Enzyme catalysed Pictet-Spengler formation of chiral 1,1’-disubstituted- and spiro-tetrahydroisoquinolines

Lichman, Benjamin R.; Zhao, Jianxiong; Hailes, Helen C.; Ward, John M.

doi:10.1038/ncomms14883

Cited by 78 publications

(115 citation statements)

References 44 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…Additionally, we added ascorbic acid as antioxidant or MeOH as additive to the EziG3 immobilized enzyme to see their influence the course of the reaction. Ascorbic acid has previously been used in NCS reactions to reduce problems due to the oxidation of dopamine or products …”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Library of Norcoclaurine Synthases and Their Immobilization for Biocatalytic Transformations

Lechner

Soriano

Poschner

et al. 2017

Biotechnology Journal

Self Cite

View full text Add to dashboard Cite

Norcoclaurine synthases (NCS), catalyzing a Pictet-Spengler reaction in plants as one of the first enzymes in the biosynthetic benzylisoquinoline pathway, are investigated for biocatalytic transformations. The library of NCS available is extended by two novel NCSs from Argemone mexicana (AmNCS1, AmNCS2) and one new NCS from Corydalis saxicola (CsNCS); furthermore, it is shown that the NCS from Papaver bracteatum (PbNCS) is a highly productive catalyst leading to the isoquinoline product with up to >99% e.e. Under certain conditions lyophilized whole Escherichia coli cells containing the various overexpressed NCS turned out to be suitable catalysts. The reaction using dopamine as substrate bears several challenges such as the spontaneous nonstereoselective background reaction and side reactions. The PbNCS enzyme is successfully immobilized on various carriers whereby EziG3 proved to be the best suited for biotransformations. Dopamine showed limited stability in solution resulting in the coating of the catalyst over time, which could be solved by the addition of ascorbic acid (e.g., 1 mg ml À1 ) as antioxidant.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Recently, the substrate scope of the NCS from Coptis japonica (CjNCS2) and from Thalictrum flavum (TfNCS) was elucidated and showed that a broad scope of aldehydes is accepted, while the number of possible amines is more restricted …”

Section: Introductionmentioning

confidence: 99%

Library of Norcoclaurine Synthases and Their Immobilization for Biocatalytic Transformations

Lechner

Soriano

Poschner

et al. 2017

Biotechnology Journal

Self Cite

View full text Add to dashboard Cite

show abstract

“…[5] Dopamine (2) is generated through ortho-hydroxylation and decarboxylation of l-tyrosine (4)b yatyrosine hydroxylase and DOPA decarboxylase (DODC), respectively.I nap arallel pathway, 4-HPAA (3)i sf ormed through the deamination of 4 to 4hydroxyphenylpyruvate by at yrosine aminotransferase,f ollowed by decarboxylation to 3 by a4-hydroxyphenylpyruvate decarboxylase. [7][8][9][10][11] X-ray crystallographic and modelling studies have also enhanced our mechanistic understanding. Recent reports using recombinant NCSs from Thalictrum flavum (TfNCS), Coptis japonica (CjNCS), and Papaver bracteatum (PbNCS) have highlighted their versatility in BIA and tetrahydroisoquinoline (THIA) synthesis using arange of aldehydes and several ketones.…”

mentioning

confidence: 99%

Design and Use of de novo Cascades for the Biosynthesis of New Benzylisoquinoline Alkaloids

et al. 2019

Self Cite

View full text Add to dashboard Cite

The benzylisoquinoline alkaloids (BIAs) are an important group of secondary metabolites from higher plants and have been reported to show significant biological activities. The production of BIAs through synthetic biology approaches provides ah igher-yielding strategy than traditional synthetic methods or isolation from plant material. However,t he reconstruction of BIA pathwaysi nm icroorganisms by combining heterologous enzymes can also give access to BIAs through cascade reactions.M ost importantly,n on-natural BIAs can be generated through such artificial pathways. In the current study,w ed escribe the use of tyrosinases and decarboxylases and combine these with atransaminase enzyme and norcoclaurine synthase for the efficient synthesis of several BIAs,including six non-natural alkaloids,incascades from ltyrosine and analogues.

show abstract

“…[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.…”

mentioning

confidence: 99%

“…In arecent study,this variant had also demonstrated increased conversion compared to the wild-type enzyme for reactions with dopamine and ketones. [18] Therefore, TfNCS-A79I was selected for apreparative (50 mmol) biotransformation reaction for product identification, using 4 and (1R,2S)-3 from ac ommercial source.T he THIQ product (1S,3S,4R)-1-benzyl-3-methyl-1,2,3,4-tetrahydroisoquinoline-4,6-diol (5)w as isolated in excellent yield (92 %, 5·HCl) and purity (de 99 %). Analysis by both HPLC on ac hiral stationary phase and two-dimen- With the isolated product 5 and analytical data for the isolated stereoisomer as well as asuitable separation method for all possible stereoisomers in hand (Section S3), the entire three-step three-enzyme cascade was demonstrated.…”

mentioning

confidence: 99%

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Enzyme catalysed Pictet-Spengler formation of chiral 1,1’-disubstituted- and spiro-tetrahydroisoquinolines

Cited by 78 publications

References 44 publications

Library of Norcoclaurine Synthases and Their Immobilization for Biocatalytic Transformations

Library of Norcoclaurine Synthases and Their Immobilization for Biocatalytic Transformations

Design and Use of de novo Cascades for the Biosynthesis of New Benzylisoquinoline Alkaloids

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

Contact Info

Product

Resources

About