ChemInform Abstract: 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].

Abstract

Benzimidazole derivatives R 0200 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]. -The asymmetric hydrogenation of ketones (II) in the presence of 19 ligands is investigated. The title ligand (I) affords the corresponding alcohols in excellent enantiomeric purity. The outcome of the reaction and the rate of the competing base-catalyzed process leading to by-products such as (VI) depends on the substitution pattern of the ketone and the stoichiometry of the base. After optimization of the conditions, alcohols (IIIa) and (IIIb) are isolated in high yields and enantioselectivities and used as key intermediates for the synthesis of the pharmaceutically active chromenoimidazoles (IV). -(PALMER*, A. M.; CHIESA, V.; HOLST, H. C.; LE PAIH, J.; ZANOTTI-GEROSA, A.; NETTEKOVEN, U.; Tetrahedron: Asymmetry

Tetrahydrochromenoimidazoles as Potassium-Competitive Acid Blockers (P-CABs): Structure−Activity Relationship of Their Antisecretory Properties and Their Affinity toward the hERG Channel

“…To examine the influence of the aryl residue on the pharmacological activity and the hERG affinity of the respective benzimidazole derivative, a similar approach was pursued as previously described for the candidate 4 (Scheme 2, Table 2). 14,15 The prochiral ketones 47-61 were prepared by transformation of the Mannich base 46 with different 1-(1-arylvinyl)pyrrolidines. Ketones 62 and 63, containing a carboxylic ester moiety, were used as versatile intermediates for rapid variation of the carboxamide moiety and as starting material for the synthesis of the 5-methoxymethylene-substituted target compound 43.…”

“…Noyori asymmetric hydrogenation of the respective ketones 47-61, 73-77, and 81 in the presence of RuCl 2 [(S)-Xyl-P-Phos][(S)-DAIPEN] 82 (Figure 2) afforded the alcohols 83-103, typically in 80-98% ee. 14,[30][31][32][33][34] The synthesis of the target compounds 21, 25, 39, 43, and 104-120 was then completed by Mitsunobu cyclization of the diols 83-103 using triphenylphosphine and DIAD (Table 2). In the 4-chlorophenyl series and in the 4-chloro-2-methylphenyl series, a variation of the carboxamide residue CONR1R2 was performed by applying the methods discussed in Scheme 1 (Scheme 3).…”

“…This heterocyclic scaffold emerged from the systematic investigation of possible variations of the well-known imidazo[1,2-a]pyridine motif. 5 In comparison to the isomeric imidazo[1,2-a]pyridines 1, represented by 3 (BYK 311319), 5 the respective benzimidazoles 2, represented by 4 (BYK 405879), 14,15 possess a lower pK a value, resulting in a more selective accumulation in the parietal cell and a better safety profile. Enantiopure P-CABs belonging to both structural classes can be prepared in an analogous manner (asymmetric reduction of ketones followed by Mitsunobu cyclization of the resulting diols), and the large scale synthesis of the candidate 4 was based on this synthetic strategy.…”

“…Enantiopure P-CABs belonging to both structural classes can be prepared in an analogous manner (asymmetric reduction of ketones followed by Mitsunobu cyclization of the resulting diols), and the large scale synthesis of the candidate 4 was based on this synthetic strategy. [14][15][16][17] Although the tetrahydrochromenoimidazole 4 constitutes a P-CAB with well-balanced properties, we studied the SAR within this lead series in more detail focusing on (a) optimum pharmacological activity in two species (Ghosh Schild rat and fistula dog) and (b) low affinity toward the hERG channel. The primary objective of the study was to identify P-CABs with a longer duration of action in the fistula dog than the current candidate 4.…”

“…b pIC 50 value of the inhibition of H þ /K þ -ATPase derived from hog gastric mucosa (competitive binding assay). c pIC 50 value of the inhibition of 14 C-dimethylaminopyridine accumulation in intact gastric glands isolated from New Zealand rabbits. d Pentagastrin-stimulated acid secretion of the perfused rat stomach (Ghosh Schild rat): ED 50 (μmol/kg) or dose (μmol/kg)/reduction (%).…”