An efficient route to enantiomerically pure antidepressants: tomoxetine, nisoxetine and fluoxetine

Schneider, Manfred; Goergens, U.

doi:10.1016/s0957-4166(00)80257-8

Cited by 43 publications

(8 citation statements)

References 8 publications

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“…for the kinetic resolution of racemic mixtures of secondary alcohols in hydrolysis~Laumen & Schneider, 1988;Liang & Paquette, 1990;Caron & Kazlauskas, 1991;Schneider & Georgens, 1992;Bän-ziger et al, 1993;Itoh et al, 1993;Partali et al, 1993;Takano et al, 1993;Waldinger et al, 1996!, esterification~Burgess & Jennings, 1991Uejima et al, 1993;Chadha & Manohar, 1995;Gaspar & Guerrero, 1995;Hamada et al, 1996;Petschen et al, 1996!, andtransesterification~Kaminska et al, 1996;Takagi et al, 1996!. The mechanistic details of the catalytic reaction of serine hydrolases~Chapus et al, 1976;!…”

mentioning

confidence: 99%

Stereoselectivity of Pseudomonas cepacia lipase toward secondary alcohols: A quantitative model

2000

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The lipase from Pseudomonas cepacia represents a widely applied catalyst for highly enantioselective resolution of chiral secondary alcohols. While its stereopreference is determined predominantly by the substrate structure, stereoselectivity depends on atomic details of interactions between substrate and lipase. Thirty secondary alcohols with published E values using P. cepacia lipase in hydrolysis or esterification reactions were selected, and models of their octanoic acid esters were docked to the open conformation of P. cepacia lipase. The two enantiomers of 27 substrates bound preferentially in either of two binding modes: the fast-reacting enantiomer in a productive mode and the slow-reacting enantiomer in a nonproductive mode. Nonproductive mode of fast-reacting enantiomers was prohibited by repulsive interactions. For the slow-reacting enantiomers in the productive binding mode, the substrate pushes the active site histidine away from its proper orientation, and the distance d~H NE Ϫ O alc ! between the histidine side chain and the alcohol oxygen increases. d~H NE Ϫ O alc ! was correlated to experimentally observed enantioselectivity: in substrates for which P. cepacia lipase has high enantioselectivity~E Ͼ 100!, d~H NE Ϫ O alc ! is Ͼ2.2 Å for slow-reacting enantiomers, thus preventing efficient catalysis of this enantiomer. In substrates of low enantioselectivity~E Ͻ 20!, the distance d~H NE Ϫ O alc ! is less than 2.0 Å, and slow-and fast-reacting enantiomers are catalyzed at similar rates. For substrates of medium enantioselectivity~20 Ͻ E Ͻ 100!, d~H NE Ϫ O alc ! is around 2.1 Å. This simple model can be applied to predict enantioselectivity of P. cepacia lipase toward a broad range of secondary alcohols.Keywords: enantioselectivity; lipase; model; molecular dynamics; Pseudomonas cepacia; secondary alcohol; stereopreference Lipase from Pseudomonas cepacia~EC 3.1.1.3! is a popular catalyst in organic synthesis~Kazlauskas & Bornscheuer, 1998! for the kinetic resolution of racemic mixtures of secondary alcohols in hydrolysis~Laumen & Schneider, 1988;Liang & Paquette, 1990;Caron & Kazlauskas, 1991;Schneider & Georgens, 1992; Bän-ziger et al., 1993;Itoh et al., 1993;Partali et al., 1993;Takano et al., 1993;Waldinger et al., 1996!, esterification~Burgess & Jennings, 1991Uejima et al., 1993;Chadha & Manohar, 1995;Gaspar & Guerrero, 1995;Hamada et al., 1996;Petschen et al., 1996!, and transesterification~Kaminska et al., 1996;Takagi et al., 1996!. The mechanistic details of the catalytic reaction of serine hydrolases~Chapus et al., 1976;! have been well investigated by quantum-chemical methods like the ab initio and density functional theory~Hu et al., 1998!, and by semiempirical methods~Monecke et al., 1998!. The reaction mechanism of ester hydrolysis~Fig. 1! starts with the formation of a Michaelis complex followed by a first transition state~19! to the first tetrahedral intermediate~2!, where the substrate is covalently linked to side-chain oxygen Og of catalytic serine. The crucial hydrogen bonds...

