetraiodide led to 391 without by-products 89MI4, 90JAP(K)02/022268. These compounds have been evaluated for cytotoxicity and inhibition of HIV replication in MT4, but no activities were detected.

The introduction of an amino function into the acyclic sugar moiety started with the treatment of 3-benzyloxypropylene oxide with concentrated aqueous ammonium hydroxide, which then underwent SN2 substitution to give 1-amino-3-benzyloxy-2-propanol. Further reaction with phthalic anhydride in toluene resulted in the formation of N-(3-benzyloxy-2-hydroxypropyl)phthalimide. Chloromethylation by reaction with paraformaldehyde and dry HCl in 1,2-dichloroethane yielded (1-benzyloxy-3-phthalimido-2-propoxy)methyl chloride (394). Alternatively, reaction of epichlorohydrin with potassium phthalimide gave 396. It was converted with sodium benzoate in the presence of benzoic acid in DMF, and then treated with 1,3,5-trioxane in presence of HCl to 395. With 394 and 395, the persilylated bases were alkylated, and the phthaloyl protecting group was removed with hydrazine in ethanol to form 397 from 394 and 398 from 395. Deprotection by cyclohexene in ethanol with a catalytic amount of Pd(OH)2 afforded 398 (91MI5). Most showed little toxicity toward HeLa cells and 50% inhibitory levels against HSV-1 (90HCA912).

Scheme 76

The aminodeoxy analogs were found to be very potent inhibitors of uridine phosphorylase isolated from sarcoma, and they exhibited no apparent cytotoxicity against sarcoma 180 host cells. Furthermore, they have shown excellent water solubility, which is a factor critical for the formulation that often limits the usefulness of a particular compound as a chemotherapeutic agent (85JMC971).

Similarly, the puromycin analogs were prepared from 399 by chloromethylation and coupling with 6-chloropurine to give 400, which was reacted with dimethylamine, followed by dephthaloylation, coupling with dl-N-carbobenzoxyphenylalanine, and then hydrogenolysis to give 401 (85JPS1302).

Scheme 77

Branched-Chain Analogs

The trihydroxy analog 407 was prepared by acetylation of acyclovir to give 402, which monomethoxytritylated to 403 and then deacetylated to 404. Moffatt oxidation of 404 gave 405, which upon a crossed aldol-Cannizaro reaction gave 406, whose deprotection gave 407 (86JMC1384).

Scheme 78

The starting material, 1,3-dibenzyloxy-2-propanol 265, is easily oxidized to the ketone 408 using N-chlorosuccinimide and dimethyl sulfide. Compound 408 was smoothly converted into the epoxide 409. The epoxide ring was opened by the attack of benzylate anion at the least hindered site to produce 2-benzyloxymethyl-1,3-dibenzyloxy-2-propanol (410), which was activated as the thiomethyl ether system 411 using acetic anhydride in DMSO. The thiomethyl ether is readily activated by iodine, allowing nucleophilic attack at the methylene position. As a result, compound 411 was coupled to purines and pyrimidines using the silylated base procedure. As usual, the guanine derivative was produced in the lowest yield. The N-7 isomer is produced in significant quantity along with the N-9 isomer. The N-7 isomer crystallizes from solution after removal of the N-acetyl group from the direct condensation product. The route chosen to the adenine derivative involved 6-chloropurine in the condensation step. Very little of the N-7 isomer is present at the end of the reaction. The chlorine at position 6 is readily displaced by ammonia to give the adenine derivative 84CJC1622, 87BBA127. Only the guanine derivative had an ED-50 of less than 100   μg/ml with HSV-1.

Acyclo-C-nucleoside Analogs

The C-nucleoside analogs of this type of acyclonucleosides were prepared by essentially two methods: sequential O-alkylation of 265 with methyl bromoacetate followed by amidation; and sulfurization to give 413, which cyclized with ethyl bromopyruvate to the thiazole carboxylate, whose amidation and debenzylation gave thiazofurin analog 414 (87H947).

Scheme 80

Alternatively, heterocycles carrying a bromomethyl group could be used as alkylating agents to provide the targeted acyclo-C-nucleoside analogs. Thus, alkylation of the sodium salt 415 with 416 followed by substitution of the chlorine atoms gave 417 (91T10065).

Scheme 81

The acyclic analog of pyrazofurin that possesses the side chain of ganciclovir was prepared by constructing the heterocyclic ring, prepared from the hydrazone of methyl pyruvate 418, by heating with the sodium alkoxide in THF to give 419 and 420, followed by esterification and acetylation to 421. Its bromination gave 422, which, upon reaction with 415 and then deprotection, gave 423, which has no antiviral activity (91MI4).

Scheme 82

Carboacyclic Analogs

The carbo analog (Penciclovir) 431 of DHPG was prepared starting from diethyl malonate (424). Upon alkylation 424 gave 425, which was reduced and benzylated to 426. The latter was converted to 427 in four steps and then reacted with the sodium salt of guanosine, followed by debenzylation by a phase transfer catalysis to give 431 (84MI4). A shorter route to the carbo analog of DHPG 431 was carried out starting with triester 429. Its reduction gave the triol, which upon partial protection gave 428, followed by the conversion of the unprotected hydroxy group to a bromine to give 430 (85TL4265). Alkylation of 2-amino-6-chloropurine with the bromodeoxy derivative 430 gave the 9-isomer, whereas the 7-isomer was barely detectable. Acid hydrolysis of the 9-isomer converted the 6-chloro to the 6-oxo function and removed the acetonide group to give 431 (87JMC1636), which showed the highest activity against herpes simplex virus type 1 and to a lesser extent type 2. In some tests it is more active than acyclovir 87JMC1636, 92MI1. The dihexanoate ester is the most active ester 84MI4, 87JMC1636. The same strategy was used to prepare C-substituted analogs starting with substituted ethyl bromoacetates [88JCS(P1)2757].

