合成路线1

The chiral cyclohexenone intermediate (VII) was prepared as follows. Epoxide ring opening of (S)-glycidol (I) with the Grignard reagent (II) produced diol (III), which was protected as the isopropylidene ketal (IV) by treatment with 2,2-dimethoxypropane. Addition of bromine to olefin (IV) and further cyclization of the resultant dibromide in the presence of potassium hexamethyldisilazide gave rise to the spiro cyclopentene (V). Ozonolysis of (V), followed by reductive work-up, yielded the keto aldehyde (VI), which upon treatment with KOH underwent intramolecular aldol condensation to the target cyclopentenone (VII).

合成路线2

Advanced intermediate phosphonium salt (XLI). The protection of (R)(+)-glycidol (XXV) with Pmb-Cl and NaH gives the benzyl ether (XXVI). Which is condensed with methyl phenyl sulfone (XXVII) by means of BuLi in THF/HMPA to yield the secondary alcohol (XXVIII). The reaction of (XXVIII) with Tbdms-OTf and lutidine affords the silyl ether (XXIX) (3), which is converted into the aldehyde (XXX) by debenzylation with DDQ, followed by oxidation with DMP. The condensation of (XXX) with phosphorane (XXXI) in refluxing benzene gives the unsaturated ester (XXXII), which is reduced with DIBAL in dichloromethane and protected with Ph-CH2Br and NaH to yield the benzyl ether (XXXIII). The condensation of sulfone (XXXIII) with the iodomethyl intermediate (XXIV) by means of BuLi in THF/HMPA affords the adduct (XXXIV), which is desulfurized by reaction with BuLi, diiodomethane and isopropylmagnesium chloride to provide the methylene compound (XXXV). The elimination of the benzyl protecting group of (XXXV) by means of LiDBB, followed by oxidation with DMP gives the carbaldehyde (XXXVI), which is condensed with CH2=PPh3 in THF to yield compound (XXXVII) (2).

合成路线3

Synthesis of intermediate (XXXIII): The silylation of epoxide (XXI) with TBDMSCl gives the silyl ether (XXII), which is condensed with 1,3-dithiane (VI) by means of n-BuLi to yield the alcohol (XXIII). Epoxidation of (XXIII) with TBAF and NaH affords the epoxide (XXIV), which is condensed with vinyl lithium and CuCN to provide the allyl alcohol (XXV). The methylation of (XXV) with MeI and NaH in THF gives the methyl ether (XXVI). The silylation of epoxide (XXI) with TBDPSCl gives the silyl ether (XXVII), which is condensed with vinyl lithium (II) by means of CuCN in THF, yielding the allyl alcohol (XXVIII). The reaction of (XXVIII) with Boc-ON, n-BuLi and IBr affords the cyclic carbonate (XXIX), which is treated with K2CO3 in MeOH and silylated with TBDPSCl to provide the protected epoxide (XXX). The condensation of epoxide (XXX) with allyl ether (XXVI) by means of NaOtBu and n-BuLi in THF furnished the adduct (XXXI), which is cyclized by means of TBAF and converted into the acetylenic tetrahydropyran (XXXII). Finally, the iodination and reprotection of (XXXII) with Bu3SnH, AIBN, NIS, Mpm-OCH2Cl and DIEA gives the desired intermediate (XXXIII).

合成路线4

3) The catalytic hydrogenation of (S)-glycidol (XVI) over Pd/C gives the (R)-1,2-propanediol (XVII), which is esterified with diethyl carbonate (XVIII)/NaOEt, yielding the cyclic carbonate (XIX). The reaction of (XIX) with adenine (V) by means of NaOH in DMF affords 9-[2(R)-hydroxypropyl]adenine (VII), which is condensed with tosyloxymethylphosphonic acid diethyl ester (XX) by means of lithium tert-butoxide in THF, giving 9-[2(R)-(diethoxyphosphorylmethoxy)propyl]adenine (XXI). Finally, this compound is hydrolyzed with bromotrimethylsilane as before. Compound (XX) is obtained by reaction of diethyl phosphite (XXII) with paraformaldehyde, yielding hydroxy- methylphosphonic acid diethyl ester (XXIII), which is finally tosylated as usual.

合成路线5

Treatment of (R)-1-chloro-2,3-propanediol (I) with either K2CO3 or Cs2CO3 in CH2Cl2, followed by O-protection with Trt-Cl and Et3N in CH2Cl2, yields (S)-trityl glycidol (II). Alternatively, derivative (II) can also be obtained either by direct O-protection of (R)-glycidol (III) by means of Trt-Cl and Et3N in refluxing CH2Cl2 or by cyclization of protected propanediol derivative (IV)--obtained from treatment of compound (I) with Trt-Cl and Et3N in CH2Cl2--by means of KOH in EtOH. Reaction of (S)-trityl glycidol (II) with vinyl magnesium bromide (V) by means of CuI in THF provides (S)-1-(triphenylmethoxy)-4-penten-2-ol (VI), which is then condensed with allyl bromide (VII) with KOtBu or NaH in THF to afford compound (VIII). Ozonolysis of (VIII) in CH2Cl2/MeOH, followed by reductive quench with NaBH4 in NaOH, gives (S)-3-(2-hydroxyethoxy)-4-(triphenylmethoxy)-1-butanol (IX), which is then treated with MsCl/Et3N in CH2Cl2 to yield bismesylate (X). Coupling of compound (X) with 2,3-bis(1H-indol-3-yl)-N-methylmaleimide (XI) [obtained by treatment of dichloromaleic anhydride (XII) with methylamine hydrochloride by means of NaOMe in HOAc to furnish dichloro-N-methylmaleimide (XIII), followed by Grignard reaction of (XIII) with indole (XIV) in toluene/THF by means of EtMgBr in Et2O] by means of Cs2CO3 in DMF gives the 14-membered macrocycle (XV).