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confidence: 99%

Stereoselectivity of Pseudomonas cepacia lipase toward secondary alcohols: A quantitative model

2000

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“…The combined methanol solution was evaporated in vacuo and the residue was purified by chromatography using CH 2 Cl 2 as eluent to yield a white powder (464 mg, 99%). Mp 132 • C (dec.); IR (KBr): m 3381, 3033,2978,1688,1590,1517,1452,1319,1450 (15). A solution of (469 mg, 1 mmol), 3-bromopropionic acid (153 mg, 1 mmol) and Cs 2 CO 3 (652 mg, 2 mmol) in 10 mL of acetone was heated at reflux for 24 h. The volatiles were removed in vacuo and the residue was triturated with CH 2 Cl 2 .…”

Section: -(Benzyloxy)benzenesulfonyl Chloride (11)mentioning

confidence: 99%

“…8 138-140 • C); [a] 20 D +13.5 (c 1, CHCl 3 ) (lit. 15 [a] 20 D +13.9 (c 1.01, CHCl 3 )); d H (500 MHz, CDCl 3 ): 2.50 (m, 2 H, CH 2 N + ), 2.64 (s, 3 H, CH 3 ), 3.21 (m, 2 H, CH 2 CH), 5.51 (dd, J = 6.2 Hz, 1 H, CHC 6 H 5 ), 6.91 (d, J = 8.5 Hz, 2 H, C 6 H 4 ), 7.21-7.53 (m, 7 H, C 6 H 5 +C 6 H 4 ).…”

Section: General Procedures For the Asymmetric Transfer Hydrogenationmentioning

confidence: 99%

Preparation of polymer-supported Ru-TsDPEN catalysts and use for enantioselective synthesis of (S)-fluoxetine

et al. 2005

Org. Biomol. Chem.

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Polymer-supported chiral ligands 9 and 17 were prepared based on Noyori's (1S,2S)- or (1R,2R)-N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine. The combination with [RuCl2(p-cymene)]2 has been shown to exhibit high activities and enantioselectivities for heterogeneous asymmetric transfer hydrogenation of aromatic ketones (19a-c) with formic acid-triethylamine azeotrope as the hydrogen donor, whereby affording the respective optically active alcohols 20a-c, the key precursors of chiral fluoxetine. As exemplified by ligand 17 for substrate 19c, the catalysts can be recovered and reused in three consecutive runs with no significant decline in enantioselectivity. The procedure avoids the plausible contamination of fluoxetine by the toxic transition metal species.

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“…Aromatic sec -alcohols, such as 1-PEA, are important chiral building blocks. 3-Chloro-1-phenyl-1-propanol is a key precursor for the synthesis of antidepressants, such as Tomoxetine, Nisoxetine, and Fluoxetine . Isoproterenol is part of the core scaffold of a β 3 -adrenergic receptor agonist .…”

Section: Introductionmentioning

confidence: 99%

Revealing Cutinases’ Capabilities as Enantioselective Catalysts

Tyrikos‐Ergas

Shirke

et al. 2018

ACS Catal.

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The specific activity and enantioselectivity of immobilized cutinases from Humicola insolens (HiC) and Aspergillus oryzae (AoC) were compared with those of Lipase B from Candida antarctica (CALB) for a series of 1-phenylethanol (1-PEA) structural analogues. The aim was to understand their catalytic behavior by rationally studying three structural elements of the substrates: the length of the alkyl chain, the position of methylation of the aromatic ring, and the aromatic character of the ring. All enzymes were immobilized on the macroporous support Lewatit VP OC 1600 at loadings of ∼10% w/w. Docking studies revealed structural features of the enzymes that led to activity differences. All three enzymes exhibit (R)-selectivity. AoC, due to its more open and accessible active site, possesses high activity that exceeds in most cases that of HiC and CALB. By increasing the substrate’s alkyl chain length from methyl to n-propyl, the activity for the (R)-enantiomer of all three enzymes decreased significantly (≥70%), while the enantioselectivity of both cutinases was larger than that of CALB for the bulkier substrate. Methylation of the ring in the ortho-position led to loss of activity (≥55%); however, AoC retained substantial activity. For all three enzymes, the planar character of the substrate phenyl ring is crucial for stabilizing the substrate in the active sites via π–π stacking. HiC displays high enantioselectivity with most substrates, despite its wide active site, due to a “bottleneck” produced over the catalytic serine from Leu66 and Ile169.

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An efficient route to enantiomerically pure antidepressants: tomoxetine, nisoxetine and fluoxetine

Cited by 43 publications

References 8 publications

Stereoselectivity of Pseudomonas cepacia lipase toward secondary alcohols: A quantitative model

Stereoselectivity of Pseudomonas cepacia lipase toward secondary alcohols: A quantitative model

Preparation of polymer-supported Ru-TsDPEN catalysts and use for enantioselective synthesis of (S)-fluoxetine

Revealing Cutinases’ Capabilities as Enantioselective Catalysts

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