Scheme 83

Tosylation of the isobutylidene analog of 428 followed by reaction with iodine and coupling with the sodium salt of guanine and then deprotection gave 431 (86JMC1384).

Alkylation of the thymine with bromide 427 presents a problem. The best condition to introduce the alkyl group onto N-1 is to use excess thymine and K2CO3 in DMF–H2O, whereby the product was obtained in addition to the N-3 mono- and N-1, N-3 dialkylated derivatives, as well as monobenzylated derivatives. Debenzylation gave 432 (X = OH), whose reaction with Ph3P/CBr4/LiN3 gave 432 (X = N3) in low yield as a racemate (92MI5).

Scheme 84

The crystal and molecular structures of 9-[4-hydroxy-3-(hydroxymethyl)-butyl]guanine (BRL39123; Penciclovir) and its prodrug 9-[4-acetoxy-3-(acetoxymethyl)butyl]-2-aminopurine (BRL42810, Famciclovir) were reported (90MI2).

The 2,6-dichloropurine analog 434 was prepared in two ways, either by alkylation of the base with 2-acetoxymethyl-4-iodobutylacetate to give 434 and its 7-isomer, or by chlorination of 433. Hydrolysis of 434 gave 435, in which the chlorine could be substituted with amines to give 436 [89JCS(P1)2207]. The 2-amino-6-iodopurine may also be used as a base in the coupling (90EUP352953). The respective 2-N-hydroxyguanine showed potent antiherpes virus activity in a cell culture test [89JCS(P1)2207]. Functional group conversion of one hydroxyl group of 436 was achieved via the bis(monomethoxytrityl) derivative 437 by bromination and deprotection to 438 (X = Br). Its conversion to the azide followed by reduction gave the amine whose formylation gave the formyl derivative, which showed moderate antiherpes virus activity, whereas 438 (X = N3) showed only weak activity [88JCS(P1)2777].

The corresponding ethers proceeded from diol 439. Selective acetylation of 439 and then methylation gave 441 (R = H). In contrast, selective allylation of 439 followed by hydroxylation gave 440. Periodate oxidation and reduction gave the corresponding alcohol, whose acetylation gave 441. Debenzylation by catalytic hydrogen transfer or hydrazinolysis followed by bromination gave 442; subsequent alkylation of the base and then deprotection gave 443 [88JCS(P1)2777]. A weak antiherpes virus activity was observed for 443 (R1  = CH2OH).

Scheme 85

Modified Carboacyclic Analogs

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-bisbenzoxyacetone 408 by reaction with triethyl phosphonoacetate to give 444, followed by reduction of the ester group to give the alcohol that upon attempted tosylation gave the chloro derivative 445. Coupling of either adenine or the guanine precursor 2-amino-6-chloropurine with 445 formed the nucleosides 446, whose debenzylation gave 447. In the case of a guanine precursor, further treatment with alkali was required to obtain the guanine analog, which exhibited significant antiviral activity against HSV-2 (87JMC943).

Scheme 86

The preparation of 2,2-bis(hydroxymethyl)cyclopropyl analogs 450 and 452 was accomplished starting with the cyclopropane derivatives 448, which, when reduced, benzoylated, ozonized, reduced, and then tosylated, gave 449. Coupling of the latter with adenine and then debenzoylation gave 450, whereas coupling with 2-amino-6-chloropurine gave 451 followed by acid hydrolysis to give the guanosine 452 (88JMC2304).

Scheme 87

The branched-chain analogs were prepared as shown previously for the nonbranched ones from triester 429. Alkylation of its anion with iodomethane or benzyl chloromethyl ether gave 453, followed by reduction with sodium borohydride or LiAlH4 to give the respective triol. Acetonation of the triol was accomplished with little selectivity, whereby 454a was formed in appreciable quantities in addition to 454b. Bromination of the latter gave 455. Coupling of 455 with 2-amino-6-chloropurine gave 456, whose hydrolysis gave the guanosine analog 457 [88JCS(P1)2767].

Scheme 88

The fluoro analog 463 was prepared from diethyl acetoxymalonate 458 by alkylation of its anion with benzyl-2-bromoalkyl ether to give 459, whose reduction followed by benzoylation gave 460. Fluorination of 460 gave 461. Debenzylation followed by bromination gave 462, which was used in the alkylation of 2-amino-6-chloropurine followed by acidic hydrolysis to give 463 [88JCS(P1)2767].

Scheme 89

An alternative route to the carba-ganciclovir and its modified side chain was started by the malonate derivatives 464, where the allyl group serves as a masked 2-hydroxyethyl function. Thus, reduction of 464 gave the respective diol that was protected as the isopropylidene 465, which upon ozonolysis, reduction, and tosylation gave 466. The respective tosylates were used in the alkylation of 2-amino-6-benzyloxypurine to give 467, in addition to the 7-isomeric product. Hydrolysis gave the carba-ganciclovir analog 468 (89JHC1261). Their antiviral activities were evaluated.

Scheme 90

The alcohol 470 was prepared from the mesylate 469 by reaction with diethyl malonate followed by reduction to give 470, whose selective acetylation was carried out by reaction with trimethyl orthoacetate followed by acid hydrolysis of the cyclic orthoester intermediate. Bromination and then coupling gave 471 [88JCS(P1)2757].

Scheme 91

The analogs 479 and 480 were prepared from the O-protected glycoaldehyde diethylacetals 472 by a trans-acetalization to 473, which was chlorinated to 474 and then reacted with diethyl malonate followed by reduction to give 475 or 476. Cyclohexylidenation and then debenzoylation of 475 gave 481. Benzoylation of 476 gave 477, which upon debenzylation, tritylation, and then fluorination gave 478. Detritylation of the last gave the respective alcohols. The alcohols from 478 and 481 were converted to the bromides and/or the mesylates. Alkylation of 2-amino-6-chloropurine with these bromides or mesylates gave 479 and 480, which were converted to the racemic 9-substituted guanines [88JCS(P1)2757].

