合成路线1

1) The cyclization of ketene diethylketal (I) with diethyl fumarate (II) in hot tert-butanol gives trans-3,3-diethoxycyclobutane-1,2-dicarboxylic acid diethyl ester (III), which is saponified with KOH in hot methanol to the corresponding racemic diacid (IV). The condensation of (IV) with (R)-(-)-2-phenylglycinol (V) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane followed by fractionated crystallization of the resulting diastereomeric mixture yields the diamide (VI). The hydrolytic reduction of (VI) by sequential treatments with trimethylsilyl chloride and imidazole, dinitrogen tetraoxide and finally with LiBH4 affords (S,S)-trans-3,3-diethoxycyclobutane-1,2-dimethanol (VII), which is benzoylated with benzoyl chloride in pyridine to the dibenzoate (VIII). The cleavage of the ketal group of (VIII) with H2SO4 in acetonitrile gives the cyclobutanone (IX), which is reduced with LS-Selectride in THF yielding [1S-(1alpha,2beta,3beta)]-3-hydroxycyclobutane-1,2-dimethanol 1,2-dibenzoate (X). The reaction of (X) with p-toluenesulfonyl chloride affords the corresponding tosylate (XI), which is condensed with 6-O-benzylguanidine (XII) by means of K2CO3 and 18-crown-6 in hot DMF giving [1R-(1alpha,2beta,3alpha)]-6-O-benzyl-9-[2,3-di(benzoyloxymethyl) cyclobutyl]guanine (XIII). Finally, this compound is treated with sodium methoxide in hot methanol. 2) The reaction of 6-chloropurine-2-amine (XIV) with 47% HI gives 6-iodopurine-2-amine (XV), which is condensed with [1S-(1alpha,2beta,3beta)]-3-(trifluoromethylsulfonyloxy)cyclobutane-1,2-dimethanol 1,2-dibenzoate (XVI) (obtained by treatment of the previously described cyclobutanol [X] with trifluromethanesulfonyl anhydride [Tf2O]) by means of benzyltriethylammonium hydroxide and pyridine in dichloromethane to afford the condensed iodopurine (XVII). The reaction of (XVII) with sodium methoxide hydrolyzes the benzoyl groups affording the 6-O-methylguanine derivative (XVIII), which is finally treated with aqueous HCl at 95 C.

合成路线2

5) The thermal rearrangement of 3-bromo-4,6-dimethyl-2-oxo-2H-pyran-5-carboxylic acid ethyl ester (XXXIX) with NaOH in refluxing water gives (rac)-trans-3-methylenecyclopropane-1,2-dicarboxylic acid (XL), which was submitted to optical resolution with (R)-alpha-methylbenzylamine (XLI) yielding, after crystallization, the corresponding (R,R)-enantiomeric salt (XLII). The decomposition of the salt and esterification of the free acid with trimethyl orthoformate affords (1R-trans)-3-methylenecyclopropane-1,2-dicarboxylic acid dimethyl ester (XLIII), which is reduced with LiAlH4 in THF to (1R-trans)-3-methylenecyclopropane-1,2-dimethanol (XLIV). The esterification of (XLIV) with benzoic anhydride and triethylamine in ethyl acetate affords the corresponding dibenzoate (XLV), which is epoxidized with m-chloroperbenzoic acid (MCPBA) in dichloromethane to afford the oxirane (XLVI). The isomerization of (XLVI) by means of LiI in ethyl acetate gives (2S-trans)-2,3-bis(benzoyloxymethyl)cyclobutanone (IX), which is reduced with lithium trisiamylborohydride in THF yielding [1S-(1alpha,2beta,3beta)]-3-hydroxycyclobutane-1,2-dimethanol 1,2-dibenzoate ester (X). The reaction of (X) with p-toluenesulfonyl chloride in pyridine affords the corresponding tosylate (XI), which is condensed with 6-O-benzylguanine (XII) by means of K2CO3 and 18-crown-6 in DMF yielding the substituted guanine (XIII). Finally, this compound is deprotected by treatment first with sodium methoxide in hot methanol, and then with 3N HCl.

