Enantioselective Synthesis of β‐Blockers via Hydrolytic Kinetic Resolution of Terminal Oxiranes by Using Bimetallic Chiral {{2,2′‐[Cyclohexane‐1,2‐diylbis(nitrilomethylidyne)]bis[phenolato]}(2−)}cobalt ([Co(salen)])‐Type Complexes

Abstract

The synthesis of chirally pure b-blockers was successfully achieved via hydrolytic kinetic resolution of butyl (AE)-4-(oxiran-2-ylmethoxy)benzeneacetate ((AE)-1) and (AE)-4-(oxiran-2-ylmethoxy)benzeneacetonitrile ((AE)-2) in the presence of bimetallic chiral [Co(salen)]-type complexes. The newly synthesized bimetallic chiral [Co(salen)]-type complexes exhibited excellent enantioselectivities of up to > 98% ee in good yields (Tables 1 -3).Introduction. -The synthesis of chirally pure b-blockers is a very important task in the asymmetric catalysis as well as of pharmaceutical interests [1]. The b-adrenergic blocking agents (b-blockers) are used as antihypertensive drugs, they reduce the risk of producing long-lasting cardiac depression, since the effect of the drug would rapidly dissipate upon termination of the infusion [2]. In this category, atenolol (¼ 4-{2-hydroxy-3-[(1-methylethyl)amino]propoxy}benzeneacetamide) and propranolol (¼ 1-[(1-methylethyl)amino]-3-(naphthalen-1-yloxy)propan-2-ol) are the most important and widely prescribed drugs on the large scale [3]. In the last 15 years, numerous efforts have been devoted to the synthesis of b-blockers via lipase catalysis or hydrolytic kinetic resolution (HKR), or by a nitrile hydration catalytic method [4]. To the best of our knowledge, only a few syntheses of atenolol from racemic epichlorohydrine (¼ 2-(chloromethyl)oxirane; ECH) have been reported [5]. On the basis of these facts, the great utility of chiral oxiranes in stereoselective synthesis provided the motivation to develop a new method from which chiral atenolol could be prepared from racemic oxiranes. Among these available methods, HKR provides a general protocol to achieve highly enantiomer-enriched chiral building blocks that are available from inexpensive racemic materials [6]. In our previous study, we have shown that [Co(salen)]-type complexes bearing group-13 transition-metal salts display good enantioselectivity and reactivity for the HKR of racemic terminal oxiranes [7].In continuation of our efforts directed towards the designing of bimetallic chiral [Co(salen)]-type catalyst systems for HKR, we report herein a new method to produce bimetallic chiral [Co(salen)]-type catalysts bearing transition-metal salts attached to the O-atoms of the salen-type complexes, and their successful application to the HKR of various terminal epoxides. This type of salen catalysts has never been used as a

Synthesis and application of bimetallic chiral [Co(salen)]‐type complexes: a new catalytic approach to synthesis of optically pure β‐blockers via kinetic resolution of epichlorohydrin

“…The [Co II (salen)] complex A exhibited O 1s core level peak at a binding energy of ca 531 eV, while the transition-metal-containing cobalt-salen-type complexes showed a binding energy at higher value of ca 532 eV, and are in accordance with the earlier literature. [19] The observed change in binding energy of 1 eV (i.e. from ca 531 to 532 eV) for the Co(salen) containing transition-metal sample could be attributed to the differences in the coordination environments of transition metal and confirms the interaction with oxygen of cobalt salen.…”

“…[20] The PKR displays more attractive features with regards to the substrates of HKR. [19] In addition, the nucleophilic components can be varied, and phenols with a wide range of electronic properties are effective substrates. This raises the interesting possibility of applying this methodology to enantioselective catalytic synthesis of β-blockers through PKR.…”

“…[17,18] In our recent study, we have shown that [Co(salen)]-type complexes bearing transitionmetal salts exhibited good enantioselectivity and reactivity for the HKR of racemic terminal oxiranes in the synthesis of chiral atenolol. [19] From a practical synthetic point of view, phenol derivatives are appealing candidates as nucleophiles for the ring opening of (±)-ECH, providing direct access to enantiopure α-aryloxy alcohols using chiral cobalt-salen complexes. [20,21] These chiral intermediates are valuable for the synthesis of β-blockers.…”

Synthesis of New Bimetallic Chiral Salen Catalyst Bearing Co(BF4)2Salt and Its Application in Asymmetric Ring Opening of Epoxide

“…In the previous our study, the dimeric or dinuclear salen complexes have shown the excellent activity in the asymmetric kinetic resolution (AKR) of terminal epoxides. 9 Recently we have isolated the new salen catalysts containing transition metals salts, such as CoCl 2 , Co(NO3)2, FeCl2, NiCl2, in the ligand structure. 10,11 Their catalytic activity and enantioselectivity were dependent on the type of metal salts combined to the salen complexes in AKR reactions.…”