Scheme 92

Synthesis of the 1′-methoxy derivative 484 commenced with the alkylation of the anion of diethyl malonate with a suitable bromoacetal, followed by reduction to give 482, which upon acetylation and then reaction with acetyl chloride and thionyl chloride gave the α-chloroether 483. Reaction of 483 with the trimethylsilylated 2-N-acetylguanine using tin (IV) chloride as a catalyst gave a mixture of 9- and 7-alkylation products, whose deacetylation gave 484 and its isomeric product, respectively [88JCS(P1)2767]. All of these acyclonucleosides with branched chains were tested for antiviral activity in cell cultures. The most active was the 3′-fluoro, but it had only about one-third of the activity of the lead compound 9-(4-hydroxy-3-hydroxymethylbutyl)guanine against herpes viruses.

Scheme 93

This type of acyclic nucleoside could be prepared by a Michael addition process. Thus, when 2-amino-6-chloropurine was reacted with 485, and 8:1 mixture of the N-9 (486) and N-7 cyclopropylpurines was produced. When the chloroethylidene malonate was used, the ratio became 40:1. Catalytic hydrogenation of 486 in presence of base effected both dehalogenation and 1, 2-cyclopropane bond fission to provide 487. Its reduction and acetylation gave Famciclovir 488 91EUP420559, 92TL4609.

Scheme 94

Carboacyclic Analogs via Heterocyclic Ring Construction

The synthesis of the carboacyclic analogs may be performed by constructing the heterocyclic ring on a suitable functionalized side chain. Thus, the acetal 489 was synthesized in a similar manner to 426. Its reaction with hydroxylamine hydrochloride gave a mixture of the oxime 490 and nitrile 491, which upon reduction gave 492. Reaction of 492 with 5-amino-4,6-dichloropyrimidine followed by cyclization with ethyl orthoformate gave 494, which upon hydrolysis gave the hypoxanthine analogs 495; its amination, however, gave the adenine analogs (72SC345). The respective guanine analog 496 was prepared by cyclization of 493. Debenzylation of 496 gave 497. The crystal and molecular structure of Penciclovir (BRL 39123) and Famciclovir (BRL 42810) were determined. In the former, the plane of the acyclic N-9 substituent is orthogonal to the purine ring. It has an extensive network of intermolecular hydrogen bonds. In Famciclovir, however, there are no major hydrogen bonding interactions, but there are π–π interactions between parallel overlapping pyrimidine moieties (90MI2).

Scheme 95

The pyrimidine ring in 499 could be constructed by the condensation of 492 with acrylamide 498, followed by base-catalyzed cyclization to 499 (72SC345). Cyanoethylation of 492 gave 500, whose cyclization gave 501, which upon bromination and dehydrobromination gave 502 (72SC345).

Scheme 96

Carboacyclic C-Nucleoside Analogs

The carboacyclic C-nucleosides could be constructed from 489 by cyanomethylation to give 503, which upon reduction gave 504. Iminoolefination of 504 gave 505, whose reaction with ethyl chloroformate gave 506, which was cyclized to the pyrrole 507; the pyrimidine ring then was formed to give 508 [91JCS(P1)195].

Scheme 97

Scheme 98

A series of conformationally restricted acyclic pyrimidine nucleosides fixing the base–sugar orientation in the anticonformation by forming a carbon bridge between them has been prepared. This was based on the hypothesis that if the nucleoside is to be a good substrate for HSV-TK and be active against herpes viruses, it must exist in the anti conformation rather than the syn conformation. Thus, the C-6 side chain was connected via an addition reaction of the lithiated 6-methyl pyrimidine derivatives 509 with 1,3-bis(benzyloxy)-2-propanone 408 to give 510. The lithio derivatives were prepared from the pyrimidine bases with LDA in tetrahydrofuran. The tertiary hydroxyl group of the side-chain group was smoothly converted to 511 on treatment with a mixture of acetic anhydride and anhydrous dimethyl sulfoxide. Ring closure of 511 to bicyclic 512 was accomplished with iodine in dry tetrahydrofuran. An initial electrophilic activation of the sulfur atom of the (methylthio)methyl group by the iodine took place to generate a reactive sulfonium species, which promoted the nucleophilic attack at the methylene position by the nitrogen of the pyrimidine ring. Deprotection of 512 gave 513 or 514, whereas the cytidine derivative was obtained by debenzylation with boron trichloride, followed by a displacement of the methoxy group using saturated methanolic ammonia (92JOC3354).

Translocation of Oxygen with Carbon and Aza Analogs

Analogs with a translocated atom of the ether linkage by a carbon atom have been also prepared. Thus, reaction of 2-amino-2-cyanoacetamide hydrochloride 516 with N,N-dimethyl-N′-benzyloxymethanimidamide 515 in methanol gave 517 as an unstable intermediate. Cyclization of 517 with the Lewis acid diethylether–boron trifluoride in 1,2-dimethoxyethane followed by catalytic hydrogenolysis over 10% palladium on charcoal afforded 518, isolated as its hydrochloride. Its alkylation with the 5-iodomethyl-2,2-dimethyl-1,3-dioxane, in the presence of potassium carbonate, gave the 1-alkoxyimidazole. A similar yield was obtained by using the mesylate and catalytic amounts of lithium iodide. Deprotection under acidic conditions gave the imidazol-1-yloxyalcohols 521 (90S893).

Scheme 99

Alternatively, the construction of these nucleosides was achieved from the alkoxyamine derivative 520 by conversion to the respective formamidine 519. Transamidination followed by boron-trifluoride-catalyzed cyclization gave the imidazoles 522. Their cyclization was effected using sodium methylxanthate to give the purine thiolates, which upon oxidation with MCPBA gave the sulfonate, which directly reacted with hydroxylamine. Deprotection gave 523 [89JCS(P1)2207].

