合成路线1

The alkylation of the protected hydroxyproline (I) with 4-iodo-1-butene (II) by means of LDA in THF gives the 2-alkylproline (III), which is reduced with DIBAL in toluene to yield the carbinol (IV). The oxidation of (IV) by means of TPAP and NMO in dichloromethane affords the carbaldehyde (V), which is oxidated at its terminal vinyl group by means of PdCl2, CuCl2 and O2 in aqueous DMF to provide the methyl ketone (VI). The cyclization of (VI) by means of KOH in ethanol furnishes the cyclic aldol (VII), which is treated with Ms-Cl and TEA to give the mesylate (VIII). The elimination reaction of (VIII) over chromatographic silicagel yields enone (IX), which is hydrogenated with H2 over Pd/C in benzene to afford the spiranic ketone (X). The reaction of (X) with ethyleneglycol and Ts-OH in refluxing benzene provides the ethylene ketal (XI), which is desilylated by means of TBAF in THF to gives the alcohol (XII). The reaction of (XII) with DPPA, DEAD and PPh3 in THF yields the azide (XIII), which is subjected to removal of the Boc protecting group by means of TFA affording unprotected spiro pyrrolidine derivative (XIV). Alkylation of (XIV) with ethyl bromoacetate (XV) by means of K2CO3 in acetonitrile provides the ester (XVI), which is reduced at the azido group by means of H2 over Pd/C in methanol to give the aminoester (XVII). The hydrolysis of the ester group of (XVII) with LiOH in water yields the spiranic aminoacid (XVIII), which is cyclized by means of DPPA and TEA in DMF to afford the tetracyclic amide (XIX). Finally this compound is methylated by means of methyl iodide and NaH in THF to provide the target tetracyclic intermediate (XX) (see scheme no.18599903a, intermediate (XV)).