Asymmetric hydrolytic kinetic resolution with recyclable polymeric Co(iii)–salen complexes: a practical strategy in the preparation of (S)-metoprolol, (S)-toliprolol and (S)-alprenolol: computational rationale for enantioselectivity

Abstract

A series of chiral polymeric Co(III) salen complexes based on a number of achiral and chiral linkers were synthesized and their catalytic performances were assessed in asymmetric hydrolytic kinetic resolution of terminal epoxides. The effect of the linker were judiciously studied and it was found that in case of chiral BINOL based polymeric salen complex 1, there was certain enrichment in catalyst reactivity and enantioselectivity of the unreacted epoxide particularly in the case of shor t as well as long chain aliphatic epoxides. Good isolated yield of the unreacted epoxide (up to 46% out of 50% theoretical yield) along with high enantioselectivity (up to >99%) were obtained in most of the cases using catalyst 1. Further studies exhibited that the catalyst 1 could retain its catalytic activity for six cycles under the present reaction conditions without any significant loss in activity and enantioselectivity. To show the practical applicability of the above synthesized catalyst we have car ried out synthesis of some potent chiral -blockers using complex 1 in moderate yield and high enantioselectivity. The DFT (M06 -L/6-31+G**//ONIOM(B3LYP/6-31G*:STO-3G)) calculations revealed that the chiral BIN OL linker influences the enantioselectivity with Co(III)salen complexes. Further, the transition state calculations show that the R-BINOL linker with (S,S)-(salen)Co(III) complex is energetically preferred over the corresponding S-BINOL linker with (S,S)-(salen)Co(III) complex for HKR of 1,2-epoxyhexane. The role of non-covalent C-H… π interaction and steric effects has been discussed to control the HKR reaction of 1,2 -epoxyhexane.

Chiral Cobalt‐Salen Complexes: Ubiquitous Species in Asymmetric Catalysis

“…The cobalt‐salen promoted kinetic resolution of terminal epoxides has been indeed extensively studied for the synthesis of chiral, highly enantioenriched bioactive molecules, at different stage of their preparation. Without being here exhaustive, convincing examples can be found for the preparation of β‐adrenergic antagonist drugs such as Timolol [36a] or other β‐blockers, [36b,c] as antihypertensive drugs. The protocol was efficiently extended to the aminolytic kinetic resolution of epoxides to allow the preparation of other important drugs [36d] .…”

Chiral Salen Complexes for Asymmetric Heterogeneous Catalysis: Recent Examples for Recycling and Cooperativity

“…This efficient procedure was ultimately used for the preparation of chiral drugs, (R) ‐Naftopidil and (S) ‐Propanolol. The same polymeric systems were also used for a related catalytic transformation, the HKR of epoxides (21 examples) …”

“…The same polymeric systems were also used for a related catalytic transformation, the HKR of epoxides (21 examples). [50] Furthermore, manganese salts have also been introduced, and the corresponding polymers were tested for the enantioselective epoxidation of non-functionalized alkenes. [51] Catalysts issued from the linear polymers proved all active with the best results obtained for the epoxidation of indene, when the spacer was the flexible trigol bridge.…”

Kinetic resolution of (RS)-1-chloro-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol: a metoprolol intermediate and its validation through homology model of Pseudomonas fluorescens lipase

“…13 A number of chemical methods have been described in the literature for the synthesis of enantiopure metoprolol. [14][15][16][17][18][19][20][21][22] However, most of the chemical synthesis methods suffer from some disadvantages, such as poor enantioselectivity, long reaction time, hazardous reaction conditions, formation of by products, and higher cost. Biocatalytic approach has also been used for the synthesis of chiral intermediates of metoprolol.…”