Formal total synthesis of the potent renin inhibitor aliskiren: application of a SmI2-promoted acyl-like radical coupling.
A formal total synthesis of the potent renin inhibitor aliskiren is disclosed exploiting an alternative coupling strategy recently developed by this laboratory for the preparation of the hydroxyethylene isostere-based class of protease inhibitors. The thioester derivative of the amino acid representing the C5-C9 fragment of the aliskiren carbon skeleton underwent a carbon chain extension via a SmI2-promoted radical addition to n-butyl acrylate. Introduction of the C3-isopropyl group with the correct relative configuration was accomplished via stereoselective reduction of the obtained ketone with concomitant lactonization, followed by an aldol reaction with acetone. Further functional group and protecting group manipulation culminated in a formal total synthesis of aliskiren in 10 steps from the corresponding fully protected non-natural amino acid.
Lindsay
Karl B
KB
Center for Insoluble Protein Structures, Department of Chemistry, University of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark.
Skrydstrup
Troels
T
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005609:Free Radicals / Q000737:chemistry; D005650:Fumarates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000577:Amides; D004791:Enzyme Inhibitors; D005609:Free Radicals; D005650:Fumarates; D000092502:Renin Inhibitors; C446481:aliskiren