The alkoxyamine 524 was converted to the urea derivative 525, whose cyclization with 3,3-dimethyloxypropionate or ethyl-3,3-diethoxy-2-methyl-propionate was effected to give the pyrimidine derivatives 526. Their catalytic hydrogenation gave 527 (88TL4013). The cytosine derivative 529 was prepared via the triazolo derivatives 528, which upon aminolysis and deprotection gave 529. None of these compounds had significant antiviral activity.

Scheme 100

The 5-fluoro analog 531 was prepared by alkylation of 5-fluoro-1-hydroxyuracil, via initial formation of its dianion with the appropriately functionalized halide 530 and then conventional deprotection [90JCS(P1)2175]. No significant activity was noted against herpes simplex virus type 1 and 2, varicella zoster, cytomegalovirus, or Epstein–Barr virus.

Scheme 101

Replacement of the oxygen by nitrogen in the preceding analogues led to the 9-alkylaminoguanines 536. They were prepared from the 9-aminoguanine 533, by condensing it with aldehyde 532 to give 534. Reduction of 534 gave 535, which was followed by desilylation to give 536 (88TL5995). They are selective antiherpes virus agents, although less potent than analogous 9-alkyl and 9-alkoxyguanines.

Scheme 102

1′,2′- and 4′,5′-diseco-Nucleosides (Type 2.2)

General Methods of Construction

Acetoxymethyl ethers 539 and 540 could be prepared from the mixture of glycerol formals 537 and 538. Reaction of 539 with GuAc2 gave N-9 (541) (and N-7) guanine derivatives as racemic forms whose deacetylation gave 542 84TL905, 85JMC926.

Scheme 103

Alkylations of benzimidazole 547 and benzotriazole 548 with the triacylated derivatives 543 or 545 and their dideoxy derivative 544 gave after deprotection 550 and 551, respectively (88KFZ714). The benzotriazoles had greater antiviral activity to enterovirus than the benzimidazoles. The acyclic derivatives derived from 549 are only moderately virucidal to some RNA-containing viruses (89KGS493). The reaction of 546 with 1(3)-H-imidazo[4,5-b]pyridine gave the 1- and 3-isomers 553 and 554 (90MI1). 552 was formed similarly.

Scheme 104

The respective optical isomers (R)- and (S)-iNDG were prepared by reacting the enantiomers of the 1,2-di-O-benzylglycerols 556 and 565 with paraformaldehyde and anhydrous HCl to give the corresponding chloromethyl ether 557 and its isomer 566, respectively. They reacted with the tris (trimethylsilyl)guanine to give 558 and 567, respectively. Their catalytic hydrogenation gave the corresponding 559 and 568 (85JMC926). The precursor for the chiral glycerol 556 was the d-mannitol derivative 555, whose periodate oxidation and reduction gave 556, whereas the other isomer 565 was prepared from the d-mannitol derivatives 560, whose oxidation and reduction gave 561. The last, upon benzylation and hydrolysis, gave 562, which upon tritylation gave 563; subsequent benzylation gave 564. Hydrolysis then gave 565. The racemic form exhibited potent antiviral activity (84TL905). The (S)-iNDG was found to be more active than the R enantiomer against HSV-1 and HSV-2 in cell culture; it had an ED50 comparable to those for ACV and 2′ NDG. The inferior activity of (R)-iNDG parallelled the poor inhibition of viral DNA polymerase by its phosphorylation products. In mice (S)-iNDG was less efficacious than 2′NDG, but comparable to or more active than ACV 85EUP130126, 85JMC926.

Scheme 105

Scheme 106

Scheme 107

An alternative source for the chiral nucleoside 559 utilizes methyl-2,3,4-tri-O-benzyl-α-d-glucopyranoside (569); this was chloromethylated to give 570, which upon reaction with 2-amino-6-benzyloxypurine gave 571. Debenzylation of 571 gave 572, whose periodate oxidation followed by reduction gave the glycerol derivative 573, which upon acid hydrolysis gave 559 (85TL1815).

1-Hydroxy-2-azido-3-propoxymethylpyrimidines 577 were synthesized from 574 by displacement with azide ion to give 575, followed by ringopening with acetyl bromide to give 576, which upon reaction with base and deacetylation gave 577 (89MI7).

Scheme 108

The dl-serine uracil derivative 580 was prepared from dl-serine methyl ester hydrochloride by N-benzoylation to give 578; chloromethylation gave 579, which then was substituted by the silylated uracil (88ZOB2404).

Reaction of the chloromethyl derivative 581 with a uracil derivative gave a mixture of 582 and 583 (91KFZ44).

Scheme 109

Deoxy and Branched-Chain Analogs

Selective benzoylation of the triol 584 gave 585, whose acetoxymethyl ether 586 condensed with diacetylguanine in the presence of bis(p-nitrophenyl) phosphate and sulfolane to give 587, which upon deprotection gave 588 (86JMC1384). Another precursor for branched-chain nucleosides was pentaerythritol triacetate 589, which upon chloromethylation gave 590. Condensation of 590 with 6-chloropurine or N-acetylguanine gave a mixture of the 7- and 9-isomers, whose deprotection gave 591. The pyrimidine analogs were prepared from the silylated pyrimidine (84MI5). All showed activity against herpes viruses.

Scheme 110

Acyclo-C-Nucleoside Analogs

The C-nucleoside analogs were prepared when 5-hydroxylmethyluracil 592 and glycerine were condensed in the presence of HCl to give 593, whose methylation with DMF–dimethylacetal gave 595. Further reaction with guanidine gave the isocytidine analog 597, which was purified via its acetyl derivative 596. In contrast, methylation of 593 with HMDS/MeI gave 594, whose separation was achieved via acetylation and deacetylation (86JHC1621).

