Biocatalytic asymmetric formation of tetrahydro-β-carbolines

Bernhardt, Peter; Usera, Aimee; O’Connor, Sarah E.

doi:10.1016/j.tetlet.2010.06.075

Cited by 45 publications

(32 citation statements)

References 20 publications

(7 reference statements)

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“…Notably, a range of achiral aldehydes are accepted by the enzyme, which can now be utilized to form highly enantioenriched tetrahydro-b-carbolines (ee > 98 %). [39] Table 1 summarizes the amine components tested for conversion into strictosidines in the presence of N-terminal His 6 -tagged STR1, thus illustrating the variety of strictosidines that are now enzymatically available by using the Pictet-Spenglerase. These strictosidines appear to be applicable in further synthetic or chemoenzymatic approaches.…”

Section: Substrate Specificity Of Str1mentioning

confidence: 99%

The Pictet–Spengler Reaction in Nature and in Organic Chemistry

et al. 2011

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Alkaloids are an important class of natural products that are widely distributed in nature and produced by a large variety of organisms. They have a wide spectrum of biological activity and for many years were used in folk medicine. These days, alkaloids also have numerous applications in medicine as therapeutic agents. The importance of these natural products in inspiring drug discovery programs is proven and, therefore, their continued synthesis is of significant interest. The condensation discovered by Pictet and Spengler is the most important method for the synthesis of alkaloid scaffolds. The power of this synthesis method has been convincingly proven in the construction of stereochemicaly and structurally complex alkaloids.

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Section: Substrate Specificity Of Str1mentioning

confidence: 99%

The Pictet–Spengler Reaction in Nature and in Organic Chemistry

et al. 2011

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“…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%

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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“…We failed to detect any product for enzymatic reactions utilizing the native aldehyde substrate 4-HPAA ( 4 ) and the commercially available phenethylamines 41 – 44 (Scheme 1). Tryptamine ( 45 ), the natural substrate of strictosidine synthase, the Pictet-Spenglerase that catalyzes formation of tetrahydro-β-carbolines, 15 was also not turned over. Overall, this substrate specificity is consistent with earlier mechanistic studies of NCS.…”

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confidence: 99%