合成路线3

The regioselective reaction of cyclopentadiene (I) and sodium or commercial sodium cyclopentadienide (II) with benzyl chloromethyl ether (III) by means of the chiral catalyst (-)-diisopinocampheylborane in THF, followed by hydroxylation with H2O2/NaOH, gives (1S-trans)-2-(benzyloxymethyl)-3-cyclopenten-1-ol (IV), which is regioselectively epoxidized with tert-butyl hydroperoxide and vanadyl acetylacetonate in 2,2,4-trimethylpentane, yielding [1S-(1alpha,2alpha,3beta,5alpha)-2-(benzyloxymethyl)-6-oxabicyclo[3.1.0]hexan-3-ol (V). The protection of (V) with benzyl bromide and NaH affords the corresponding ether (VI), which is condensed with 6-O-benzylguanine (VII) by means of LiH in DMF to give the guanine derivative (VIII). The protection of the amino group of (VIII) with 4-methoxyphenyl(diphenyl)chloromethane (IX), TEA and DMAP in dichloromethane gives intermediate (X), which is oxidized at the free hydroxyl group with methylphosphonic acid, DCC and oxalic acid in DMSO or Dess Martin periodinane in dichloromethane, yielding the cyclopentanone derivative (XI). The reaction of (XI) with (i) Zn/TiCl4/CH2Br2 complex in THF/CH2Cl2, (ii) activated Zn/PbCl2/CH2I2/TiCl4 in THF/CH2Cl2 (2), (iii) Nysted reagent/TiCl4 in THF/CH2Cl2 or (iv) Tebbe reagent in toluene affords the corresponding methylene derivative (XII), which is partially deprotected with 3N HCl in hot THF, providing the dibenzylated compound (XI). Finally, this compound is treated with BCl3 in dichloromethane. (Scheme 18263401a)

合成路线4

The condensation of diethyl malonate (I) with (R)-(-)-epichlorohydrin (II) by means of NaOEt in ethanol gives (3aS,4aR)-3-oxo-3,3a,4,4a-tetrahydro-1H-cyclopropa[c]furan-3a-carboxylic acid ethyl ester (III), which is selectively reduced at the lactone group by means of sodium borohydride in ethanol to yield (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylic acid ethyl ester (IV). The protection of (IV) with 2,2-dimethoxypropane (V) and Ts-OH in DMF affords the cyclic acetonide (VI), which is reduced with LiBH4 in THF to provide the hydroxymethyl acetonide (VII). The protection of the OH group of (VII) with benzyl bromide and NaH in DMF gives the benzyl ether (VIII), which is treated with HCl in THF/water to cleave the acetonide ring and yield the bis hydroxymethyl compound (IX). The acylation of (IX) with benzoyl chloride and pyridine affords the dibenzoate (X), which is debenzylated with H2 over Pd/C in ethanol/acetic acid to provide (1S,2R)-1,2-bis(benzoyloxymethyl)cyclopropanemethanol (XI). The reaction of (XI) with Ts-OH and DMAP in dichloromethane gives the corresponding tosylate (XII), which is condensed with 6-O-benzylguanine (XIII) by means of K2CO3 in DMF to yield the fully protected nucleoside (XIV). The hydrolysis of the benzoyl group of (XIV) by means of NaOMe in methanol affords the dihydroxy compound (XV), which is finally debenzylated by means of HCl in ethanol/water to provide the target guanine cyclopropyl nucleoside.

合成路线5

In a further procedure, the prochiral diol (XX) was converted to the asymmetric mono-stearate ester (XXXII) employing vinyl stearate (XXXI) and lipase PS 30. After tosylation of alcohol (XXXII), the resulting diethoxy acetal (XXXIII) was hydrolyzed to aldehyde (XXXIV) employing different acidic catalysts. Reduction of aldehyde (XXXIV) to the corresponding alcohol (XXXV) was effected by means of catalytic hydrogenation over Ra-Ni or borane-tert-butylamine complex. Alcohol (XXXV) was further condensed with N-Cbz-L-valine (XVI), producing the diester tosylate (XXXVI). The analogous N-Boc- and N-Alloc-protected valine esters were similarly prepared. 6-Benzyloxy-2-aminopurine (XXXVII) was prepared by treatment of chloropurine (I) with benzyl alcohol and NaH or NaOH. Alkylation of purine (XXXVII) with tosylate (XXXVI) furnished adduct (XXXVIII), which was finally deprotected by catalytic hydrogenation. Optionally, tosylate (XXXVI) was condensed with chloropurine (I) to give (XXXIX). Hydrolysis of the chloropurine ring of (XXXIX) to the guanine derivative (XIII) employing either Et3N or HOAc, followed by catalytic hydrogenation as above, provided an alternative access to the title compound.

合成路线6