Scheme 111

Acyclic analogs of pyrazofurin were prepared by heating 422 with alcohol 598 in the presence of sodium acetate followed by deprotection and amidation to give 599. The respective 3′-deoxy analog was also prepared from the respective alcohol and exhibited slight activity against human cytomegalovirus (91MI4).

Scheme 112

Translocation of the Oxygen with Carbon Analogs

Translocation of the oxygen side chain with one of the two adjacent carbons could lead to two isomeric structures. Thus, nucleosides with C-1′ translocated with the oxygen of the side chain have been synthesized. The need for protecting groups was obviated by introducing the hydroxy functionalities of the acyclic substituent at a later stage in the synthesis, by hydroxylation of an exocyclic double bond. Thus, cyclization of unsaturated ureas 600 gave the pyrimidines 602, which, on treatment with osmium tetroxide and N-methylmorpholine N-oxide in aqueous acetone, gave the acyclonucleosides 603 [90JCS(P1)2175]. The guanine acyclonucleosides having 2,3-dihydroxybutoxy side chains were prepared via the alkenoxy amines 601 by condensation with 4,6-dichloro-2,5-diformamidopyrimidine to give 604. Closure of the imidazole ring was achieved by heating with diethoxymethyl acetate followed by treatment with ammonia and cis- hydroxylation to give 605, which upon treatment with formic acid gave 607 and upon catalytic hydrogenation gave 606. Treatment of 605 with sodium methoxide gave the 4-methoxy derivative (91JMC57).

Scheme 113

Nucleosides with a translocation of the oxygen with C-4′ were prepared by coupling of the chloroacetate 608 with various bases, followed by deprotection to give 609. Similarly, the respective ethers 611 were prepared from 610 89CS379, 96UP1.

Scheme 114

2′,3′- and 3′,4′-diseco-Nucleosides (Type 2.3)

Debenzoylation of the nucleoside analogs 612 gave 613, which upon periodate oxidation and reduction gave the optically pure enantiomers 614. Similarly, uracil analog 615 gave also the corresponding 614 (88KGS223).

Scheme 115

The racemic analogue 620 was prepared by alkylation of N-2,9-diacetylguanine with 2,3-dichlorotetrahydrofuran 616. The adduct 617 was deacetylated to give 618, and then monomethoxytritylated followed by elimination of HCl to give 619. Treatment of 619 with OsO4–NaIO4 and then reduction gave 620 (86CJC1885).

Scheme 116

The racemic analogs were also obtained by replacement of the halogen atom in 2-chloromethyldioxolane 622, obtained from ethylene glycol and 621, by an acetoxy group to give 623. Subsequent opening of the dioxolane ring with acetic anhydride in presence of ZnCl2 gave 624, followed by reaction with the base to give 625. 1-Alkyl derivatives were almost the only product of the alkylation of trimethylsilyl derivatives of pyrimidine bases, whereas a mixture of the 9- and 7-substituted isomers was formed in the case of 6-N-benzoyladenine. Treatment of the protected analogs with a methanolic solution of ammonia led to 626 (88KGS223).

Scheme 117

Alternatively, ring opening of various 2-substituted dioxolanes 627 with trimethylsilyl iodide provided acyclic sugar analogs 629, via 628; these are lacking only C-3′. Coupling with the sodium salt of 6-chloropurine gave 630, whose reaction with NH3 gave 631 (79JOC3733). Other pyrimidine analogs 632 were also prepared from 1,3-dioxolanes 627 by treatment with base in the presence of a Lewis acid (anhydrous stannic chloride or zinc chloride) in an inert solvent under similar conditions to those of the modified Hilbert–Johnson method. This was followed with methanol containing sodium hydrogen carbonate or aqueous sodium hydroxide to give N-1-substituted pyrimidine (uracil) acyclonucleosides 632 and a minor product of the respective N-1,N-3-bis-substituted derivatives (85CPB1703).

Scheme 118

Modified Side-Chain Analogs

The syntheses of di- and trifluoromethyl acyclonucleosides 634 are based on the substitution of the mesylates of the corresponding hemiacetals 633, obtained by condensing ethylene glycol monobenzyl ether with di- or trifluoroacetaldehyde followed by mesylation. Their substitution by 2-amino-6-chloropurine or N 4-acetylcytosine gave 634, followed by hydrolysis and then hydrogenolysis (91TL3823). They were less active than acyclovir.

Scheme 119

Reacting ethylene glycol monobenzoate 635 with acetaldehyde and HCI gas gave 636, whose reaction with pyrimidine derivatives followed by debenzoylation gave 637 (86JHC1651). The base-catalyzed hydrolysis of 6-substituted 9-(l-ethoxyethyl)purines takes place by nucleophilic attack of hydroxyl ion on C-8 of the purine moiety [82ACSA(B)707].

Scheme 120

Condensation of 2-(benzyloxy)ethanol with a mixture of the hydrate and methyl hemiacetal of methyl glyoxalete 638 gave a hemiacetal, which was converted directly with methanesulfonyl chloride to α-chloro ether 639. It condensed with silylated uracil, 5-fluorouracil, and N 4-acetylcytosine, generated in situ from the bases and N,O-bis(trimethylsilyl)acetamide (BSA), in presence of stannic chloride to give pyrimidine acyclonucleosides 640. Reaction of the ester with NH2OH was unsuccessful. Therefore, the esters were saponified to the corresponding acids 641 and then coupled to O-benzylhydroxylamine to give 646. Didebenzylation of a uracil derivative was smoothly accomplished with PdO-catalyzed transfer hydrogenation. However, the 5-fluoro derivative could not be obtained in sufficient purity. This problem required the development of a mild method generating the hydroxamic acid as the final step in the synthesis. Lactones seemed ideally suited for this purpose. Catalytic transfer hydrogenation of 642 gave 643; this, upon lactonization, gave 644, which reacted with NH2OH to give 645. The hydroxamates inhibited CDP reductase activity (89JMC1879).

