Synthesis of enantiopure 3,6,7,8-tetrahydrochromeno[7,8-d]imidazoles via asymmetric ketone hydrogenation in the presence of RuCl2[Xyl-P-Phos][DAIPEN]

Asymmetric homogeneous hydrogenations at scale

“…The reaction outcome was still susceptible to the exact structure of the substrate; some analogues gave competing reactions. 342,343 Earlier results with ferrocene-based bisphosphines (7) and BINAP (10) systems under hydrogen required protection of the phenolic hydroxy group. 344 Merck has used an asymmetric hydrogen transfer reaction to prepare the phenylethanol derivative 207 (Scheme 74); the asymmetric hydrogenation approach has been discussed (Scheme 68).…”

Large-Scale Asymmetric Synthesis of the 3,6,7,8-Tetrahydrochromeno[7,8-d]imidazole BYK 405879: A Promising Candidate for the Treatment of Acid-Related Diseases

“…In the course of our P-CAB lead optimization program, we identified several compounds belonging to the classes of 7 H -8,9-dihydropyrano[2,3- c ]imidazo[1,2- a ]pyridines 3 (e.g., BYK 311319, 4 ) and 3,6,7,8-tetrahydrochromeno[7,8- d ]imidazoles 7 (e.g., BYK 405879, 8 ) that are potent reversible inhibitors of the gastric proton pump enzyme and possess promising pharmacological properties. , Consequently, we designed an asymmetric synthesis that permitted the ready preparation of multigram quantities of target compounds 3 and 7 (Scheme ). , …”

“…In both classes, the same retrosynthetic strategy was applied comprising the asymmetric catalytic hydrogenation of ketones 1 and 5 and subsequent Mitsunobu cyclization of the resulting diols 2 and 6 affording P-CABs 3 and 7 . In collaboration with Johnson Matthey, Catalysis and Chiral Technologies, we developed for the hydrogenation reaction the previously unknown catalyst RuCl 2 [( S )-Xyl-P-Phos][( S )-DAIPEN] 9 (Figure ), which belongs to the class of Noyori catalysts of the general formula RuCl 2 [PP][NN]. − The RuCl 2 [PP][NN]-catalyzed hydrogenation of ketones is typically performed in the presence of catalytic amounts of a base using 2-propanol as a solvent . However, due to the presence of the acidic phenol group, an excess of the base was required for the reduction of ketones 1 and 5 (one equivalent of base to deprotonate the phenol moiety and a small excess to activate the hydrogenation catalyst). , Despite the similarity of ketones 1 and 5 , the efficiency of the hydrogenation reaction varied considerably between the two structural classes.…”

“…In collaboration with Johnson Matthey, Catalysis and Chiral Technologies, we developed for the hydrogenation reaction the previously unknown catalyst RuCl 2 [( S )-Xyl-P-Phos][( S )-DAIPEN] 9 (Figure ), which belongs to the class of Noyori catalysts of the general formula RuCl 2 [PP][NN]. − The RuCl 2 [PP][NN]-catalyzed hydrogenation of ketones is typically performed in the presence of catalytic amounts of a base using 2-propanol as a solvent . However, due to the presence of the acidic phenol group, an excess of the base was required for the reduction of ketones 1 and 5 (one equivalent of base to deprotonate the phenol moiety and a small excess to activate the hydrogenation catalyst). , Despite the similarity of ketones 1 and 5 , the efficiency of the hydrogenation reaction varied considerably between the two structural classes. In the imidazo[1,2- a ]pyridine class, the hydrogenation of ketones 1 was feasible at high S/C ratios giving the corresponding chiral alcohols 2 in excellent yields and optical purities (e.g., R′ = R′′ = Me, Ar = Ph: 1.2 equiv of t -BuOK, catalyst 9 , S/C = 1000:1, 2-PrOH, t -BuOH, H 2 O, 80 bar H 2 , 65 °C, 22 h, 93% yield, 98% ee or 1.1 equiv of t -BuOK, catalyst 9 , S/C = 5000:1, 2-PrOH, t -BuOH, H 2 O, 25 bar H 2 , 75 °C, 15 h, 75% yield, 97% ee) .…”

“…In the imidazo[1,2- a ]pyridine class, the hydrogenation of ketones 1 was feasible at high S/C ratios giving the corresponding chiral alcohols 2 in excellent yields and optical purities (e.g., R′ = R′′ = Me, Ar = Ph: 1.2 equiv of t -BuOK, catalyst 9 , S/C = 1000:1, 2-PrOH, t -BuOH, H 2 O, 80 bar H 2 , 65 °C, 22 h, 93% yield, 98% ee or 1.1 equiv of t -BuOK, catalyst 9 , S/C = 5000:1, 2-PrOH, t -BuOH, H 2 O, 25 bar H 2 , 75 °C, 15 h, 75% yield, 97% ee) . In contrast, in the benzimidazole class, higher amounts of hydrogenation catalyst were required to ensure a smooth transformation of ketones 5 to diols 6 (e.g., R′ = R′′ = Me, Ar = Ph: 1.5 equiv of t -BuOK, catalyst 9 , S/C = 310:1, 2-PrOH, t -BuOH, H 2 O, 80 bar H 2 , 65 °C, 23 h, 70%, 98% ee) . Moreover, under certain reaction conditions (high S/C ratio, presence of a large excess of a base), a competing reaction was observed .…”