Efficient 2-step biocatalytic strategies for the synthesis of all nor(pseudo)ephedrine isomers

Sehl, Torsten; Hailes, Helen C.; Ward, John M.; Menyes, Ulf; Pohl, Martina; Rother, Dörte

doi:10.1039/c4gc00100a

Cited by 77 publications

(69 citation statements)

References 35 publications

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“…For example, the presence of d-norpseudoephedrine in Ephedra plants is demonstrated to have the same chemical structure as cathine (1S,2S-(+)-norpseudoephedrine) which is present in the khat plant [44][45][46][47], suggesting that isomer identification is essential to determine the source of d-norpseudoephedrine.…”

Section: Resultsmentioning

confidence: 99%

Postmortem Distribution of Cathinone and Cathine in Human Biological Specimens in a Case of Death Associated with Khat Chewing

Attafi¹,

Albeishy²,

Oraiby³

et al. 2018

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Chewing khat leaves has been associated with several adverse health effects, and there are very few case reports of cardiotoxicity, stroke and death resulting from this. In addition, postmortem distribution of cathine and cathinone, active components of khat, are not yet fully clear. This postmortem case report aimed to identify and determine the concentration of cathine and cathinone in different body organs and green chewed plants found in the mouth of the deceased. Immunoassay and non-targeted GC-MS analysis showed that samples were only positive for amphetamine type stimulants. LC-MS/MS quantitative analysis confirmed that samples were positive for cathinone and cathine. The results showed that cathinone concentration was 0.03, 0.03, 0.06, 0.07, 1.85 and 31 μg/ml in brain, liver, blood, vitreous humor, stomach and chewed green plant, respectively. Whereas, the concentration of cathine was 0.31, 3.28, and 141 μg/ml in kidney, stomach and chewed green plant, respectively. Cathine and cathinone concentrations were found to be changed with respect to site of sampling. The results suggest that stomach and chewed green plants are considered as good samples to show the concentration for both cathine and cathinone at the time of death of the khat chewer. This paper reports a postmortem case whose death was suspected to be khat overdose. The deceased, a young

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Section: Resultsmentioning

confidence: 99%

Postmortem Distribution of Cathinone and Cathine in Human Biological Specimens in a Case of Death Associated with Khat Chewing

Attafi¹,

Albeishy²,

Oraiby³

et al. 2018

AJFSFM

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“…that has been used previously in various cascade reactions. [18] It exhibits rare compatibility with sterically hindered ketones, which makes it a potentially useful biocatalyst. To avoid the use of stoichiometric amounts of the cofactor, which is prohibitively expensive for most fine-chemical synthesis, we paired RADH with the homodimeric phosphite dehydrogenase (PTDH) from Pseudomonas stutzeri.…”

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Bootstrapped Biocatalysis: Biofilm‐Derived Materials as Reversibly Functionalizable Multienzyme Surfaces

et al. 2017

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Cell-free biocatalysis systems offer many benefits for chemical manufacturing, but their widespread applicability is hindered by high costs associated with enzyme purification, modification, and immobilization on solid substrates, in addition to the cost of the material substrates themselves. Herein, we report a “bootstrapped” biocatalysis substrate material that is produced directly in bacterial culture and is derived from biofilm matrix proteins, which self-assemble into a nanofibrous mesh. We demonstrate that this material can simultaneously purify and immobilize multiple enzymes site specifically and directly from crude cell lysates by using a panel of genetically programmed, mutually orthogonal conjugation domains. We further demonstrate the utility of the technique in a bienzymatic stereoselective reduction coupled with a cofactor recycling scheme. The domains allow for several cycles of selective removal and replacement of enzymes under mild conditions to regenerate the catalyst system.

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“…Thee nzymes described for this two-step cascade have been valuable catalysts for cascade reactions with unsubstituted aromatic aldehydes and hydroxyketones. [25,29] Here,t hey also proved to be suitable catalysts for as ubstituted benzaldehyde,y ielding biocatalytic access to (1R,2S)-3 (metaraminol), an a 1 adrenergic receptor agonist that acts as av asoconstrictor. [30] Compound 3 was then used for asubsequent PSR.…”