Scheme 121

The ring-opened analog of 5′-aminocordycepin was prepared by reaction of 6-chloropurine with phthalamide 647 to give 648, which upon conversion of the chloro substituent to amine, reduction of the ester group, and hydrazinolysis gave 649 (87MI1).

Scheme 122

3′,4′- and 4′,5′-diseco-Nucleosides (Type 2.4)

Typical Examples

Reaction of 2,3-diacetoxy-1,1-dimethoxypropane and 1,3-diacetoxy-1-methoxypropane 650 with bis-O-trimethylsilyluracils and N,O-bis-trimethylsilyl-N-acetylcytosine in the presence of stannic chloride, a modification of the Helbert–Johnson reaction, gave 651. Also, 2,3-divaleryloxy-1,1-dimethoxypropane was used (85MI6). Similarly, reaction of pertrimethylsilyl derivatives of N-benzoyladenine with 1,2,3-triacetoxy-1-methoxypropane gave N-9 and N-7 isomers, whereas the reaction with 1,3-diacetoxy-1-methoxypropane afforded the N-9 isomer (87MI3). Nucleoside analogs of 2-N-acetylguanine, hypoxanthine, and diacetamide purine were also prepared (87MI3). Acetyl groups were subsequently removed from most of the protected analogs by treatment with ammonia in aqueous methanol, except in the case of 5-trifluoromethyluracil, which gave the 5-cyano derivative. Because fluoride ion is normally a poor leaving group in displacement and elimination reactions, direct displacement of fluoride by ammonia seemed unlikely, and a more plausible mechanism for this transformation involved initial attack of ammonia at C-6. 2,3-Bis(trimethylsilyloxy)-1,1-dimethoxypropane was used where subsequent removal of the O-trimethylsilyl groups under neutral aqueous conditions was required. Under the reaction conditions employed, condensation of bis-O-trimethylsilyl-5-nitrouracil and N,O-bis-trimethylsilyl-N-acetylcytosine with 1,3-diacetoxy-1-methoxypropane afforded, not only the 1-N alkylated products, but also the 1,3-disubstituted pyrimidines. The activity of these acyclonucleosides was studied toward influenza A, parainfluenza type 1, and herpes simplex type 1 viruses.

Scheme 123

Michael addition of nucleobases to diethyl maleate followed by reduction gave 652 and 653 (92MI6). The uracil analog exhibited only marginal activity against HIV.

Scheme 124

Condensation of N-alkyladenine with 2-deoxyribose (654) in a phosphorus pentoxide mixture gave 655 via a probable Michael-type addition to an α,β-unsaturated sugar aldehyde formed in situ from 2-deoxyribose. Reduction of 655 gave 656 (92JHC511). Neither 655 nor 656 showed any significant activity against HSV-1.

Scheme 125

Reaction of 1,3,4-tri-O-benzoyl-2-deoxy-d-ribofuranose (132) with the silyl derivative of benzoyladenine in the presence of TiCl4 gave a mixture of 657. They were also formed by reaction of the respective 1-chlorosugar with the adenine derivative. The high reactivity of the sugar derivative resulted in a facile elimination of hydrogen chloride. Cis-hydroxylation of one of the isomers of 657 gave an anomeric mixture of 658, whose reduction gave 659; a migration of the benzoyl group had taken place. Debenzoylation of 659 gave 662, whereas its periodate oxidation and reduction gave 660, which upon debenzoylation gave 661 (91T9993).

Scheme 126

EHNA Analogs

The acyclicnucleoside erythro-9(2-hydroxy-3-nonyl)adenine 74JMC6, 78MI1 is abbreviated as EHNA. Because of its importance as an inhibitor of adenosine deaminase, various approaches were reported for the synthesis of the chiral isomers 81JMC1383, 81MI1, 82JOC2179, 82MI2, 88JMC390. Thus, the synthesis of both isomers of EHNA from d- and l-rhamnose was reported (82JOC2179). Scheme 127 depicts those derived from d-rhamnitol. The key intermediate R-2-(benzyloxy)propanal (664) derived from 5-O-benzyl-d-rhamnitol (663) was condensed with hexylmagnesium bromide to give a 3:1 mixture of threo/erythro alcohols. Both were converted to the respective mesylated products 665 and 666, whose displacement with (adenin-9-yl) sodium salt gave the erythro 667 and threo 668 isomers of EHNA, respectively. A similar sequence was also depicted for the other two isomers from l-rhamnitol.

Scheme 127

Alternatively, the heterocyclic ring was built onto an amino alcohol precursor that is derived from the sugar precursor methyl-l-amicetoside (669), obtained from l-rhamnose, by tosylation followed by azide displacement, reduction, acetylation, and then hydrolysis to give 670. Reaction of 670 with a Wittig reagent gave the acetylamino alcohol 671, whose hydrolysis with HCI gave the threo-aminoalcohol (2S,3S)-672. However, treatment with thionyl chloride prior to hydrolysis with HCI resulted in the inversion of configuration of C-2 by an SN1 mechanism, involving an oxazoline intermediate to provide the erythro isomer (2R,3S)-674. The other two isomers could be prepared from methyl α-rhodinoside, obtained from 669 by an inversion of configuration at C-4, by a similar sequence of reactions on 669 shown in Scheme 128 (81JMC1383). The amino alcohols were converted to their respective adenine analogs by condensation with 5-amino-4,6-dichloropyrimidine to give 673 and 675, which was followed by cyclization and reaction with ammonia to give 676 and 667, respectively (74JMC6).

