1699-46-3Relevant academic research and scientific papers
The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet-Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids
Bartel, Karin,Bracher, Franz,Geisslinger, Franz,Keller, Marco,Sauvageot-Witzku, Karl,Schaefer, Michael,Urban, Nicole
, p. 2716 - 2725 (2022/01/12)
We present a systematic investigation on an improved variant of the N-acyl-Pictet-Spengler condensation for the synthesis of 1-benzyltetrahydroisoquinolines, based on our recently published synthesis of N-methylcoclaurine, exemplified by the total syntheses of 10 alkaloids in racemic form. Major advantages are a) using ω-methoxystyrenes as convenient alternatives to arylacetaldehydes, and b) using the ethoxycarbonyl residue for both activating the arylethylamine precursors for the cyclization reaction, and, as a significant extension, also as protective group for phenolic residues. After ring closure, the ethoxycarbonyl-protected phenols are deprotected simultaneously with the further processing of the carbamate group, either following route A (lithium alanate reduction) to give N-methylated phenolic products, or following route B (treatment with excess methyllithium) to give the corresponding alkaloids with free N-H function. This dual use of the ethoxycarbonyl group shortens the synthetic routes to hydroxylated 1-benzyltetrahydroisoquinolines significantly. Not surprisingly, these ten alkaloids did not show noteworthy effects on TPC2 cation channels and the tumor cell line VCR-R CEM, and did not exhibit P-glycoprotein blocking activity. But due to their free phenolic groups they can serve as valuable intermediates for novel derivatives addressing all of these targets, based on previous evidence for structure-activity relationships in this chemotype.
Organocatalytic Enantioselective Pictet-Spengler Approach to Biologically Relevant 1-Benzyl-1,2,3,4-Tetrahydroisoquinoline Alkaloids
Ruiz-Olalla, Andrea,Würdemann, Martien A.,Wanner, Martin J.,Ingemann, Steen,Van Maarseveen, Jan H.,Hiemstra, Henk
, p. 5125 - 5132 (2015/05/27)
(Figure Presented) A general procedure for the synthesis of 1-benzyl-1,2,3,4-tetrahydroisoquinolines was developed, based on organocatalytic, regio- and enantioselective Pictet-Spengler reactions (86-92% ee) of N-(o-nitrophenylsulfenyl)-2-arylethylamines with arylacetaldehydes. The presence of the o-nitrophenylsulfenyl group, together with the MOM-protection in the catechol part of the tetrahydroisoquinoline ring system, appeared to be a productive combination. To demonstrate the versatility of this approach, 10 biologically and pharmaceutically relevant alkaloids were prepared using (R)-TRIP as the chiral catalyst: (R)-norcoclaurine, (R)-coclaurine, (R)-norreticuline, (R)-reticuline, (R)-trimemetoquinol, (R)-armepavine, (R)-norprotosinomenine, (R)-protosinomenine, (R)-laudanosine, and (R)-5-methoxylaudanosine.
Deracemization by simultaneous bio-oxidative kinetic resolution and stereoinversion
Schrittwieser, Joerg H.,Groenendaal, Bas,Resch, Verena,Ghislieri, Diego,Wallner, Silvia,Fischereder, Eva-Maria,Fuchs, Elisabeth,Grischek, Barbara,Sattler, Johann H.,MacHeroux, Peter,Turner, Nicholas J.,Kroutil, Wolfgang
supporting information, p. 3731 - 3734 (2014/04/17)
Deracemization, that is, the transformation of a racemate into a single product enantiomer with theoretically 100-% conversion and 100-% ee, is an appealing but also challenging option for asymmetric synthesis. Herein a novel chemo-enzymatic deracemization concept by a cascade is described: the pathway involves two enantioselective oxidation steps and one non-stereoselective reduction step, enabling stereoinversion and a simultaneous kinetic resolution. The concept was exemplified for the transformation of rac-benzylisoquinolines to optically pure (S)-berbines. The racemic substrates were transformed to optically pure products (ee>97-%) with up to 98-% conversion and up to 88-% yield of isolated product. From two make one: Chemo-enzymatic stereoinversion and enzymatic kinetic resolution have been combined in a simultaneous cascade process to transform racemic substrates (A, ent-A) into optically pure product P. The concept was exemplified for benzylisoquinolines rac-1 yielding optically pure berbines (S)-2. The reaction system comprised a monoamine oxidase (MAO-N), morpholine-borane, and the berberine bridge enzyme (BBE).