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confidence: 99%

“…[21] Modular biocatalytic cascades [23] for the stereoselective production of pharmaceutical compounds are exemplified by the work conducted on phenylpropanolamines. [24][25][26] All four possible isomers of nor(pseudo)ephedrine are available from simple starting materials by one-pot two-enzyme cascades when appropriate biocatalysts are selected.[26] Phenylpropanolamines with an additional 3-hydroxy group on the aromatic ring have been considered to be suitable substrates for cascades including PSRs catalyzed by NCS or phosphate. Indeed, ap revious screen of Coptis japonica NCS (CjNCS2) had suggested that (1R,2S)-2-amino-1-(3-hydroxyphenyl)propan-1-ol (also referred to as metaraminol) was accepted as as ubstrate,a nd gave the corresponding product in low yield.…”

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Enzymatic and Chemoenzymatic Three‐Step Cascades for the Synthesis of Stereochemically Complementary Trisubstituted Tetrahydroisoquinolines

et al. 2017

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Chemoenzymatic and enzymatic cascade reactions enable the synthesis of complex stereocomplementary 1,3,4-trisubstituted tetrahydroisoquinolines (THIQs) with three chiral centers in as tep-efficient and selective manner without intermediate purification. The cascade employs inexpensive substrates (3-hydroxybenzaldehyde and pyruvate), and involves ac arboligation step,asubsequent transamination, and finally aP ictet-Spengler reaction with ac arbonyl cosubstrate.A ppropriate selection of the carboligase and transaminase enzymes enabled the biocatalytic formation of (1R,2S)-metaraminol. Subsequent cyclization catalyzed either enzymatically by an orcoclaurine synthase or chemically by phosphate resulted in opposite stereoselectivities in the products at the C1 position, thus providing access to both orientations of the THIQ C1 substituent. This highlights the importance of selecting from both chemo-and biocatalysts for optimal results.The tetrahydroisoquinoline (THIQ) moiety is a" privileged scaffold", [1] and as such, it is found in numerous bioactive natural products (e.g., noscapine, [2] dioncophyllines [3] )a nd synthetic pharmaceutical drugs (e.g., solifenacin [4] ). THIQcontaining compounds demonstrate aw ide range of bioactivities,i ncluding antitumor, [2] antiparasitic, [3] and anticholinergic [4] properties. Naturally derived THIQs may be obtained by extraction or fermentation, [5] but in many cases,only small quantities are available,typically as one component of amixture.Chemical syntheses are af requent source of these compounds,b ut complex multistep asymmetric routes that give high stereoselectivities can be challenging,i ncluding at scale,a nd are often dependent on the use of toxic or environmentally harmful chemicals.[6] Therefore,n ovel synthetic routes towards THIQs are of significant interest.In vitro biocatalysis provides av iable method of producing complex THIQs in high stereoselectivities and under mild conditions. [7][8][9] Previous studies have shown norcoclaurine synthase (NCS), the Pictet-Spenglerase from plant benzylisoquinoline alkaloid biosynthesis, [10,11] to be av ersatile biocatalyst. NCS can convert 3-hydroxyphenethylamines (e.g.,d opamine) and ac arbonyl cosubstrate into a( 1 S)-THIQ with high stereoselectivities. [12][13][14][15] Thee nzyme has demonstrated ar emarkably wide carbonyl cosubstrate tolerance,a ccepting av ariety of aldehydes and ketones. [13][14][15][16][17][18][19][20] NCS has also been successfully employed in chemoenzymatic cascades. [12,15,16,21] As an alternative to NCS,i norganic phosphate can be used to catalyze the Pictet-Spengler reaction (PSR), typically forming racemic THIQs under aqueous conditions. [22] This can be successfully combined with enzyme steps. [21] Modular biocatalytic cascades [23] for the stereoselective production of pharmaceutical compounds are exemplified by the work conducted on phenylpropanolamines. [24][25][26] All four possible isomers of nor(pseudo)ephedrine are available from simple starting materials by one-pot two-enzym...

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Efficient 2-step biocatalytic strategies for the synthesis of all nor(pseudo)ephedrine isomers

Abstract: All nor(pseudo)ephedrine isomers can be synthesized step-efficiently in two different 1-pot 2-step biocatalytic cascade reactions in high optical purities.

Cited by 77 publications

References 35 publications

Postmortem Distribution of Cathinone and Cathine in Human Biological Specimens in a Case of Death Associated with Khat Chewing

Postmortem Distribution of Cathinone and Cathine in Human Biological Specimens in a Case of Death Associated with Khat Chewing

Bootstrapped Biocatalysis: Biofilm‐Derived Materials as Reversibly Functionalizable Multienzyme Surfaces

Enzymatic and Chemoenzymatic Three‐Step Cascades for the Synthesis of Stereochemically Complementary Trisubstituted Tetrahydroisoquinolines

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