合成路线6

The condensation of (S)-glycidol (XVI) with trimethylsilylacetylene (XVII) by means of tert-butyllithium in THF, followed by quenching with TBDMS triflate gives the protected acetylenic diol (XVIII), which is iodinated with K2CO3, Cp2ZnCl and I2 yielding the vinyl iodide (XIX). The condensation of (XIX) with the intermediate aldehyde (XV) in THF, followed by oxidation with DMP affords the chiral ketone (XX), which is submitted to a diastereoselective cyclization catalyzed by dichloroaluminum phenoxide (XXI) in toluene to furnish the polycyclic ketone (XXII) as a 5.7:1 diastereomeric mixture. The desilylation of this mixture with TBAF in THF allowed the separation of the mayor diastereomeric diol (XXIII) by flash chromatography. The oxidation of (XXIII) with NaIO4 affords the corresponding aldehyde (XXIV), which is condensed with the lithium 1,3-dithiane (XXV) in THF to give the secondary alcohol (XXVI). The silylation of this alcohol with TES-OTf and NaH in THF yields the silyl ether (XXVII), which is treated with Ph-NTf2 and KHMDS in THF to afford the enol ether (XXVIII).

合成路线7

The condensation of 4-aminobenzonitrile (I) with the chiral 2,3-epoxypropanol (II) in refluxing methanol gives 4-(2,3-dihydroxypropylamino)benzonitrile (III), which is cyclized with diethyl carbonate (IV) by means of tBu-OK at 100 C to yield the oxazolidinone (V). The reaction of the cyano group of (V) with hydroxylamine in methanol affords the N-hydroxyamidine (VI), which is cyclized with Ac2O at 120 C to provide the 1,2,4-oxadiazole (VII). The hydrolysis of the acetoxy group of (VII) with K2CO3 in refluxing methanol gives the primary alcohol (VIII), which is treated with Ms-Cl and pyridine to yield the corresponding mesylate (IX). The condensation of (IX) with 2-(1-piperazinyl)acetic acid ethyl ester (X) in refluxing acetonitrile affords the adduct (XI), which is hydrogenated with H2 over Pd/C and hydrolyzed with HOAc to obtain the benzamidine derivative (XII). Finally, this compound is acylated with methyl chloroformate (XIII) and NaOH in dichloromethane/water.

合成路线8

The condensation of (S)-glycidol (XVI) with trimethylsilylacetylene (XVII) by means of tert-butyllithium in THF, followed by quenching with TBDMS triflate gives the protected acetylenic diol (XVIII), which is iodinated with K2CO3, Cp2ZnCl and I2 yielding the vinyl iodide (XIX). The condensation of (XIX) with the intermediate aldehyde (XV) in THF, followed by oxidation with DMP affords the chiral ketone (XX), which is submitted to a diastereoselective cyclization catalyzed by dichloroaluminum phenoxide (XXI) in toluene to furnish the polycyclic ketone (XXII) as a 5.7:1 diastereomeric mixture. The desilylation of this mixture with TBAF in THF allowed the separation of the mayor diastereomeric diol (XXIII) by flash chromatography. The oxidation of (XXIII) with NaIO4 affords the corresponding aldehyde (XXIV), which is condensed with the lithium 1,3-dithiane (XXV) in THF to give the secondary alcohol (XXVI). The silylation of this alcohol with TES-OTf and NaH in THF yields the silyl ether (XXVII), which is treated with Ph-NTf2 and KHMDS in THF to afford the enol ether (XXVIII).

合成路线9

(S)-Glycidol (I) was selectively opened by Li2NiBr4 at 0 C to provide (S)-3-bromo-1,2-propanediol (II). Subsequent reaction of (II) with trimethyl orthoformate in the presence of p-toluenesulfonic acid generated the dioxolane (III) as a 1:1 mixture of cis and trans orthoesters. The methoxy orthoester (III) was further converted to the isopropoxy analogue (IV) by treatement with isopropanol under acidic conditions. Introduction of the phosphonate group in (IV) was achieved by means of a ZnCl2-catalyzed Arbuzov reaction with triisopropyl phosphite and phosphorus trichloride to give a 2:5 mixture of cis (V) and trans (VI) phosphonates, which were separated by flash chromatography. Displacement of cis bromide (V) with 2-amino-6-chloropurine (VII) in the presence of Cs2CO3 in DMF at 60 C provided compound (VIII). The phosphonate ester of (VIII) was then deprotected by treatment with ISiMe3, followed by aqueous hydrolysis of the intermediate silyl phosphonate (IX) and concomitant hydrolysis of the 6-chloropurine to guanine (X). Finally, absorption on a Sephadex DEAE A-25 column, followed by elution with ammonium bicarbonate solution, provided the title ammonium salt.

合成路线10

Treatment of (S)-glycidol (I) with triphenylmethyl chloride (Ph3CCl) in pyridine affords O-triphenylmethylglicydyl ether (II), which is then reduced with LiAlH4 in THF to provide alcohol (III). Hydrogenolysis of (III) over Pd/C in MeOH gives 1,2-propandiol (IV), which is then mesylated by means of methanesulfonyl chloride (MsCl) and Et3N in CH2Cl2 to furnish 1-mesyloxy-2-propanol (V). Treatment of tropane (VI) with a refluxing mixture of dioxane/H2O yields carboxylic acid (VII), which is converted into acid chloride (VIII) by means of phosphorus oxychloride (POCl3). Coupling of alcohol (V) with acid chloride (VIII) and Et3N in CH2Cl2 gives tropane derivative (IX), which is finally converted into the target compound by fluorination with tetrabutylammonium fluoride (TBAF) in THF.

合成路线11