Aluminum-catalyzed asymmetric alkylations of pyridyl-substituted alkynyl ketones with dialkylzinc reagents.
Alkylations of pyridyl-substituted ynones with Et2Zn and Me2Zn, promoted by amino acid-based chiral ligands in the presence of Al-based alkoxides, afford tertiary propargyl alcohols efficiently in 57% to >98% ee. Two easily accessible chiral ligands are identified as optimal for reactions of the two dialkylzinc reagents. Catalytic alkylations with Et2Zn require a chiral ligand carrying two amino acid moieties (valine and phenylalanine) along with a p-trifluoromethylphenylamide C-terminus. In contrast, reactions with Me2Zn are most effectively promoted in the presence of a chiral ligand containing a single amino acid (benzyl cysteine), capped by an n-butylamide. Enantiomerically enriched tertiary alcohols bearing a pyridyl and an alkyne substituent can be functionalized in a variety of manners to furnish a wide range of difficult-to-access acyclic and heterocyclic structures; two noteworthy examples are Cu-catalyzed protocols for conversion of tertiary propargyl alcohols to enantiomerically enriched tetrasubstituted allenes and bicyclic amides that bear an N-substituted quaternary carbon stereogenic center. Mechanistic models that account for the trends and enantioselectivity levels are provided.
Friel
Donna K
DK
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA.
Snapper
Marc L
ML
Hoveyda
Amir H
AH
D000478:Alkylation; D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry*; D000535:Aluminum / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D002384:Catalysis; D007659:Ketones / Q000737:chemistry*; D008024:Ligands; D000432:Methanol / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry*; D020005:Propanols / Q000138:chemical synthesis*; D011725:Pyridines / Q000737:chemistry*; D013237:Stereoisomerism
D000480:Alkynes; D000596:Amino Acids; D007659:Ketones; D008024:Ligands; D009942:Organometallic Compounds; D020005:Propanols; D011725:Pyridines; C511262:dimethylzinc; D000535:Aluminum; C028255:propargyl alcohol; C454811:diethylzinc; D000432:Methanol