合成路线1

4) Lactone form: The condensation of 2(S)-(chloromethyl)oxirane (XXXIII) with trimethylsilylacetylene (XXXIV) by means of butyllithium and BF3 ethearate in THF gives 5-chloro-4(S)-hydroxy-1-(trimethylsilyl)-1-pentyne (XXXV), which is cyclized with KOH in THF to the chiral epoxide (XXXVI). The condensation of (XXXVI) with 2-cyclopropyl-4-(4-fluorophenyl)-3-(phenylsulfanylmethyl)quinoline (XXXVII, see Scheme 5) by means of butyllithium in THF affords the silylated heptynol (XXXVIII), which is desilylated with K2CO3 in methanol to the terminal acetylene (XXXIX). The carboxylation of (XXXIX) with CO by means of PdCl2/CuCl2 in methanol yields the heptynoic acid ester (XL), which is selectively reduced with H2 over the Lindlar catalyst in methanol to the cis-heptenoic ester (XLI). The cyclization of (XLI) with PPTS in refluxing toluene affords the (S)-unsaturated lactone (XLII), which is oxidized with m-chloroperbenzoic acid to the corresponding sulfinyl derivative (XLIII).

合成路线2

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3

The reaction of diethyl malonate (I) with (R)-(-)-epichlorohydrin (II) by means of sodium ethoxide in refluxing ethanol gives the 3-oxa-2-oxobicyclic compound (III), which by reduction with NaBH4 in ethanol yields (1S,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylic acid ethyl ester (IV). The reaction of (IV) with diphenyldiazomethane by means of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in dichloroethane affords (1R,7R)-4,4-diphenyl-3,5-dioxabicyclo[5.1.0]octane-1-carboxylic acid ethyl ester (V), which is reduced with LiBH4 in THF giving the carbinol (VI). The reaction of (VI) with CBr4 and triphenylphosphine in dichloromethane yields the bromomethyl derivative (VII), which is condensed with 5-(2-(E)-bromovinyluracil (VIII) by means of K2CO3 and 18-crown-6 in hot DMF affording the expected addition compound (IX). Finally, this compound is deprotected with HCl in methanol.

合成路线4

Condensation of acetamide (I) with (R)-epichlorohydrin (II) by means of either NaOH, LiOH or NaOH/benzyltrimethylammonium chloride (BTA-Cl) in H2O yields a mixture of epoxypropane (III) and chloropropanol derivative (IV) that can be converted into the desired product either by direct coupling with isopropylamine (V) in MeOH, or by first reaction of the mixture (III)/(IV) with NaOH to give (S)-(III) and next coupling with (V) as described above (1-3). Alternatively, derivative (S)-(III) can also be obtained by coupling of glycidyl nosylate (VI) with acetamide (I) by means of CsF in DMF.

合成路线5

Treatment of sodium phenoxide derivative (I) with Amberlite IRA-400 (containing quaternary ammonium groups) provides resin (II), which is then coupled with epichlorohydrin (III) in refluxing MeOH to afford arylepoxyether (IV). Finally, (S)-atenolol is obtained by reaction of (IV) with isopropylamine (V) in refluxing MeOH.

合成路线6

The reaction of dibenzazepine (I) with the chiral epichlorohydrin (II) by means of NaNH2 in refluxing benzene gives the adduct (III), which is finally treated with isopropylamine (IV) to yield the target isopropanol derivative.

合成路线7