Scheme 128

The chiral aminoalcohol precursor for the synthesis of EHNA analogs could be obtained from l-ascorbic acid, whose isopropylidenation gave 677, which was transformed via degradation and esterification to 678 (84TL3841). Reduction of 678 followed by tosylation and epoxide formation gave 679. Addition of pentylmagnesium chloride followed by mesylation gave 680, whose azide displacement and reduction gave 681. Further conversion to the 3-deaza analog 685 was achieved via 682. Conversion of 681 to 684 was also achieved via 683. Reductive periodate cleavage of 684 gave 686, which was converted to the fluoro analog by treatment with DAST. In contrast, the respective chloro and bromo derivatives were prepared via the corresponding tosylate by treatment with Bu4NX.

Scheme 129

The erythro isomer could also be prepared from 679. Thus, reduction of 679 followed by benzylation and then hydrolysis gave 687, whose tosylation and treatment with base gave the respective epoxide, which upon addition of 1-pentenyl-5-magnesium bromide gave 688. Conversion of the alcoholic group in 688 to an amino group was achieved by a Mitsunobu reaction to the azido group followed by reduction. Amination of the chloroheterocycle followed by reduction and cyclization gave 689. Amination, hydroboration, and debenzylation then gave 690.

Scheme 130

The 7-deaza EHNA analog 691 was obtained by condensation of 4,6-dichloropyrimidine-5-acetaldehyde with 674. The 1,3-dideaza EHNA analog was prepared from erythro-3-amino-2-nonanol (674) by condensation with l-chloro-2,3-dinitrobenzene, prepared in turn from l-amino-2,3-dinitrobenzene, to give 692. Reduction followed by cyclization with formamidine acetate gave 693 (88JMC390).

Scheme 131

As a further modification of EHNA, condensation of ethyl-2-amino-2-cyanoacetate or aminomalononitrile with erythro-3-amino-2-nonanol in presence of triethyl orthoformate gave imidazole derivatives. Chemical modification of the two substituents afforded a variety of analogs (91JMC1187).

EHNA in its racemic form was designed as a semitight binding inhibitor of ADA. The synthesis of the chiral isomers allowed identification of the (+)2S,3R as the most potent ADA inhibitor. This led to enhancement of ara-A activity against human pancreatic and colon carcinomas. (+)EHNA has a short duration of action, and it is believed to be metabolized by a cytochrome P-450 mediated hydroxylation in the nonyl side chain. The 3-deaza(±)EHNA had comparable activity to (±)EHNA 84JMC274, 88JMC390. EHNA has the antineoplastic activity of adenosine analogs against human pancreatic DAN and human colon HCT-8 carcinomas (88MI1).

4′,5′-and 4′,x-diseco-Nucleosides (Type 2.5)

Although typical examples of this type are few, the respective 4′-hydroxylated analogs are frequently prepared. During work aiming to elongate the sugar chain, thiazole nucleoside 696 was prepared by an antidiastereoselective addition of 2-trimethylsilylazoles (thiazole, benzothiazole, oxazole) 695 to asymmetric aldehydes 694 to give the corresponding O-silylcarbinoles in high stereoselectivity 85TL5477, 89JOC693.

Scheme 132

Condensation of d-ribonolactone (698) with 2-(3,4-methylenedioxyphenyl)ethylamine (697) gave an amide 699, whose acetylation with Ac2O in pyridine and subsequent oxidation with m-chloroperbenzoic acid gave nitrone 700, which was then hydrogenated in an acetic acid–HCl mixture over Adams catalyst and acetylated in situ to give 701 and 702 isolated by chromatography [92JCR(S)402].

Scheme 133

The reaction of aminosugar 704 with isocyanates and isothiocyanates has been studied extensively (85AQ(C)147; 91MI2, 91MI3). The reaction gave 703 via the formation of a ureido derivative, which is too reactive to be isolated. The formation of 705 from 704 during the acetylation and deacetylation was studied.

Scheme 134

Reaction of 1-amino-1-deoxy-d-arabino hexulose 706 with cyanamide gave the imidazolin-2-ylideneammonium picrate 707 (89MI2).

Scheme 135

The reaction of d-glucosamine 704 with 1,3-dicarbonyl compounds either in an acyclic structure or in a cyclic form gave 708 84MI1, 85MI2, 92MI3.

Scheme 136

The 1,2,3-triazoles 710 readily obtained from osazones 709 could be reacted with HBr/AcOH to give 711 (96UP2).

Scheme 137

Reaction of per-O-benzoyl aldononitriles 712 with ammonium azide gave the tetrazole benzoate 713, whose debenzoylation gave 714. Other analogs with a different configuration were also prepared (79MI1).

Scheme 138

1′,x- and 4′,x-idseco-Nucleosides (Type 2.6)

The starting material was prepared by benzylation of but-3-en-1-ol followed by epoxidation with MCPBA to give an epoxide, whose ring opening was achieved with trimethylsilyl cyanide in the presence of diethylaluminium chloride to give a hydroxy nitrile derivative. Complete reduction of the nitrile with lithium aluminum hydride in diethyl ether led to 715, which was condensed with 2-amino-4,6-dichloro-5-(substituted)pyrimidine (716) to produce 717 and 718, depending on the substituent R. The latter, upon acidic hydrolysis and removal of the benzyl group, gave 719. The synthesis of guanine analog 720 was achieved by cyclization of 717 followed by hydrolysis and deprotection (90JMC2476).

Scheme 139

The cytosine analog 726 was synthesized by reacting 715 with isocyanate 721 to give 722. Cyclization then gave 723, which was deprotected to form 724. The cytidine analog was prepared from 725 by chlorination, aminolysis, and deprotection to give 726 (90JMC2476). The compound displayed no anti-HIV activity, indicating that replacement of the carbohydrate moiety of the different naturally occurring nucleosides by a pentane-3,5-diol chain does not give rise to antiviral activity against HSV-1, HCMV, and HIV-1.

