Study On The Catalytic Asymmetric Addition Of Phenylacetylene To Ketones

Catalytic asymmetric reactions are among the most important organic reactions, which create good fortunes to enantiomerically pure chiral drugs and other materials, and continue to be one of the most studied and important areas in organic chemistry. Optically active tertiary propargyl alcohols are important precursors of many chiral drugs and organic compounds. Asymmetric addition of phenylacetylene to ketones is a good process to the synthesis of optically active tertiary propargyl alcohols. Herein we mainly discuss the design of three catalytic systems and their application to the asymmetric addition of phenylacetylene to ketones.(1) From commercially available starting materials natural amino acid, P-amino alcohol ligands 3a-3i were prepared in two simple steps. The p-amino alcohol ligands containing a bulkier benzyl substituent on the chiral carbon atom were found to be more effective than those containing isopropyl, isobutyl, methyl or phenyl substituents in the asymmetric addition of phenylacetylene to acetophenone;the replacement of the diphenyl groups on the 1 -positions of 3c with diethyl or dibenzyl groups also gave low enantioselectivity;in addition, we also compared the effect when the substituents at the nitrogen are nonsubstituented, monosubstituented and bissubstituented, and found when the ligand was N-ndnsubstituented amino alcohol, the best enantiomeric excess was obtained. The use of chiral amino alcohol ligands for the enantioselective alkynylation of ketones provides a. simple, practical and inexpensive method to generate chiral propargyl alcohols with 60-80% ee.(2) When commercially available Cinchona Alkaloid 4-6 were used as catalysts for the enantioselective addition of phenylacetylene to acetophenone, in the presence of Ti(O'Pr)₄, quinine 4 was found more effective than cinchonidine 5 and cinchonine 6;furthermore, we employed quinine 4 to screen the most efficient Lewis acid, and triethylaluminum was found more effective the Ti(O'Pr)₄, Al(O'Pr)₃ and Cu(OTf)₂. Herein, commercially available quinine was used as catalyst, and industrially available triethylaluminum was used as Lewis acid to catalyze the reaction of phenylacetylene to ketones, and 70-89% ee values were obtained. Quinine and triethylaluminum are cheap and easily available, which provides a possibility to industrial production.(3) From commercially available starting materials natural camphor, C2-symmetric bis(hydroxycamphorsulfonamide) ligand 9-11 were prepared in three simple steps. Ligand 10 which contains a hydroxyl group in the endo position and the relative position of both hydroxycamphorsulfonamide moieties is meta, gave poor ee value, and ligand 9 in which both hydroxyl groups are exo is more effective than 10. In addition, Cu(OTf)2 was the most effective Lewis acid we could find. A chiral copper complex, generated from a (^-symmetric bis(hydroxycamphorsulfonamide) ligand 9 and Cu(OTf)2, has been discovered to effect high enantioselectivities to the reaction, and the alkynylation of a variety of aromatic and aliphatic ketones resulted in excellent yields and enantioselectivities (83-98% ee).