Asymmetric Hydrolytic Kinetic Resolution with Recyclable Macrocyclic Co^III–Salen Complexes: A Practical Strategy in the Preparation of (R)‐Mexiletine and (S)‐Propranolol

Abstract

A chiral cobalt(III) complex (1e) was synthesized by the interaction of cobalt(II) acetate and ferrocenium hexafluorophosphate with a chiral dinuclear macrocyclic salen ligand that was derived from 1R,2R-(-)-1,2-diaminocyclohexane with trigol bis-aldehyde. A variety of epoxides and glycidyl ethers were suitable substrates for the reaction with water in the presence of chiral macrocyclic salen complex 1e at room temperature to afford chiral epoxides and diols by hydrolytic kinetic resolution (HKR). Excellent yields (47% with respect to the epoxides, 53% with respect to the diols) and high enantioselectivity (ee>99% for the epoxides, up to 96% for the diols) were achieved in 2.5-16 h. The Co(III) macrocyclic salen complex (1e) maintained its performance on a multigram scale and was expediently recycled a number of times. We further extended our study of chiral epoxides that were synthesized by using HKR to the synthesis of chiral drug molecules (R)-mexiletine and (S)-propranolol.

Minor Enantiomer Recycling: Application to Enantioselective Syntheses of Beta Blockers

“…A variety of metal‐catalyzed synthetic procedures have also been reported. Several routes based on the nucleophilic ring‐opening of (2 S )‐3‐(1‐naphthyloxy)‐1,2‐epoxypropane, accessible by means of Sharpless epoxidation,18 dihydroxylation,19 L ‐proline‐catalyzed α‐aminoxylation,20 and kinetic resolution,21 have been explored (Scheme , route I). A route that comprises a nitroaldol condensation as the key step allowed the product to be isolated in a reasonable overall yield with up to 97 % ee (Scheme , route II) 22.…”

Imine- and Amine-Type Macrocycles Derived from Chiral Diamines and Aromatic Dialdehydes

“…The reduced form of this kind of macrocycles, i.e., rhombamines was applied in NMR enantiodiscrimination of chiral carboxylic acids and their derivatives [61,62]. The condensation of enantiopure DACH or DPEN with aromatic dialdehydes containing two phenol fragments results in the formation of the extended [2 + 2] imines 20, 21, 24-26, which can also be transformed into their reduced amine forms 22 and 23 (Figure 10) [63][64][65][66][67][68][69][70]. These enantiopure ligands contain two compartments corresponding to the chiral salen environment (the parent macrocycle 26 was called calixsalen [63]).…”

“…The energy-minimized structure of such a dinuclear complex shows a plausible intermediate in the catalytic cycle, where the epichlorohydrin molecule is bound in the center of the expanded macrocycle between the two cobalt(III) ions [64]. The extended tetraphenolic macrocycles 20-26 are predisposed to form dinuclear complexes with transition metals, such as cobalt(III), copper(II), vanadium(V), manganese(III) or titanium(IV), which exhibit interesting enantioselective catalytic activity in the kinetic resolution of epoxides [64], Henry reaction [65], aza-Henry reaction [70], Strecker reaction [67], O-acetylcyanation/cyanoformylation of aldehydes [66], asymmetric carbonylation of aldehydes [68], and epoxidation of alkenes [69]. The dinuclear copper(II) complex of another tetraphenolic [2 + 2] imine derived from DPEN was active as an enantioselective catalyst in the Henry reaction [71].…”

“…with transition metals, such as cobalt(III), copper(II), vanadium(V), manganese(III) or titanium(IV), which exhibit interesting enantioselective catalytic activity in the kinetic resolution of epoxides [64], Henry reaction [65], aza-Henry reaction [70], Strecker reaction [67], O-acetylcyanation/cyanoformylation of aldehydes [66], asymmetric carbonylation of aldehydes [68], and epoxidation of alkenes [69]. The dinuclear copper(II) complex of another tetraphenolic [2 + 2] imine derived from DPEN was active as an enantioselective catalyst in the Henry reaction [71].…”

Evaluation of enantiopure and non-enantiopure Co(III)-salen catalysts and their counter-ion effects in the hydrolytic kinetic resolution (HKR) of racemic epichlorohydrin

“…In addition, the coproduct of the reaction, a chiral diol, can be a useful building block as well, being used, for example, in the synthesis of active pharmaceutical ingredients (APIs) [12,13]. Also with respect to pharmaceutical significance, macrocyclic Co(III)-salen-PF 6 has been used as a catalyst to synthesize the chiral drugs (R)-mexiletine and (S)-propranolol via HKR [14]. From a catalysis science perspective, the Co(III)-salen catalyzed HKR reaction has become a useful test-bed for the development of supported catalysts that enhance cooperative catalysis, as the HKR reaction is now the prototypical cooperative bimolecular reaction catalyzed by a metal-ligand complex (vida infra) [15].…”