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.

The formation of the free carboxyl group derivative (IV), as shown in Scheme 22578901b, was suggested to occur through formation of the diasteromeric lactone intermediates (VIIIa, b). Although there is no evidence to support the following mechanism, it has been hypothesized that only the syn-lactone can eliminate in the presence of one equivalent of LiOEt to give the free carboxyl derivative which is then transformed into the final compound (IV). Conversely, as far as the anti-lactone derivative is concerned, it seems that, for steric reasons, this intermediate is unable to reach the necessary antiperiplanar conformation to evolve towards the Z-elimination product. In the latter case, LiOEt, acting this time as a nucleophile, could afford lithium aldolate (VII). The final retroaldolic reaction could regenerate the starting materials (II) and (III), repeating the aldol-elimination-lactonization process.

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.

The formation of the free carboxyl group derivative (IV), as shown in Scheme 22578901b, was suggested to occur through formation of the diasteromeric lactone intermediates (VIIIa, b). Although there is no evidence to support the following mechanism, it has been hypothesized that only the syn-lactone can eliminate in the presence of one equivalent of LiOEt to give the free carboxyl derivative which is then transformed into the final compound (IV). Conversely, as far as the anti-lactone derivative is concerned, it seems that, for steric reasons, this intermediate is unable to reach the necessary antiperiplanar conformation to evolve towards the Z-elimination product. In the latter case, LiOEt, acting this time as a nucleophile, could afford lithium aldolate (VII). The final retroaldolic reaction could regenerate the starting materials (II) and (III), repeating the aldol-elimination-lactonization process.

GV217828 was prepared following the synthetic route shown in Scheme 22578902a. In this event, due to the lability of the cyclic imide in basic medium, indole aldehyde (I) was transformed into the corresponding tert-butyl ester derivative (XI). Wittig reaction with phosphorane (XII) gave the olefinic intermediate (XIII) as a single E regioisomer. The removal of the tert-butyl protecting group afforded the desired compound G-217828 in high yield.

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.

The formation of the free carboxyl group derivative (IV), as shown in Scheme 22578901b, was suggested to occur through formation of the diasteromeric lactone intermediates (VIIIa, b). Although there is no evidence to support the following mechanism, it has been hypothesized that only the syn-lactone can eliminate in the presence of one equivalent of LiOEt to give the free carboxyl derivative which is then transformed into the final compound (IV). Conversely, as far as the anti-lactone derivative is concerned, it seems that, for steric reasons, this intermediate is unable to reach the necessary antiperiplanar conformation to evolve towards the Z-elimination product. In the latter case, LiOEt, acting this time as a nucleophile, could afford lithium aldolate (VII). The final retroaldolic reaction could regenerate the starting materials (II) and (III), repeating the aldol-elimination-lactonization process.

GV217828 was prepared following the synthetic route shown in Scheme 22578902a. In this event, due to the lability of the cyclic imide in basic medium, indole aldehyde (I) was transformed into the corresponding tert-butyl ester derivative (XI). Wittig reaction with phosphorane (XII) gave the olefinic intermediate (XIII) as a single E regioisomer. The removal of the tert-butyl protecting group afforded the desired compound G-217828 in high yield.