Studies On The Asymmetric α-hydroxylation Of β-ketoesters Catalyzed By In-situ Generated Salan-Metal Complexes

The demand for optically active compounds in the fields of medicine,materials and fine chemicals is growing rapidly,driving the development of asymmetric catalytic science.Chiralα-hydroxy-β-ketoesters structural scaffolds are highly important,because of their wild application as synthetic intermediates.In addition of these,there are many pharmaceutical drugs that contain this structure scaffold.Although different methods have been used for the synthesis of these compounds,there are still problems such as low catalyst efficiency,high cost,complex catalyst structure,low atomic economy and safety concern of oxidants,and difficulty in expanding the reaction scale.It is of great theoretical and practical significance to develop a catalytic system with high activity,high selectivity,low cost and environmentally friendly in the reaction process.Firstly,a series of Salan ligands with C2 or C1 symmetry were designed and synthesized as chiral control sources.The transition metal complexes generated in-situ with these Salan ligands were used as catalysts to catalyze the asymmetric a-hydroxylation of β-ketoesters.After optimizing the reaction conditions,the Salan-Zr(IV)was selected as the catalyst,and the reaction was carried out efficiently at 50 ℃ for 2 hours with an aqueous solution of 75%cumene hydroperoxide as an oxidant.Among 21 a-hydroxy-β-ketoesters,98%yield and 96%ee were obtained by column chromatography of 5-chloro-l-indanone-2-carboxylic acid methyl ester.This asymmetric hydroxylation reaction was scaled up to a gram scale to obtain a product by low temperature crystallization separation with 91%yield and 98%ee;the catalyst was further recovered by filter and reused,and the second round of catalytic reaction still achieved 91%yield and 91%ee product by low temperature crystallization separation.At the same time,the mechanism and chiral induction model of the hydroxylation reaction were studied by controlled experiments,1H-NMR analysis and simple theoretical calculations.Subsequently,the strategy of visible light catalyzed molecular oxygen was introduced into the asymmetric hydroxylation reaction of β-ketoesters,which combines asymmetric catalysis and visible light catalysis.Still using a complex formed by a chiral Salan ligand and a transition metal Lewis acid as a chiral catalyst,it was found that the Salan-Cu(II)complex has the highest catalytic activity and enantioselectivity.After optimizing the reaction conditions,the a-hydroxylation reaction was carried out at-15 ℃ and under 25 W CFL irradiation for 15 hours.Among 21 a-hydroxy-β-ketoesters,95%yield and 96%ee were obtained by column chromatography of 5-chloro-1-indanone-2-carboxylic acid methyl ester.Transformation through reduction and condensation reactions,such products can be used to prepare high value chiral 1,2-dihydroxy carboxylate compounds and a-hydroxy-β-hydrazone carboxylate compounds,and the stereocenter configuration of the products remain unchanged.According to a series of experiments,it is speculated that singlet oxygen was involved in the reaction process.Thus achieved asymmetric α-hydroxylation of β-ketoesters catalyzed by visible light and Salan-Cu(II)complex with high yield and enantioselectivity from a viewpoints of green and sustainable chemistry and great scale expansion.Finally,based on the optimal conditions of batch reaction,we applied continuous flow reaction strategy of visible light catalyzed molecular oxygen participated asymmetric hydroxylation reaction in Coming’s Lab Reactor Flow Photoreactor.30 mol%Salan-Cu(II)complex generated in-situ and 2.5 mol%tetraphenylporphyrin were used as chiral catalyst and photocatalyst respectively,using a light intensity 100 mW/cm2 4000K color temperature visible light was used as the light source and under 5 bar pressure oxygen at 25 ℃,with residence time 2.68 minutes.This continuous flow visible light reaction gave asymmetric a-hydroxylation ofβ-ketoester in 99%yield(column chromatography separation)and 70%ee.The hydroxylation reaction,which took 15 hours under batch conditions,can be shortened to 2.68 minutes using a continuous flow photocatalysis strategy,greatly increasing the conversion rate of the reaction.However,the enantioselectivity is reduced by 26%compared to the batch reaction.The key intermediates of the continuous flow reaction process were detected and confirmed by high resolution mass spectrometry as the hydrogen peroxide intermediate,further elucidated the reaction mechanism of photocatalytic hydroxylation.