Scheme 140

Acyclic nucleoside analogs were prepared containing C-5′ hydroxyalkyl fragments, where the distance between the 5′-hydroxyl group and the heterocyclic moiety corresponds to that in dideoxydidehydronucleosides (as confirmed by computer modeling). Condensation between 5-O-acetyl-1-bromo-2-pentene (727) and persilylated heterocyclic bases (pyrimidines and guanine) or adenine sodium salt gave rise to the acyclic nucleosides 728. Deprotection by NH3/MeOH gave the desired nucleosides 729 (91MI1).

Scheme 141

1′,x- and 4′,5′-diseco-Nucleosides (Type 2.7)

Acyclo-N-Nucleoside Analogs

The starting 733 could be prepared from the d-glucose derivative 730 by benzoylation to 731, followed by partial deisopropylidenation to 732 and then periodate oxidation, reduction, and tosylation. Alternatively, it was formed from the d-xylose derivative 735 by partial hydrolysis to 734, followed by tosylation and then benzoylation. Reaction of 733 with the sodium salt of bases gave 736. Hydrolysis of the isopropylidene group followed by periodate oxidation, reduction, and then debenzoylation gave 737 (79CCC593).

Scheme 142

The synthesis of the enantiomeric threo analogs started from d- or l-arabinose (79CCC593). Thus, the adenine analog 743 was prepared from d-arabinitol 738 by conversion to the benzyliaene derivative 739. Its periodate oxidation and reduction gave 740, which was tosylated and then benzoylated to give 741. Reaction of 741 with the sodium salt of adenine gave 742, which was deprotected to give 743.

Scheme 143

The racemic dl-threo derivative 747 was prepared starting from ethyl dl-tartarate, whose reaction with dimethoxypropane gave 744. Subsequent reactions, as shown in Scheme 144 , gave 745, then 746, which was deprotected to 747. An analogous synthetic procedure was also done for the preparation of the racemic erythro derivative (79CCC593).

Scheme 144

Eritadenine (750) is one of the significant hypo-cholesterolemic components of Lentinus edodes sing. Moreover, eritadenine and its stereomers have antiviral effects against vaccinia, vesicular stomatatis virus, and measles (85MI4). Several methods has already been elaborated for its synthesis. Thus, reaction of 4-amino-4-deoxy-d-erythronic acid (748) with 4-amino-6-chloro-5-nitropyrimidine followed by reduction of the nitro group gave 749, whose cyclization with formamide gave 750 (69E1237). The condensation of 2(R),3(R)-O-protected dihydroxybutyrolactone 754 with the sodium salt of adenine followed by hydrolysis gave 750 (71JOC1573). Alternatively, reaction of methyl-5-O-tosyl-2,3-O-isopropylidene-β-d-ribofuranoside (751) with the sodium salt of adenine gave the corresponding reversed nucleoside 752, whose deprotection gave 753 and whose oxidation gave 750 (73JOC2887). This approach is convenient and was used successfully for the synthesis of analogs with different configurations and chain lengths [70JCS(CC)1047]. The enantiomeric and racemic forms were also prepared (84MIP1). The ethyl-4-(2-amino-6-chloropurin-9-yl)-2-hydoxybutyrate was prepared by alkylation with the 2-hydroxy-4-bromobutyrate ester (85USP4495190).

Scheme 145

Scheme 146

A modified analog of this type (760) was prepared from the di-n-butyl ester 755 of R(−)-aspartic acid, which was reduced to the diol and then to the oxazolidinone by reaction with phosgene, followed by mesylation and displacement of the mesylate group by bromide ion to give 756, which subsequently was converted to the N-BOC 757. Regioselective formation of the desired N-1 alkylated thymine derivative was achieved in three operations involving reaction of 757 with 4-methoxy-5-methyl-2-pyrimidinone in DMF/K2CO3, followed by opening of the oxazolidinone ring, N-BOC deprotection, and concomitant liberation of the C-4 amide carbonyl. Derivatives of the amino group of 758 were prepared by reaction of 758 with KOCN/H2O, with H2CO—HCO2H or CNBr. The 3′-azido analogs 760 were prepared by reacting the O-protected amine 759 with freshly prepared triflyl azide, followed by liberation of the 4′-hydroxyl group using DOWEX (90TL4879).

Scheme 147

Reaction of 3-deoxyglucosulose 761 under physiological conditions with aminoguanidine gave a mixture of the two isomeric triazines 762 and 763 (92MI4).

Scheme 148

Reaction of methyl 2-deoxy-3,5-di-O-p-toluoyl-d-erythro-pentofuranoside 764 with the trimethylsilyl derivatives of hydantoin 765 and 768 in presence of TMS triflate gave 766 and 769, respectively (93JOC5994). The anticipated nucleoside 767 was formed in low yield in the former reaction. The formation of the acyclic analogs was accounted for by assuming the initial step to be a ring opening of the sugar to give an acyclic glycos-1-yl cation.

Scheme 149

Treatment of 1,2-diaminobenzene 771 with the furanone glycoside 770 in methanol gave the olefin 772. Treatment of 772 with AcOH followed by catalytic hydrogenation produced 2-[4-O-benzoyl-(3S)-3-hydroxybutyl]-3-methylquinoxaline, whose debenzoylation gave 773 (93H2591).

Scheme 150

Oxidation of l-ascorbic acid and analogs generally formulated as 774 gave the dehydro derivatives 775, whose reaction with 1,2-diaminobenzene or its derivatives were followed by reaction with different types of hydrazines to afford the quinoxaline derivatives 776 78MI2, 78MI3, 78MI4, 78MI5, 82MI1, 86MI1, 88MI3, 90JCS(P1)2513. The use of 2,3-diaminopyridine gave the two corresponding isomeric products (96UP3). However, reaction of 775 with thiosemicarbazide gave the respective bis(thiosemicarbazone); ring opening of the lactone followed by cyclization of the C-2 thiosemicarbazone residue with the C-1 generated carboxylic group gave 778 (92AHC233). Acetylation of 776 followed by deacetylation with methanolic ammonia gave 777 (92MI2).

Scheme 151