合成路线1

The oxidation of protected hydroxymethyl lactone (I) with DCC/DMSO gives the aldehyde (II), which is condensed with phosphorane (III) to yield the pentenone (IV). The reduction of (IV) with NaBH4 in methanol affords the pentenol (Va-b), which is further reduced with DIBAL to provide the lactol (VIa-d). The condensation of (VIa-d) with phosphorane (VII) by means of KOtBu gives the trihydroxyheptenoic acid (VIIIa-b), which is esterified with isopropyl iodide (A) and DBU, yielding the isopropyl ester (IXa-b). Finally, this compound is selectively oxidized with DDQ to afford the target compound.

合成路线2

The title compound was prepared starting from the known bicyclic lactone (VI). Oxidation of the primary alcohol function of (VI) to the corresponding aldehyde (VII) was accomplished by either following the Pfitzner-Moffat method or by means of Dess-Martin perodinane reagent. Aldehyde (VII) was then converted to enone (IX) by Wittig reaction with the phosphonium salt (VIII) or, in a related method, by Wadsworth-Emmons condensation of (VII) with phosphonate (IV). Stereoselective reduction of enone (IX) with either L-selectride or (-)-B-chlorodiisopinocampheylborane produced the (15S)-allylic alcohol (X) as the major diastereoisomer, which was isolated by flash chromatography. Then, catalytic hydrogenation of the double bond of (X) gave the saturated alcohol (XI). Reduction of the lactone function employing DIBAL led to the protected lactol (XII). Subsequent removal of the phenylbenzoyl group of (XII) with K2CO3 in methanol furnished dihydroxy lactol (XIII). In a variation of this sequence, the phenylbenzoyl group of (XI) was first removed by methanolysis, and the resultant dihydroxy lactone (XIV) was then reduced with DIBAL to lactol (XIII).

合成路线3

Oxidation of the (-)-Corey's lactone (XIV) with Collins reagent (CrO3 and pyridine) gives aldehyde (XV), which is condensed with phosphonate (IV) by means of thallium ethoxide in benzene to yield the unsaturated difluoroketolactone (XVI). Hydrogenation of compound (XVI) with H2 over Pd/C in ethyl acetate affords the saturated analogue (XVII), which is reduced with NaBH4 in methanol/THF to provide the hydroxylactone (XVIII), which is then protected at the hydroxy group with TBDMS-Cl and imidazole to give the silyl ether (XIX). Hydrolysis of the ester group of compound (XIX) in basic medium, followed by reaction with dihydropyran yields the tetrahydropyranyl ether (XX), which is reduced with DIBAL to afford the lactol (XXI). Condensation of lactol (XXI) with 4-(methoxycarbonyl)butyl triphenylphosphonium bromide (XXII) provides the unsaturated methyl ester (XXIII), which is desilylated by means of TBAF in THF to give the diol (XXIV). Finally, hydrolysis of the ester group of compound (XXIV) with NaOH in methanol yields the already described intermediate prostaglandin F2a derivative (X).

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