Abstract
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.
Highlights
The Pictet–Spengler reaction (PSR) involves the condensation and ring closure between a b-arylethylamine and a carbonyl compound
Compounds containing a-tertiary amines are typically challenging to synthesise[2], and the use of unactivated ketones in the Pictet–Spengler reaction has been limited by their low reactivity and steric bulk
We have discovered that Thalictrum flavum norcoclaurine synthase (NCS) (TfNCS), the Pictet–Spenglerase involved in benzylisoquinoline alkaloid biosynthesis, can accept a wide range of unactivated ketones in vitro in high yields
Summary
The Pictet–Spengler reaction (PSR) involves the condensation and ring closure between a b-arylethylamine and a carbonyl compound. We have discovered that norcoclaurine synthase from Thalictrum flavum (TfNCS) can catalyse the PSR between dopamine and unactivated ketones, facilitating the facile biocatalytic generation of 1,10-disubstituted THIQs. Variants of TfNCS showing improved conversions have been identified and used to synthesize novel chiral 1,10-disubstituted and spiro-THIQs. Enzyme catalysed PSRs with unactivated ketones are unprecedented, and, there are no equivalent stereoselective chemical methods for these transformations. Ketones can be employed in PSRs to yield 1,10-disubstituted tetrahydroisoquinolines (THIQs), which feature a nitrogen substituted quaternary center (a-tertiary amine) Such structures are the basis of several natural products and pharmaceutical compounds including the Erythrina alkaloids and FR115427 (Fig. 1). We have discovered that Thalictrum flavum NCS (TfNCS), the Pictet–Spenglerase involved in benzylisoquinoline alkaloid biosynthesis, can accept a wide range of unactivated ketones in vitro in high yields. We have identified TfNCS variants with improved ketone tolerance and used these enzymes for the facile biocatalytic formation of novel chiral 1,10-disubstituted- and spiro-THIQs
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