Facile one-pot synthesis of tetrahydroisoquinolines from amino acids via hypochlorite-mediated decarboxylation and Pictet–Spengler condensation

Maresh, Justin J.; Crowe, Sean O.; Ralko, Arthur; Aparece, Mark D.; Murphy, Casey M.; Krzeszowiec, Mark; Mullowney, Michael W.

doi:10.1016/j.tetlet.2014.07.043

Cited by 46 publications

(52 citation statements)

References 25 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 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%

mentioning

confidence: 99%

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

et al. 2017

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“…Minor side products were also formed;these are believed to be the ortho-cyclized products 1-(2-bromophenyl)-3-methyl-1,2,3,4-tetra-hydroisoquinoline-4,8-diol (< 4%,see Sections S3.5 and 4.3;validated by GC-TOF-MS, HPLC,a nd NMR analysis by correlation to the non-cascade KPi reaction products). [16] Overall, the conversion of the cascade from 1 to (1S,3S,4R)-7 was 77 %, based on the substrate depletion of each step.Again, the final ic value was excellent (> 97 %). Thee nzymatic synthesis of the opposite stereoisomer (1R,3S,4R)-7 was not possible as the NCS enzymes screened did not accept the sterically demanding aldehyde 2-bromobenzaldehyde as as ubstrate.…”

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confidence: 94%

“…[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%

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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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Chemo‐Enzymatic Cascade Reactions for the Synthesis of Chiral Intermediates and Nonaromatic Nitrogen Heterocycles

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et al. 2022

More Synthetic Approaches to Nonaromatic Nitrogen Heterocycles

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Facile one-pot synthesis of tetrahydroisoquinolines from amino acids via hypochlorite-mediated decarboxylation and Pictet–Spengler condensation

Cited by 46 publications

References 25 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

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

Chemo‐Enzymatic Cascade Reactions for the Synthesis of Chiral Intermediates and Nonaromatic Nitrogen Heterocycles

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