Deracemisation of benzylisoquinoline alkaloids employing monoamine oxidase variants
Schrittwieser, Joerg H.,Groenendaal, Bas,Willies, Simon C.,Ghislieri, Diego,Rowles, Ian,Resch, Verena,Sattler, Johann H.,Fischereder, Eva-Maria,Grischek, Barbara,Lienhart, Wolf-Dieter,Turner, Nicholas J.,Kroutil, Wolfgang
, p. 3657 - 3664 (2015/02/05)
Chemo-enzymatic deracemisation was applied to obtain the (S)-enantiomer of 1-benzylisoquinolines from the racemate in high isolated yield (up to 85%) and excellent optical purity (ee > 97%). The one-pot deracemisation protocol encompassed enantioselective oxidation by a monoamine oxidase (MAO-N) and concomitant reduction of the resulting iminium species by ammonia-borane. The challenge was the oxidation at the sterically demanding chiral centre. Recently developed variants of MAO-N, featuring an enlarged active-site pocket, turned out to be suitable biocatalysts for these substrates. In contrast to previous MAO-N variants, which preferentially converted the (S)-enantiomer, the MAO-N variant D11 used in the present study was found to oxidise all tested benzylisoquinoline substrates with (R)-enantiopreference. The structural determinants of enantioselectivity were investigated by means of protein-ligand docking simulations. The applicability of the deracemisation system was demonstrated on preparative scale (150 mg) for three benzylisoquinoline alkaloids (natural as well as non-natural), including the hypotensive and antispasmodic agent (S)-reticuline.
Inverting the regioselectivity of the berberine bridge enzyme by employing customized fluorine-containing substrates
Resch, Verena,Lechner, Horst,Schrittwieser, Joerg H.,Wallner, Silvia,Gruber, Karl,MacHeroux, Peter,Kroutil, Wolfgang
, p. 13173 - 13179 (2013/01/15)
Fluorine is commonly applied in pharmaceuticals to block the degradation of bioactive compounds at a specific site of the molecule. Blocking of the reaction center of the enzyme-catalyzed ring closure of 1,2,3,4- tetrahydrobenzylisoquinolines by a fluoro moiety allowed redirecting the berberine bridge enzyme (BBE)-catalyzed transformation of these compounds to give the formation of an alternative regioisomeric product namely 11-hydroxy-functionalized tetrahydroprotoberberines instead of the commonly formed 9-hydroxy-functionalized products. Alternative strategies to change the regioselectivity of the enzyme, such as protein engineering, were not applicable in this special case due to missing substrate-enzyme interactions. Medium engineering, as another possible strategy, had clear influence on the regioselectivity of the reaction pathway, but did not lead to perfect selectivity. Thus, only substrate tuning by introducing a fluoro moiety at one potential reactive carbon center switched the reaction to the formation of exclusively one regioisomer with perfect enantioselectivity. Custom-made substrates: Employing customized substrates with a fluoro atom at the normally preferred reaction site switched the regioselectivity of the berberine-bridged enzyme. With this strategy, it was possible to get access to (S)-11-hydroxy-functionalized berbines in an asymmetric fashion by using the wild-type enzyme (see scheme). Copyright
Biocatalytic organic synthesis of optically pure (S)-scoulerine and berbine and benzylisoquinoline alkaloids
Schrittwieser, Joerg H.,Resch, Verena,Wallner, Silvia,Lienhart, Wolf-Dieter,Sattler, Johann H.,Resch, Jasmin,MacHeroux, Peter,Kroutil, Wolfgang
, p. 6703 - 6714 (2011/10/18)
A chemoenzymatic approach for the asymmetric total synthesis of the title compounds is described that employs an enantioselective oxidative C-C bond formation catalyzed by berberine bridge enzyme (BBE) in the asymmetric key step. This unique reaction yielded enantiomerically pure (R)-benzylisoquinoline derivatives and (S)-berbines such as the natural product (S)-scoulerine, a sedative and muscle relaxing agent. The racemic substrates rac-1 required for the biotransformation were prepared in 4-8 linear steps using either a Bischler-Napieralski cyclization or a C1-Cα alkylation approach. The chemoenzymatic synthesis was applied to the preparation of fourteen enantiomerically pure alkaloids, including the natural products (S)-scoulerine and (R)-reticuline, and gave overall yields of up to 20% over 5-9 linear steps.
Biotransformation of phenolic 1-benzyl-N-methyltetrahydroisoquinolines in plant cell cultures followed by LC/NMR, LC/MS, and LC/CD
Cui, Wenhua,Iwasa, Kinuko,Sugiura, Makiko,Takeuchi, Atsuko,Tode, Chisato,Nishiyama, Yumi,Moriyasu, Masataka,Tokuda, Harukuni,Takeda, Kazuyoshi
, p. 1771 - 1778 (2008/09/21)
(±)-1-Benzyl-N-methyltetrahydroisoquinolines 7-10 and 11-14 with one and two hydroxy groups on the aromatic rings, respectively, were fed individually to cultured cells of Corydalis and Macleaya species, respectively. The structures of the metabolites were determined by using combinatorial techniques, including LC/NMR, LC/MS-MS, and LC/CD. The enantiomeric excesses of the metabolites were derived from LC/CD and LC/MS-MS analyses. In cell cultures of Corydalis and Macleaya species, laudanine (7), with a hydroxy group at C-3′, can form the berberine bridge at C-2′ and C-6′ to produce S- and R-enantiomers of 2,3,9,10- and 2,3,10,11-oxygenated protoberberines (20 and 21), respectively, whereas reticuline (11) and protosinomenine (12), incoporating a hydroxy group at C-3′, form the berberine bridge at C-2′ to furnish the S-enantiomer of 2,3,9,10-oxygenated protoberberines (23 and 21), respectively.
