合成路线1

3) The esterification of L-malic acid (XX) with methanol and acetyl chloride gives the dimethyl ester (XXI), which is reduced with borane-dimethyl sulfide in THF yielding 3(S),4-dihydroxybutyric acid methyl ester (XXII). Partial protection of (XXII) with trityl chloride in pyridine affords 3(S)-hydroxy-4-(trityloxy) butyric acid methyl ester (XXIII), which is hydrolyzed with NaOH to the corresponding free acid (XXIV). The condensation of (XXIV) with succinic acid monoallyl ester, magnesium salt (XXV) by means of the carbonyl diimidazole (DCI) in THF gives 5(S)-hydroxy-3-oxo-6-(trityloxy)hexanoic acid allyl ester (XXVI), which is reduced with triethylborane and NaBH4 in THF and treated with H2O2 at -70 C to afford 3(R),5(S)-6-(trityloxy)hexanoic acid allyl ester (XXVII). The protection of the hydroxyl groups of (XXVII) with tert-butyldiphenylsilyl chloride and imidazole in DMF gives the fully protected ester (XXVIII), which is treated with trifluoroacetic acid in dichloromethane yielding erythro-3(R),5(S)-bis(tert-butyldiphenylsilyloxy)-6-hydroxyhexanoic acid allyl ester (XXIX). The oxidation of (XXIX) with pyridinium chlorochromate in dichloromethane affords the oxo-ester (XXX), which is condensed with phosphonate (X), as in method 2 above, to give ester (XXXI). The hydrolysis of (XXXI) with triphenylphosphine and palladium tetrakis triphenylphosphine as before yields the protected acid (XXXII), which is finally deprotected with tetrabutylammonium fluoride, also as before. [3(R),5(S)-erythro-isomer].

合成路线2

Alternatively, compound (XV) can also be obtained as follows: Reduction of (S)-maleate (XVI) with BMS-NaBH4 in THF, followed by O-protection with TBDPS-Cl and imidazole, yields alcohol (XVII), which is first allylated with allyl trichloroacetimidate (XVIII) catalyzed by triflic acid in cyclohexanes and then reduced with DIBAL in THF to provide compound (XIX). Ozonolysis of (XIX) in MeOH, followed by reductive quench with NaBH4, gives diol (XX), which is then converted into bismesylate (XXI) by treatment with MsCl and Et3N in ether. Compound (XXI) is subjected to a double Finkelstein reaction with NaI in acetone in the presence of NaHCO3 to yield bisiodide (XXII) (1), which is then coupled with 3-bis(1H-indol-3-yl)-N-methylmaleimide (XI) by means of Cs2CO3 in DMF to give intermediate (XV).

合成路线3

The esterification of L-malic acid (VII) with methanol in acidic medium gives the dimethyl ester (VIII), which is chemoselectively reduced with BH3, Me2S and NaBH4 yielding the diol (IX). The reaction of (IX) with trimethyl orthoformate affords the cyclic orthoester (X), which is reduced with DIBAL to the aldehyde (XI). The methylation of (XI) with MeLi provides the isopropanol derivative (XII), which is submitted to a Swern oxidation to afford the corresponding ketone (XIII). The enolization of (XIII) with TBDMS-OTf and DIEA gives the silylated enol ether (XIV), which is finally cyclized to the target ketone (IV) by means of Lewis acids such as TiCl4, BF3.Et2O, SnCl4 or Et2AlCl, the best yields being obtained with the last mentioned reagent.

合成路线4