Asymmetric synthesis of tetrahydroisoquinolines by enzymatic Pictet–Spengler reaction

Nishihachijo, Masakatsu; Hirai, Yoshinori; Kawano, Shohei; Nishiyama, Akira; Minami, Hiromichi; Katayama, Takane; Yasohara, Yoshihiko; Sato, Fumihiko; Kumagai, Hidehiko

doi:10.1080/09168451.2014.890039

Cited by 60 publications

(78 citation statements)

References 23 publications

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“…Encouraged by the wide aldehyde substrate scope demonstrated by NCSs2728293031, we investigated their ability to accept ketones as substrates (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…The mechanism of phosphate catalysis and NCS enzymatic catalysis must therefore differ. Furthermore, the enzymatic ketone activity does not appear to have fully co-evolved with aldehyde reactivity, as demonstrated by poor Cj NCS2 conversion of ketones compared to Tf NCS, whereas both of these enzymes show good conversions of a range of aldehydes2728293031. It is not known whether in vivo conditions in plant vacuoles, where NCS has been shown to reside11, are conducive to activity with ketones, or whether this activity is only revealed in vitro .…”

Section: Discussionmentioning

confidence: 99%

“…The plant enzymes have a central role in engineered microbial systems for the production of alkaloids1819202122. Furthermore, the wide substrate promiscuity of these enzymes has led to their use in biocatalytic syntheses, but the carbonyl substrates employed have always been aldehydes23242526272829303132. The only example of a Pictet–Spenglerase accepting non-aldehyde carbonyl substrates was the report of a norcoclaurine synthase (NCS) from Coptis japonica ( Cj NCS2, also known as Cj PR10A) turning over 4-hydroxyphenylpyruvate and pyruvic acid, activated α-keto acids10.…”

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confidence: 99%

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

et al. 2017

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The Pictet–Spengler reaction (PSR) involves the condensation and ring closure between a β-arylethylamine and a carbonyl compound. The combination of dopamine and ketones in a PSR leads to the formation of 1,1′-disubstituted tetrahydroisoquinolines (THIQs), structures that are challenging to synthesize and yet are present in a number of bioactive natural products and synthetic pharmaceuticals. Here we have discovered that norcoclaurine synthase from Thalictrum flavum (TfNCS) can catalyse the PSR between dopamine and unactivated ketones, thus facilitating the facile biocatalytic generation of 1,1′-disubstituted THIQs. Variants of TfNCS showing improved conversions have been identified and used to synthesize novel chiral 1,1′-disubstituted and spiro-THIQs. Enzyme catalysed PSRs with unactivated ketones are unprecedented, and, furthermore, there are no equivalent stereoselective chemical methods for these transformations. This discovery advances the utility of enzymes for the generation of diverse THIQs in vitro and in vivo.

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“…Encouraged by the wide aldehyde substrate scope demonstrated by NCSs2728293031, we investigated their ability to accept ketones as substrates (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2017

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“…The stereoselective activity of NCS has prompted applications of the enzyme in both in vitro biocatalysis151617 and in vivo metabolic engineering for the purpose of synthesizing high-value BIAs18192021222324. However, measured kinetic parameters for NCS suggest an enzyme that is catalytically inefficient67142526.…”

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confidence: 99%

Genes encoding norcoclaurine synthase occur as tandem fusions in the Papaveraceae

Lee

Chang

et al. 2016

Sci Rep

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Norcoclaurine synthase (NCS) catalyzes the enantioselective Pictet-Spengler condensation of dopamine and 4-hydroxyphenylacetaldehyde as the first step in benzylisoquinoline alkaloid (BIA) biosynthesis. NCS orthologs in available transcriptome databases were screened for variants that might improve the low yield of BIAs in engineered microorganisms. Databases for 21 BIA-producing species from four plant families yielded 33 assembled contigs with homology to characterized NCS genes. Predicted translation products generated from nine contigs consisted of two to five sequential repeats, each containing most of the sequence found in single-domain enzymes. Assembled contigs containing tandem domain repeats were detected only in members of the Papaveraceae family, including opium poppy (Papaver somniferum). Fourteen cDNAs were generated from 10 species, five of which encoded NCS orthologs with repeated domains. Functional analysis of corresponding recombinant proteins yielded six active NCS enzymes, including four containing either two, three or four repeated catalytic domains. Truncation of the first 25 N-terminal amino acids from the remaining polypeptides revealed two additional enzymes. Multiple catalytic domains correlated with a proportional increase in catalytic efficiency. Expression of NCS genes in Saccharomyces cereviseae also produced active enzymes. The metabolic conversion capacity of engineered yeast positively correlated with the number of repeated domains.

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“…[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.…”

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confidence: 99%

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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Asymmetric synthesis of tetrahydroisoquinolines by enzymatic Pictet–Spengler reaction

Cited by 60 publications

References 23 publications

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

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

Genes encoding norcoclaurine synthase occur as tandem fusions in the Papaveraceae

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

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