Phosphate mediated biomimetic synthesis of tetrahydroisoquinoline alkaloids

Pesnot, Thomas; Gershater, Markus; Ward, John M.; Hailes, Helen C.

doi:10.1039/c0cc05282e

Cited by 85 publications

(136 citation statements)

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“…Changing the buffer from phosphate to HEPES removed most of the background chemical reaction 11 generally leading to an increase in product formation (Table 2). However, at lower concentrations of 2a (20 mM) the use of 20% v.v −1 CV2025 lysate, rather than 30%, was optimal.…”

Section: Resultsmentioning

confidence: 97%

One-pot triangular chemoenzymatic cascades for the syntheses of chiral alkaloids from dopamine

et al. 2015

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Section: Resultsmentioning

confidence: 97%

One-pot triangular chemoenzymatic cascades for the syntheses of chiral alkaloids from dopamine

et al. 2015

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“…Racemic (2a) was prepared as described by Pesnot et al 13) Dopamine-HCl (194 mg, 1.0 mmol) and 1-butylaldehyde (111 mg, 1.5 mmol) were added to 1.94 mL of 100 mM potassium phosphate buffer (pH 6.5) and stirred for 2 h at 40°C. The reaction products were then extracted with 1-butanol (2 × 4 mL), and the extracts were dehydrated with sodium sulfate.…”

Section: Preparation Of 3-(4-trifluoromethylphenyl)-1-propylaldehyde mentioning

confidence: 99%

Asymmetric synthesis of tetrahydroisoquinolines by enzymatic Pictet–Spengler reaction

Nishihachijo

Hirai

Kawano

et al. 2014

Bioscience, Biotechnology, and Biochemistry

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Norcoclaurine synthase (NCS) catalyzes the stereoselective Pictet–Spengler reaction between dopamine and 4-hydroxyphenylacetaldehyde as the first step of benzylisoquinoline alkaloid synthesis in plants. Recent studies suggested that NCS shows relatively relaxed substrate specificity toward aldehydes, and thus, the enzyme can serve as a tool to synthesize unnatural, optically active tetrahydroisoquinolines. In this study, using an N-terminally truncated NCS from Coptis japonica expressed in Escherichia coli, we examined the aldehyde substrate specificity of the enzyme. Herein, we demonstrate the versatility of the enzyme by synthesizing 6,7-dihydroxy-1-phenethyl-1,2,3,4-tetrahydroisoquinoline and 6,7-dihydroxy-1-propyl-1,2,3,4-tetrahydroisoquinoline in molar yields of 86.0 and 99.6% and in enantiomer excess of 95.3 and 98.0%, respectively. The results revealed the enzyme is a promising catalyst that functions to stereoselectively produce various 1-substituted-1,2,3,4-tetrahydroisoquinolines.

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“…[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.…”

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confidence: 99%

“…[22] In the initial screening with (1R,2S)-3 and 4 (which was selected for the three-step enzyme cascade), phosphate catalysis was observed to give rise to three products (Section S3.4), where one of the minor products was (1S,3S,4R)-5.T op robe the stereoselectivity of the phosphate-catalyzed PSR, various other aldehydes were examined. Anumber of carbonyl cosubstrates were screened, and the product selectivities were monitored (Section S7).…”

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confidence: 99%

“…Avital feature of 3 is the presence of the meta-hydroxy group,which is mechanistically required for both the mild phosphatecatalyzed and the enzyme-catalyzed PSR. [22,31] Thec arbonyl cosubstrate phenylacetaldehyde (4)w as selected as ar epresentative aldehyde for the proof-of-principle reactions using NCSs.N CS wild-type enzymes from Coptis japonica and Thalictrum flavum and available variants were screened against 3 and 4,and the formation of products was monitored by HPLC analysis (see the Supporting Information, Section S6 for details). Thev ariant TfNCS-A79I was found to produce the largest quantity of product.…”

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confidence: 99%

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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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Phosphate mediated biomimetic synthesis of tetrahydroisoquinoline alkaloids

Abstract: A one-pot synthesis of tetrahydroisoquinoline alkaloids in a phosphate buffer has been achieved, and a reaction mechanism proposed. The utilisation of mild reaction conditions readily afforded a range of isoquinolines, including norcoclaurine.

Cited by 85 publications

References 33 publications

One-pot triangular chemoenzymatic cascades for the syntheses of chiral alkaloids from dopamine

One-pot triangular chemoenzymatic cascades for the syntheses of chiral alkaloids from dopamine

Asymmetric synthesis of tetrahydroisoquinolines by enzymatic Pictet–Spengler reaction

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

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