Synthesis Of New Chiral Pyridine-Phosphite Ligands And Their Applications In Copper Catalyzed 1, 4-Conjugate Additions Of Diethylzinc To Acyclic Enones

The structure of chiral ligands plays a key role in the area of transition metal catalyzed asymmetric reactions,thus,designing and synthesizing of new chiral ligands have been becoming one of the most active research topics in this area.As one type of the most successful ligands in the asymmetric catalysis,P,N ligand has received much attention since first P,N ligand developed in 1990s.In this paper,a novel P,N ligand was designed and synthesized with commercially available 2-chloro-6,7-dihydro-SH-cyclopenta[b]pyrindine and 2-chloro-5,6,7,8-tetrahydroquinoline as the starting materials.The syntheses were consequently carried out through following steps.The starting materials were transferred into their corresponding N-oxide with aqueous H₂O₂ in acetic acid.The unseparated N-oxide intermediates were tumed into their acetic esters by treatment with acetic anhydride.Then the obtained esters were hydrolyzed into alcohols 4a-b in KOH/EtOH under room temperature.The racemic alcohol 4a was transformed to its corresponding ketone 5a by aerobic oxidation procedure.Chiral reduction of ketone 5a with(S)-Me-CBS-borane system generated(R)-alcohol 4a, which was subjected to yield optically pure alcohol R-4a via recrystallization.The key intermediate alcohols R-6a and racemic 6b were prepared via Pd-catalyzed Suzuki coupling from R-4a and racemic 4b. Optically pure alcohol R-6b could be prepared through two steps,Swern oxidation then followed by chiral reduction with(S)-Me-CBS-borane system.Chiral alcohols R-4a,R-6a and R-6b could be conveniently converted into the novel chiral phosphate-pridine(P,N) ligands L9-a,L9-b, L9-c,L9-d,L9-e,L9-f.The novel P,N ligands were applied in the Cu-catalyzed enantioselective 1,4-conjugate addition of diethylzinc to acyclic enones.It was found that the less expensive and easily available CuBr₂ showed superior catalytic performance to the expensive Cu(OTf)₂ in this reaction. Moreover,the research results demonstrated that the ligands derived from (R)-alcohols and(S)-BINOL were matched for the high enantioselectivity, the chirality of BINOL moiety played a crucial role in the absolute configuration of the addition products.Ligand L9-a afforded the best enantioselectivities in the Cu-catalyzed 1,4-conjugate addition of Et₂Zn to substituted chalcones and substituted trans-4-aryl-3-buten-2-ones,with ee up to 92%and 84%yield at the temperature of-40℃.