Study On Asymmetric Oxidative Cross-coupling Reactions Combining The Non-natural Catalytic Activity Of Enzyme With Photo-/electro-catalysis

The non-natural catalytic activity of enzymes,also known as enzyme promiscuity,is mainly manifested by the ability of an enzyme to catalyze chemical reactions other than natural ones that may not be related to their natural activity.The discovery of enzyme promiscuity overcomes the drawbacks of a single type of enzymatic reaction and a narrow range of substrates.Besides,it also extends the application range of enzymes from aqueous solution to non-aqueous media.The combination of enzyme catalysis and photo-/electro-redox not only can utilize the advantages of enzyme catalysis,but also can fully highlights the unique chemical conversion ability of photo-/electro-chemistry.It has many advantages,such as new reactivity,high enantioselectivity,green synthesis,and high yields.In the past decades,the strategies of enzymatic photo-/electro-catalysis have mainly used photo-/electro-chemistry to regenerate cofactors of enzymes,and is confined to the natural catalytic activity of oxidoreductases,which greatly limited their reaction types and substrate range.Combining enzyme promiscuity and organic electrosynthesis/photocatalysis are emerging asymmetric synthesis strategies.In particular,the combination of the non-natural catalytic activity of enzyme and organic electrosynthesis is an efficient and green asymmetric catalytic method.To the best of our knowledge,this strategy has not been reported so far.In this thesis,the current research status of asymmetric organic electrosynthesis and asymmetric photocatalysis was reviewed firstly.We emphatically focused on the recent progress in asymmetric enzymatic electrosynthesis and asymmetric synthesis catalyzed by enzyme promiscuity combined with photoredox catalysis.In the second chapter of this thesis,we have developed the enantioselective oxidative cross-coupling of secondary amines with ketones by combining the non-natural catalytic activity of lipase with electrosynthesis.A total of 362,2-disubstituted 3-carbonyl indoles with a tetrasubstituted carbon stereocenter including 12 new compounds were synthesized from 2-substituted indoles in yields up to 78% with good enantio-and diastereoselectivities(up to 96:4 er and > 20:1 dr).This unprecedented protocol demonstrated that hydrolase catalysis is compatible with electrosynthesis,and the reaction can be carried out in organic solvents with a broad substrate scope,good stereoselectivity and coenzyme-free.This work provides insights into combining enzymes with organic electrosynthesis for asymmetric electrosynthesis.In the third chapter of this thesis,we have carried out for the first time an asymmetric oxidative cross-dehydrogenation coupling reaction that combines lipase promiscuity with photocatalysis to catalyze acyclic secondary benzylamines with aliphatic ketones.A series of optically pure β-amino ketones could be efficiently prepared under mild conditions.A total of 25 desired products were synthesized,including 12 new compounds.The reaction features simple operation,oxidant-and cofactor-free,moderate to good enantio-and diastereoselectivities(up to 89:11 er and93:7 dr),high yields(up to 89%)and excellent functional group tolerance.When different aliphatic ketones,such as cyclic ketones and oxygenated linear ketones were used as coupling substrates,syn-and anti-selective products could be obtained,respectively.Based on the work of Chapter 3,in order to improve enantioselectivity,we have developed an enantioselective oxidative cross-dehydrogenative coupling of acyclic benzylic secondary amines with simple ketones by combining photocatalysis and L-/D-proline catalysis in the fourth chapter of this thesis.A total of 43 desired products were synthesized,including 25 new compounds.This method has the characteristics of simple operation,oxidant-free,mild reaction conditions,good yields(up to 86%),high enantio-and diastereoselectivities(up to 99% ee and > 99:1 dr),and excellent functional group tolerance.In addition,the desired products with opposite configurations can be easily obtained by employing cheap and commercially available L-/D-proline as chiral organocatalysts.The scale-up experiments further prove the utility of the reaction.Compared to the photoenzymatic approach in Chapter 3,this work mainly realized the expansion of unactivated linear ketones,such as acetone and butanone.Besides,the syn-product with the opposite diastereoselectivity to the above method was obtained when using oxygenated ketones as the substrate.