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A biocatalytic redox cascade approach for one-pot deracemization of carboxyl-substituted tetrahydroisoquinolines by stereoinversion

Optically pure 1,2,3,4-tetrahydroisoquinoline carboxylic acids are important chiral building blocks in the pharmaceutical and fine chemical industries. However, the existing chemo-enzymatic deracemization method employing d-amino acid oxidase from Fusarium solani M-0718 (FsDAAO) suffers from the requirement for a large excess of a nonselective chemical reducing agent. To explore an alternative method, we envisaged a concurrent biocatalytic oxidation and reduction cascade in one pot. Herein, we report a novel biocatalytic route for the asymmetric reduction of 3,4-dihydroisoquinoline-1-carboxylic acids employing Delta1-piperidine-2-carboxylate/Delta1-pyrrolidine-2-carboxylate reductase from Pseudomonas putida KT2440 (PpDpkA) as a biocatalyst, yielding the corresponding (S)-1-carboxyl-substituted tetrahydroisoquinolines with high conversions and enantiomeric excess (>99% ee). By combining FsDAAO and PpDpkA in one pot, a fully biocatalytic method was demonstrated for the deracemization of a range of racemic 1-carboxyl substituted tetrahydroisoquinolines to produce the corresponding (S)-enantiomers with >99% conversions and >99% ee. Furthermore, preparative-scale biotransformation of racemic 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid gave the (S)-enantiomer with 89% isolated yield and >99% ee. Taken together, we provide an enantioselective biocatalytic redox cascade method for the one-pot synthesis of enantiopure 1,2,3,4-tetrahydroisoquinoline carboxylic acids.

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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CONFORMATIONAL AND BIOLOGICAL ANALYSIS OF &alpha-MSH FRAGMENT ANALOGUES WITH STERICALLY CONSTRAINED AMINO ACID RESIDUES

Conformational and biological analysis of the linear 4-11 fragment analogues, Ac--alpha-MSH4-11-NH2 (II) and Ac--alpha-MSH4-11-NH2 (III) and related analogues have been undertaken.In solution, the peptide backbone is flexible, but in the case of D-Phe7 analogues an interaction of the His6.D-Phe7 and Arg8 amino acid side chain groups may be present based on the shielding patterns observed in the proton NMR and on comparison of NT1 values.The importance of the position 7 to the biological and conformational properties was further examined by substitution of either L- or D-phenylglycine (Pgl) or L- and D-1,2,3,4-tetrahydroisoquinoline carboxylic acid (Tic) for phenylalanine-7.Ac--alpha-MSH4-11-NH2 (IV), Ac--alpha-MSH4-11-NH2 (V), Ac--alpha-MSH4-11-NH2 (VI), and Ac--alpha-MSH4-11-MH2 (VII) were prepared.These substituted analogues were examined for their biological activities and conformational properties with emphasis on the three-dimensional orientation of the aromatic ring in the position 7, and the effects of the aromatic ring on adjacent amino acids and on biological activities.The relative potencies of the analogues in the frog skin assay system were: II (1.00); III (118); IV (82.4); V (0.18); VI (0.18); and VII (0.14); and in the lizard skin bioassay they were: II (1.00); III (10.0); IV (0.14); V (0.005); VI (0.00025); and VII (0.01).On the basis of the NMR studies the L-phenylglycine substitution results in an enhanced ring stacking interaction between the phenyl ring of Pgl7 and the indole ring of Trp9.The 1,2,3,4-tetrahydroisoquinoline carboxylic acid (Tic) substitution leads to significant backbone restriction and an interaction of the alpha proton of His6 with the carbonyl of Glu5.The possible relationships of these effects to biological activity are discussed.

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Tetrahydroisoquinoline – Wikipedia,
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Extracurricular laboratory:new discovery of (S)-1,2,3,4-Tetrahydroisoquinoline-1-carboxylic acid

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SGC STIMULATORS

Compounds of Formulae (I’) and (I) are described, which are useful as stimulators of sGC, particularly NO-independent, heme-dependent stimulators. These compounds are also useful for treating, preventing or managing various disorders that are herein disclosed.

