Skeletal diversity in small-molecule synthesis using ligand-controlled catalysis.
Two Pd-catalyzed reductive transformations of diynes tethered through a silyl ether linkage were developed, where the reaction outcomes were controlled solely by selection of phosphine ligand. We screened Pd precatalysts, ligands, and additives to optimize conditions selective either for reductive cyclization or hydrogenation of this substrate class. Sixteen silyl ether-tethered diynes were prepared and subjected to the best catalyst/ligand combinations for each pathway. Silacyclic dienes and silyl-tethered enyne products of these reactions were elaborated to densely substituted, stereochemically- and appendage-rich, bicyclic and tricyclic small molecules in 1-3 synthetic steps. These studies illustrate how small modifications to a transition-metal catalyst can be used to access a diverse set of small molecules, in a fashion analogous to biosynthetic pathways such as terpene biosynthesis, where minor changes to enzyme structure direct skeletal differentiation.
Gray
B Lawrence
BL
Howard Hughes Medical Institute, Broad Institute of Harvard and MIT, Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.
Schreiber
Stuart L
SL
D002384:Catalysis; D003500:Cyclization; D053280:Diynes / Q000138:chemical synthesis*; D004987:Ethers / Q000737:chemistry*; D006865:Hydrogenation; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D017646:Organosilicon Compounds / Q000138:chemical synthesis*; D010165:Palladium / Q000737:chemistry; D010720:Phosphines / Q000737:chemistry
D053280:Diynes; D004987:Ethers; D008024:Ligands; D017646:Organosilicon Compounds; D010720:Phosphines; D010165:Palladium; C044646:phosphine