14752-49-9

Upstream product

• 21411-21-2 1,2-dehydroreticulinium iodide 
• 864-68-6 (R)-7-Benzyloxy-1-(3-benzyloxy-4-methoxy-benzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinoline 
• 133343-35-8 Acetic acid (R)-((S)-7-benzyloxy-4-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-(3-benzyloxy-4-methoxy-phenyl)-methyl ester 
• 133343-36-9 Acetic acid (R)-((S)-4-acetoxy-7-benzyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-(3-benzyloxy-4-methoxy-phenyl)-methyl ester 
• 133343-20-1 3,3'-Dibenzyloxy-4,4'-dimethoxystilben 
• 133343-22-3 (4R,5R)-4,5-Bis-(3-benzyloxy-4-methoxy-phenyl)-[1,3,2]dioxathiolane 2-oxide 
• 133343-26-7 (4R,5R)-4,5-Bis-(3-benzyloxy-4-methoxy-phenyl)-[1,3,2]dioxathiolane 2,2-dioxide 
• 133343-25-6 (S)-7-Benzyloxy-1-[(R)-(3-benzyloxy-4-methoxy-phenyl)-hydroxy-methyl]-6-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-ol 
• 133343-27-8 Acetic acid (1R,2S)-1,2-bis-(3-benzyloxy-4-methoxy-phenyl)-2-[(2,2-dimethoxy-ethyl)-methyl-amino]-ethyl ester 
• 140687-76-9 (1R,2R)-1,2-Bis-(3-benzyloxy-4-methoxy-phenyl)-ethane-1,2-diol 
• 133343-24-5 (1R,2S)-1,2-Bis-(3-benzyloxy-4-methoxy-phenyl)-2-[(2,2-dimethoxy-ethyl)-methyl-amino]-ethanol 
• 6346-05-0 3-benzyloxy-4-methoxybenzaldehyde 
• 621-59-0 isovanillin 
• 1131-94-8 homoisovanillic acid 

Downstream Products

• 4090-18-0 salutaridine 
• 74080-68-5 (R)-(-)-<2',6',8-3H3>reticuline 
• 56435-41-7 yenhusomine 
• 32728-75-9 cavidine 
• 524-46-9 (+)-adlumine 
• 3019-51-0 isoboldine 
• 517-56-6 corytuberine 

Relevant academic research and scientific papers

PURIFICATION AND PROPERTIES OF 1,2-DEHYDRORETICULINE REDUCTASE FROM PAPAVER SOMNIFERUM SEEDLINGS

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.

Organocatalytic Enantioselective Pictet-Spengler Approach to Biologically Relevant 1-Benzyl-1,2,3,4-Tetrahydroisoquinoline Alkaloids

(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

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

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

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

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.

ASYMMETRIC SYNTHESIS OF (R)-RETICULINE - A NEW STRATEGY FOR THE ASYMMETRIC SYNTHESIS OF ISOQUINOLINES VIA ENANTIOSELECTIVE EPOXIDATION OR DIHYDROXYLATION

A new strategy for the asymmetric synthesis of 1-benzyl-1,2,3,4-tetrahydroisoquinolines 7 - 9 has been developed.The route involves introduction of asymmetry via enantioselective epoxidation or dihydroxylation of corresponding stilbene precursors followed by aminolysis and Pomeranz-Fritsch cyclization.The strategy has been successfully applied to the asymmetric synthesis of (R)-reticuline (9), the key intermediate in the synthesis of morphine alkaloids on the biomimetic route.