Novel strategies for catalytic asymmetric synthesis of C1-chiral 1,2,3,4-tetrahydroisoquinolines and 3,4-dihydrotetrahydroisoquinolines

Liu, Wangsheng; Li, Shasha; Jin, Ronghua; Guo, Hao; Zhao, Jinbo

doi:10.1039/c4qo00294f

Cited by 80 publications

(31 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, to our knowledge, there are no general methods for stereoselective chemical PSRs with ketones. Importantly, efficient routes to chiral 1,1′-disubstituted THIQs remain a significant unsolved challenge within synthetic chemistry8.…”

mentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

mentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The reductive cyclization was performed with benzylamine in the presence of NaBH(OAc) 3 as the reducing agent (Scheme 11). [53] This method was extended and further optimized for the preparation of 7-hydroxymethyl-3,4,5-trihydroxyazepane (76). The route, starting from a protected cyclohexenetriol, included only three steps: ozonolysis, reductive amination, and deprotection (Scheme 12).…”

Section: Transformation Of Dialdehyde Derivatives Into Functionalizedmentioning

confidence: 99%

“…Several drugs, such as some antidiuretics, antidepressants, hallucinogens and antihypertensive agents, contain a THIQ motif. [74][75][76][77][78][79] Because of these relevant properties, many synthetic approaches towards the creation of an isoquinoline or THIQ core have been described so far. [80][81][82][83][84][85][86][87] The well-known procedures are the Pictet-Spengler, Bischer-Napieralski, and Pomeranz-Fritsch-Bobbit cyclizations, which are widely-applied synthetic methodologies to create a number of important isoquinoline alkaloids.…”

Section: Synthesis Of Fluorine-containing 1234-tetrahydro-isoquinomentioning

confidence: 99%

Stereocontrolled Synthesis of Functionalized Azaheterocycles from Carbocycles through Oxidative Ring Opening/Reductive Ring Closing Protocols

Kiss

Ouchakour

Ábrahámi

et al. 2019

The Chemical Record

View full text Add to dashboard Cite

Fluorine‐containing organic scaffolds are of significant interest in medicinal chemistry. The incorporation of fluorine into biomolecules can lead to remarkable changes in their physical, chemical, and biological properties. There are already many drugs on the market, which contain at least one fluorine atom. Saturated functionalized azaheterocycles as bioactive substances have gained increasing attention in pharmaceutical chemistry. Due to the high biorelevance of organofluorine molecules and the importance of N‐heterocyclic compounds, selective stereocontrolled procedures to the access of new fluorine‐containing saturated N‐heterocycles are considered to be a hot research topic. This account summarizes the synthesis of functionalized and fluorine‐containing saturated azaheterocycles starting from functionalized cycloalkenes and based on oxidative ring cleavage of diol intermediates followed by ring expansion with reductive amination.

show abstract

“…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.…”

mentioning

confidence: 99%

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

et al. 2017

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

Novel strategies for catalytic asymmetric synthesis of C1-chiral 1,2,3,4-tetrahydroisoquinolines and 3,4-dihydrotetrahydroisoquinolines

Abstract: This review summarizes recent progress in catalytic asymmetric construction of 1,2,3,4-tetrahydroisoquinolines and 3,4-dihydroisoquinolines, among the most important “privileged scaffolds”.

Cited by 80 publications

References 78 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

Stereocontrolled Synthesis of Functionalized Azaheterocycles from Carbocycles through Oxidative Ring Opening/Reductive Ring Closing Protocols

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

Contact Info

Product

Resources

About