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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Lipase-catalyzed kinetic and dynamic kinetic resolution of 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

A dynamic kinetic resolution method for the preparation of enantiopure 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (R)-2 was developed involving the CAL-B-catalyzed enantioselective hydrolysis of the corresponding ethyl ester (¡À)-1 in toluene/acetonitrile (4:1) containing 1 equiv of added water and 0.25 equiv of dipropylamine. This method allowed the preparation of (R)-2 (ee = 96%) with 80% isolated yield. The kinetic resolution of (¡À)-1 in diisopropyl ether at 3 C afforded both enantiomers with ee ?92%.

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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In heterogeneous catalysis, the catalyst is in a different phase from the reactants. name: (S)-1,2,3,4-Tetrahydroisoquinoline-1-carboxylic acid, At least one of the reactants interacts with the solid surface in a physical process called adsorption in such a way. 151004-92-1, name is (S)-1,2,3,4-Tetrahydroisoquinoline-1-carboxylic acid. In an article£¬Which mentioned a new discovery about 151004-92-1

Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction

A high-throughput screen (HTS) of the MLPCN library using a homogenous fluorescence polarization assay identified a small molecule as a first-in-class direct inhibitor of Keap1-Nrf2 protein-protein interaction. The HTS hit has three chiral centers; a combination of flash and chiral chromatographic separation demonstrated that Keap1-binding activity resides predominantly in one stereoisomer (SRS)-5 designated as ML334 (LH601A), which is at least 100¡Á more potent than the other stereoisomers. The stereochemistry of the four cis isomers was assigned using X-ray crystallography and confirmed using stereospecific synthesis. (SRS)-5 is functionally active in both an ARE gene reporter assay and an Nrf2 nuclear translocation assay. The stereospecific nature of binding between (SRS)-5 and Keap1 as well as the preliminary but tractable structure-activity relationships support its use as a lead for our ongoing optimization.

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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Chemoenzymatic Approach to (S)-1,2,3,4-Tetrahydroisoquinoline Carboxylic Acids Employing D-Amino Acid Oxidase

Optically pure 1,2,3,4-tetrahydroisoquinoline carboxylic acids constitute an important class of building blocks for the synthesis of natural products and synthetic pharmaceuticals. However, redox deracemization of racemic 1,2,3,4-tetrahydroisoquinoline carboxylic acids as an attractive method is still challenging for the lack of suitable oxidoreductases. Herein, a D-amino acid oxidase from Fusarium solani M-0718 (FsDAAO) with broad substrate scope and excellent enantioselectivity was exploited through genome mining, and applied for the kinetic resolution of a number of racemic 1- and 3-carboxyl substituted tetrahydroisoquinolines to yield the corresponding (S)-enantiomers with excellent enantiomeric excess (ee) values (up to >99%). By using FsDAAO in combination with ammonia-borane in one pot, deracemization of these racemic carboxyl-substituted tetrahydroisoquinolines was achieved with conversions up to >98% and >99% ee. Preparative-scale deracemization of racemic 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid and 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid was also demonstrated with good isolated yields (82% and 73%, respectively) and ee>99%. Our study provides an effective method for the synthesis of enantiomeric pure 1,2,3,4-tetrahydroisoquinoline carboxylic acids. This method is expected to provide access to chiral carboxyl-substituted 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydro-ss-carbolines. (Figure presented.).

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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Substituted iminoacid derivatives, process for preparing them and their use as enzyme inhibitors

Bicyclic imino acids, particularly 2-carboxylic acid derivatives of azabicycloalkanes and process for preparing them. These compounds have therapeutical activity and may be used as medicines, particularly as cardiovascular and antihypertensive drugs in human or veterinary medicine.

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem