A "chiral aldehyde" equivalent as a building block towards biologically active targets.
Chiral gamma-aryloxybutenolides, readily accessible through dynamic kinetic asymmetric transformation (DYKAT) of racemic acyloxybutenolides, were utilized as "chiral aldehyde" building blocks for intermolecular cycloadditions and Michael reactions. Unprecedented selectivity in trimethylenemethane cycloadditions with this building block allowed an efficient synthesis of a novel metabotropic glutamate receptor 1 antagonist in development by the Bayer corporation. These studies further inspired work that culminated in the total synthesis of (+)-brefeldin A, a natural product with a range of significant biological properties. All of the stereochemistry in this target molecule was derived from two palladium-catalyzed asymmetric allylic alkylation reactions. The trans-alkenes were synthesized by a Julia olefination and a ruthenium-catalyzed trans-hydrosilylation-protodesilylation protocol. The route to (+)-brefeldin A lends itself to analogue syntheses and was completed in 18 steps in 6 % overall yield.
Trost
Barry M
BM
Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA. bmtrost@stanford.edu
Crawley
Matthew L
ML
D000447:Aldehydes / Q000737:chemistry*; D000475:Alkenes / Q000138:chemical synthesis; D020126:Brefeldin A / Q000138:chemical synthesis / Q000737:chemistry; D002384:Catalysis; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D010165:Palladium / Q000737:chemistry; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors; D012428:Ruthenium / Q000737:chemistry; D013237:Stereoisomerism
D000447:Aldehydes; D000475:Alkenes; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D020126:Brefeldin A; D010165:Palladium; D012428:Ruthenium