A Decennary Journey towards the Efficient Asymmetric Hydrogenation of Highly Functionalized Ketones

Around 2006, our group launched a long-term project on the asymmetric hydrogenation of functionalized ketones by using ruthenium complexes with SunPhos ligands. In this review, we recount the burgeoning and blossoming of this project. At the outset, we attempted some benchmark reactions with an array of monofunctionalized ketones, including alpha- and beta-keto esters/amides, beta-keto sulfones, phosphonates, and alpha-hydroxy ketones. For alpha-keto esters and amides, we discovered that CeCl3 center dot 7H(2)O was an efficient additive for both activity and enantioselectivity. The element iodine was found to be a valid additive for beta-keto sulfones. beta,gamma-Unsaturated alpha-keto acids and esters were also hydrogenated to the saturated chiral blocks with good enantioselectivity and a high turnover number. For the alpha-substituted beta-keto esters and phosphonates, exceptionally high stereoselectivity was achieved through dynamic kinetic resolution. Based on these incipient successes, we diverted to bifunctionalized ketone substrates, such as gamma-heteroatom-substituted beta-keto esters and delta-ketal-beta-keto esters. For the delta-ketal-beta-keto esters, CaCO3 was added to stabilize the delta-ketal groups, which ensured the formation of delta-ketal-beta-hydroxy esters in good yields and high ee values. More interestingly, gamma-halo-gamma,delta-unsaturated-beta-keto esters were hydrogenated to afford highly enantiopure chiral allyl alcohols under mild and neutral conditions. The distance effect of the directing groups was investigated in beta-, gamma-, and delta-keto amides; the last two were hydrogenated with the Ru-SunPhos-diamine system. To implement the pinpoint recognition of two carbonyl groups in similar chemical propinquity, we compared the reaction rates of different beta-keto acid derivatives. THF was found to be a helpful coordinative solvent to control the chemo-and enantioselectivity for more challenging polycarbonyl substrates, such as 3-oxo glutaric acid derivatives, beta,delta-diketo carboxamides, and gamma-heteroatom-substituted beta-diketones. The effects of solvents and heteroatoms in these substrates were also studied. Applications of these hydrogenation reactions were also exemplified by the employment of the products for important pharmaceutical syntheses.