Synthesis Of Thiol Chiral Ligands And Their Performance In Asymmetric 1,4-conjugate Addition Of Grignard Reagents

Copper-catalyzed asymmetric 1,4-conjugate addition of Grignard reagents is an important method to build up a carbon chiral center,which exists in the key intermediates of many natural products and chiral drugs.In the first part of this paper,the copper-catalyzed asymmetric 1,4-conjugate addition of Grignard reagents to ?,?-unsaturated compounds was summarized systematically,and such acceptors as ?,?-unsaturated ketones,esters,lactones,aldehydes,thioesters as well as sulfones were involved.In addition,the addition mechanism is also introduced in detail.In the second part of this paper,the L-hydroxy proline-derived thiol chiral ligands,L3,L4,L5,were first synthesized via six steps from the cheap L-hyroxy proline,and the total yield reached 43.7%,36.8%,29.4%respectively.In addition,the new intermediate compounds,3d,3e,4b,4c,5a-5c,were also synthesized and their structures were comfirmed by 1H NMR,13C NMR,IR,MS.In the third part of this paper,the asymmetric 1,4-conjugate addition of Grignard reagents to ?,?-unsaturated compounds,catalyzed by the complex of thiol chiral ligand L3 and copper salt,was systematically investigated.Firstly,different addition acceptors were screened to study the catalytic performance of L3.The results show that the thiol chiral ligand L3 displays some regio-and stereoselectivity for?,?-unsaturated ketones,but only regionselectivity for ?,?-unsaturated esters and lactones.Secondly,the various factors which may affect the regio-and stereoselectivity were optimized.The experimental results show that the optimal reaction condition contains-50 ? for reaction tempreture,CuCl for copper salt,MTBE for solvent,8 mol%for ligand load,ligand:copper salt(mole ratio)=1.2:1.Under the optimal conditions,the regio-and stereoselectivity of asymmetric addition of EtMgBr to trans-4-phenyl-3-buten-2-one reach 99:1(1,4:12)and 80.5%(ee),respectively.Finally,the asymmetric conjugate addition of different Grignard reagents to trans-4-phenyl-3-buten-2-one was discussed.The results indicate that chiral ligand L3 is suitable for the addition of different Grignard reagents(except 1-naphthylmagesium bromide)and provides exclusively the product of 1,4-addition(regioselectivity?99:1)with high enantioselectivity(ee up to 86.1%)in linear Grignard reagents cases.The branch Grignard reagents such as i-PrMgBr and CyMgBr is also successfully used in the enantioselective conjugate addition with 83.3%ee and 80.3%ee,respectively.The Grignard reagents containing carbon-carbon double bonds such as vinylmagnesium bromide were also tolerated with 80.9%ee.In addition,the addition of chalcone with EtMgBr give a high regioselectivity(1,4:1,2>99:1)and good enantioselectivity(82.0%ee).Furthermore,the asymmetric 1,4-conjugate addition of Grignard reagents to trams-4-phenyl-3-buten-2-one,catalyzed by thiol chiral ligands(L4,L5)with different substituent groups,was also investigated.Compared with ligand L3,it can be concluded that the rigid rings in the branch of the ligands is essential for reaching a good stereoselectivity.