Purification and characterization of coclaurine N-methyltransferase from cultured Coptis japonica cells
Choi, Kum-Boo,Morishige, Takashi,Sato, Fumihiko
, p. 649 - 655 (2007/10/03)
S-Adenosyl-L-methionine (SAM): coclaurine N-methyltransferase (CNMT), which catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to the amino group of the tetrahydrobenzylisoquinoline alkaloid coclaurine, was purified 340-fold from Coptis japonica cells in 1% yield to give an almost homogeneous protein. The purified enzyme, which occurred as a homotetramer with a native Mr of 160 kDa (gel-filtration chromatography) and a subunit Mr of 45 kDa (SDS-polyacrylamide gel electrophoresis), had an optimum pH of 7.0 and a pI of 4.2. Whereas (R)-coclaurine was the best substrate for enzyme activity, Coptis CNMT had broad substrate specificity and no stereospecificity; CNMT methylated norlaudanosoline, 6,7-dimethoxyl-1,2,3,4-tetrahydroisoquinoline and 1-methyl-6,7-dihydroxy-1,2,3,4,-tetrahydroisoquinoline. The enzyme did not require any metal ion. p-Chloromercuribenzoate and iodoacetamide did not inhibit CNMT activity, but the addition of Co2+, Cu2+ or Mn2+ at 5 mM severely inhibited such activity by 75, 47 and 57%, respectively. The substrate-saturation kinetics of CNMT for norreticuline and SAM were of the typical Michaelis-Menten-type with respective Km values of 0.38 and 0.65 mM.
PHELLODENDRINE ANALOGS AND ALLERGY TYPE IV SUPPRESSOR CONTAINING THE SAME AS ACTIVE INGREDIENT
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, (2008/06/13)
Phellodendrine analogs represented by general formula (I), wherein A represents the group (a); B represents hydrogen, lower alkyl or lower acyl, or alternatively A and B together with the adjacent nitrogen atom form a substituted 1,2,3,4-tetrahydroisoquinoline ring represented by general formula (II), R11, R12, R21, R22, R31 and R32 represent each hydrogen, hydroxyl or lower alkoxy; n1 represents a number of 0 to 2; n2 represents a number of 1 and 2; and m1 represents a number of 0 to 1, provided tsat when A represents the group (b), and n2 is 2, B is lower acyl, and that when A and B together form a substituted 1,2,3,4-tetrahydroisoquinoline ring, n1 is 1 and m1 is not 0. These analogs (I) and related compounds have an excellent activity of suppressing allergy type IV and hence are utilizable as a medicine efficacious against diseases wherein allergy type IV participates, such as chronic hepatitis, intractable asthma, nephrotic syndrome or rheumatism.
PURIFICATION AND PROPERTIES OF 1,2-DEHYDRORETICULINE REDUCTASE FROM PAPAVER SOMNIFERUM SEEDLINGS
De-Eknamkul, Wanchai,Zenk, Meinhart H.
, p. 813 - 822 (2007/10/02)
1,2-Dehydroreticuline reductase, the NADPH-dependent enzyme which reduces stereospecifically 1,2-dehydroreticuline to (R)-reticuline has been discovered in seedlings of the opium poppy (Papaver somniferum).The enzyme has been purified to apparent electrophoretic homogeneity by ammonium sulphate precipitation and five subsequent column chromatography steps.The isolated enzyme is a single polypeptide with Mr 30000 and has a pH optimum at 8.5 and a temperature optimum at 30 deg.The apparent Km values for 1,2-dehydroreticuline and NADPH are 10 and 7 μM, respectively.The enzyme mediates the transfer of the pro-S-hydride of NADPH to C-1 of 1,2-dehydroreticuline with high substrate specificity; neither 1,2-dehydrynorreticuline nor 1,2-dehydrococlaurine are utilized by the enzyme.The enzyme activity is inhibited by (S)- and (R)-reticuline with I50 values of 0.05 and 0.10 mM, respectively.The reductase is a cytosolic enzyme and present only in morphinan alkaloid-containing plants.This highly species-, substrate- and stereospecific enzyme catalyses the provision of (R)-reticuline for the formation of morphinan alkaloids that possess also (R)-configuration at that chiral centre. Key Word Index - Papaver somniferum; Papaveraceae; 1,2-dehydroreticuline; (R)-reticuline; 1,2-dehydroreticuline reductase; purification; characterization; alkaloid biosynthesis; morphinans.
