Synthesis of Atorvastatin Lactone Linker Constructs for Target Fishing

With the aim of connecting atorvastatin lactone 9 to a linker for affinity-based target fishing, a concise route to the pyrrolecarboxylic acid 8 was developed. Key features of the synthesis of the diol-containing side-chain were a catalytic enantioselective vinylogous aldol reaction resulting in 5-hydroxy-enoate 14 (88 % ee). Subsequent intramolecular oxa-Michael addition and amide reduction furnished key building block 5. As we have described previously, Paal–Knorr reaction of amine 5 with diketone 6 led to pyrrole 7, which – after carboxylation – provided acid 8. Since atorvastatin lactone is an aniline derivative of acid 7, we prepared two linkers having an aniline terminus. For this purpose ethylene glycol based allyl ethers 20 and 27 were combined with nitrostyrene 22 by cross-metathesis. After hydrogenation of the nitro group and the double bond, anilines 25 and 29, respectively, were obtained. The anilines were condensed with carboxylic acid 8 to afford the corresponding amides 30 and 35. Elaboration of the side-chain then provided atorvastatin lactone linker constructs 34 and 39, respectively.