- A biocatalytic redox cascade approach for one-pot deracemization of carboxyl-substituted tetrahydroisoquinolines by stereoinversion
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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 Δ1-piperidine-2-carboxylate/Δ1-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.
- Ju, Shuyun,Qian, Mingxin,Li, Jing,Xu, Gang,Yang, Lirong,Wu, Jianping
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- Chemoenzymatic Approach to (S)-1,2,3,4-Tetrahydroisoquinoline Carboxylic Acids Employing D-Amino Acid Oxidase
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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-?-carbolines. (Figure presented.).
- Ju, Shuyun,Qian, Mingxin,Xu, Gang,Yang, Lirong,Wu, Jianping
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supporting information
p. 3191 - 3199
(2019/05/15)
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- Lipase-catalyzed kinetic and dynamic kinetic resolution of 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid
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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 (±)-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 (±)-1 in diisopropyl ether at 3 °C afforded both enantiomers with ee ≥92%.
- Paal, Tihamer A.,Forro, Eniko,Liljeblad, Arto,Kanerva, Liisa T.,Fueloep, Ferenc
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p. 1428 - 1433
(2008/02/10)
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- SUBSTITUTED TETRAHYDROISOCHINOLINES USED IN THE FORM OF MMP INHIBITORS, METHOD FOR THE PRODUCTION AND USE THEREOF IN THE FORM OF DRAGS
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The invention relates to compounds of formula (I), wherein R1, R2, R3, R4, A, n and L have the significances indicated in the description. The use of the inventive compounds in the form of drags for preventing and/or treating diseases in which progression an active reinforced matrix-metalloproteinases take part is also disclosed.
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Page/Page column p. 36; 51
(2010/02/15)
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- Substituted iminoacid derivatives, process for preparing them and their use as enzyme inhibitors
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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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