Low Ligand Loading, Highly Enantioselective Addition Of Alkyne To Ketones Catalyzed By Schiff-Base Amino Alcohols-Zn Complex

Synthesis of chiral propargargylic alcohols has received much attention because they are important precursors for the synthesis of many biologically active compounds and natural products. One of the powerful methods for the catalytic asymmetric generation of chiral propargargylic alcohols is the enantioselective addition of alkynylzinc reagents addition to adehydes and ketones. Currently, there are an extensive number of reports on asymmetric alkynylation of aldehydes, and the common theme in most of the cases is showing high reactivity and enantioselectivity. However, the using of ketones as alkynyl group acceptors is facing a challenge. The main drawback of this addition reaction ascribe to reducing the propensity of ketones to coordinate to Lewis acids. Therefore, it is not surprising that recent efforts have focused on the development of catalytic asymmetric alkynylation of ketones. The current contributions to this area have been highlighted by the studies of Cozzi and Chan. Cozzi first reported that a Zn (salen) I promoted alkynylation of ketones with moderate enantioselectivities (20 mol % I, ee from 32% to 81%). He considered that the success of this addition ascribed to the salen-metal complex which could behave as a bifunctional Lewis acid-Lewis base catalyst (10 mol % II, ee from 71% to 97%). In the same year, Chan and co-workers described the alkynylzinc addition to ketones with very high ee values in the presence of chiral camphorsulfonamide ligand II and a stronger Lewis acid Cu(OTf)₂. Subsequently, Cozzi and our research group developed an asymmetric addition of alkynylation of ketones in the presence of BINOL III and Ti. Although these advances have been achieved, there are still various challenging problems to face in developing catalytic asymmetric reaction of low ligand loading to synthesize chiral proparglic alcohols (usually 20 mol %).The MeZnC≡CPh could be directly added to the simple ketones without any ligand reported by Cozzi. It is because that the electron-withdrawing nature of the alkynyl affected zinc center in MeZnC≡CPh, thus increasing the polarity of the C-Zn bond and Lewis acidity of the metal to great extend. This kind of zinc complex has enough Lewis acidity to activate the carbonyl group in the ketone. On the basis of this idea, we easily adopted available chiral Schiff-base amino alcohols as the chiral ligand and zinc as the Lewis acid in the asymmetric addition of phenylacetylene to ketones. Therefore, we reported here an example of highly efficient chiral ligand IV which could catalyze the enantioselective addition of alkynylzinc to simple ketones with high ee values and good yields in low loading of ligand, and to the best of our knowledge, 1 mol % was the lowest amount reported in this reaction. Furthermore, This system does not need to add any other stronger Lewis acid except zinc and to prepare the alkynylzinc in advance.At the same time, we chose a series of sulfonamide alcohols and classical diol ligands which were all showed a poor reactivity in the asymmetric addition of phenylacetylene to acetophenone (yield<28%) .Carbon-carbon bond forming reactions catalyzed by a metal-free organic molecule, and organic reactions in water without using harmful organic solvents are of much current interest because of demanding for green chemistry. However, organic reactions using polymer-supported catalysts have received much attention because of their practical advantages. As part of our ongoing studies on the application of Schiff-base amino alcohols-zinc complexes to promote asymmetric alkynylzinc of ketones, we reported here an example of heterogeneous system for the enantioselective addition of alkynylzinc to ketones. The catalytic capability of polymer-supported Schiff-base amino alcohol V was retained in successive five addition cycles.