合成路线1

To prepare GV196771, the starting synthetic plan, shown in Scheme 22578901a, was to build the exocyclic double bond present at the position C-3 of the indole nucleus by way of an aldol condensation-elimination starting from a known indole aldehyde (I). The first issue to solve was the choice of the protecting group of the indole nitrogen and 2-(trimethylsilyl)ethoxymethyl (SEM) group was selected based on its high stability in basic conditions. The lithium enolate of N-phenylpyrrolidone (III), prepared by treatment of (III) with a stoichiometric amount of t-BuLi -78 C was reacted with (II) in THF allowing to increase the temperature from -78 C to 20 C. A single polar reaction product was detected by HPLC analysis. After treatment with TMSCHN2 in CH2Cl2/MeOH 4:1 as solvent and purification by flash chromatography, the methyl ester derivative (V) was isolated in 56% overall yield from (II). The removal of the SEM protecting group under strong acidic conditions (HCl 6N, EtOH), followed by basic hydrolysis of the ester (LiOH) and acidification of the solution, gave the target compound GV196771 in high yield, which was then transformed into the corresponding sodium salt.