Reticuline synthesis

An enzyme-catalyzed appHcation has been used to prepare the enantiomers of hydroxy-substituted tetrahydroisoquinolines (160). The synthesis of ( V)-reticuline [485-19-8] (30) has been reported using similar methodology (161). The substitution of formic acid and paraformaldehyde in this method leads to lower reaction temperatures, freedom from hydrolysis of protective groups, and improved yields (162). 

A concise total synthesis of (7 )-Reticuline has been reported using the Pomeranz-... 

Reticuline (38), one of the most important intermediates in the biosynthesis of opium alkaloids, has been synthesized in racemic form (Scheme 7) (78). 6-Methoxy-7-benzyloxyisoquinoline (39), prepared from O-benzylisovanillin via a modified Pomeranz-Fritsch isoquinoline synthesis, was treated with benzoyl chloride and potassium cyanide to obtain Reissert compound 40. Alkylation of the anion generated from 40 with 3-benzyloxy-4-methoxybenzyl chloride gave the corresponding 1-substituted Reissert compound 41 which was hydrolyzed in alkaline medium to 1-benzylisoquinoline derivative 42. Quatemarization of 42 with methyl iodide followed by sodium borohydride reduction and debenzylation led to ( )-reticuline (38) in about 25% overall yield from 39. 

The isolation of the cDNAs encoding the enzymes involved in diverse isoquinoline alkaloid formation in plants and microorganisms allowed the first metabolic engineering routes to be developed and paved the way for new ways of future production of isoquinoline alkaloids. For instance, transgenic opium poppy plants were created in which codeinone reductase was suppressed by RNAi, resulting in the substitution of morphine synthesis with the non-narcotic precursor reticuline [110]. In a similar approach, RNAi suppression or overexpression of salutaridinol 1-0-acetyltransferase in opium poppy led to accumulation of salutaridine or increase of morphine, codeine and thebaine content [111], suppression of the BBE led to accumulation of berberine in California poppy cells [112],... 

Bischler-Napieralsky synthesis of the benzylisoquinoline (39), iV-formylation, cyclization, and oxidation has given the pentamethoxy-compound (40), identical with glabrine dimethyl ether and glabrinine methyl ether.114 Reticuline N-oxide has... 

The oxidation of the nor-reticuline derivatives (40a) and (40b), using a variety of tetraethylammonium diacyloxyiodates as oxidizing agents, supplied good yields of the norisoboldines (41a) and (41b).46a This marks the first recorded use of diacyliodates for the synthesis of aporphines. 

A more recent attempt<34) to improve yields at the phenolic oxidation stage of the Barton synthesis rested on the argument that species such as hypervalent iodine(35) offered milder reaction conditions because the iodine (III <= I) redox is closer to the potential required for the reticuline-salutaridine transformation. A range of aryliodosobistrifluoracetates was used, with the... 

Is (/ )-reticuline, which is required for the synthesis of morphine in plants (272,273) and formed from the (5 )-enantiomer in benzyliso-quinoline-producing plants (274) by an oxidation-reduction sequence (257), also the crucial intermediate in the biosynthesis of mammalian morphine Confirmation that it is must await its detection. Conversion of... 

With the assumption that reticulines are also precursors in mammalian synthesis of morphine, it was challenging to investigate whether they could be produced by enzymatic reactions similar to those utilized in benzylisoquinoline-producing plants (274). This plan focused attention on reactions controlled by the enzyme catechol 0-methyltransferase (COMT), using 5-adenosyl-L-methionine (SAM) for the methylation reaction. Mammalian COMT is present in mammalian tissues, particularly the liver, and an enzyme preparation from rat liver was used for the experiments. It was found that (S)-norcoclaurine, which is the first isoquinoline produced in benzylisoquinoline-producing plants, was similarly O-methylated in vitro by SAM in the presence of COMT, and a reverse proportion of methylated products was obtained with the (/ )-enantiomer (277). Similar 0-methylation of (5)-4 -demethylreticuline (3 -hydroxy-N-methylcoclaurine), prepared by total synthesis (162), however, afforded almost exclusively (5)-orientaline, with a methoxy group at C-3 and not at C-4 as in (5)-reticuline (Fig. 37) (762). 

High enantioselectivity is also possible in these reactions by using an optically active amidine, readily available from (S)-valinol. A recent synthesis of ( -)-reticuline made degant use of this chiral intermediate (equation 26). ° Likewise, (-)-yohimbone was prepared in 98% enantiomaic excess using these reactions. ... 

The first synthesis ever reported of the alkaloid isoboldine (XXVIII) has also been achieved, Reticuline (LXI) was oxidized at —10° with ferricyanide anion to give a 0.5% yield of the alkaloid. Even the bromo-reticuline LXII upon phenolic oxidative coupling afforded isoboldine in an improved yield of 2.5% rather than the expected bromocorytuberine LXIII 20). 

Synthetic applications of AD which have already appeared and which are of potential industrial interest include the synthesis of propranolol (9) [48], diltiazem (10) [49], carnitine, and 4-amino-3-hydroxybutyric acid (11) [50], azole anti-fungals (12) [51], chloramphenicol (13) [52], reticuline intermediates (14) [53], camptothecin analogs (15) [54], khellactone (16) derivatives [55], taxol C-13 side chain (17) [56], halosarin [64], dehydro- xo-brevicomin [65], and antimalar-ial active cyclopenteno-l,2,4-trioxanes [57], as summarized in Figure 4. 

A synthesis of (R)-reticuline included a comparison of epoxide and cyclic sulfate chemistry (Scheme 3.31) [345]. 

Sz ntay et al. [36) succeeded in a biomimetic synthesis of ( )-salutari-dine (52) in 2.7% overall yield from ( )-reticuline (51) with the aid of LTA oxidation conducted in CH2CI2 in the presence of trichloroacetic acid, with ( )-isoboldine (35) also being formed (Scheme 7). Since morphinan-dienone 52 (65) is an important precursor to morphine, the above synthesis is quite interesting in spite of the low yield. 

If it is difficult to spot where a product results from a dihydroxylation because there is only one oxygen in the product then it must be even more difficult to spot when there are none. Reticuline 117 is a natural product which can be used in the synthesis of morphine 116. 

The disconnection we used to plan the synthesis of reticuline is rather unusual. Reticuline is often drawn in a way 117b that is rotated clockwise by 60° from the way drawn above 117a. The disconnections are more often a C-C disconnection between the aromatic ring and an imine resembling the Mannich reaction as the imine is formed by the attack of an amine 125 on an aldehyde 126. This is an easy reaction to carry out but it forms two bonds and a chiral centre all in one step and is difficult to make asymmetric. Because we wanted to use AD, we needed a different disconnection. 

An improved synthesis of polyhydroxybenzylisoquinolines without protection of the hydroxy-groups has been reported, in which Bischler-Napieralsky ring closure of the appropriate amide is achieved with phosphorus oxychloride in acetonitrile coclaurine, isococlaurine, and reticuline, as well as a key intermediate in the synthesis of multifloramine, have been prepared in this way. 

Bischler-Napieralski and Pictet Spengler reactions continue to serve well for benzylisoquinoline syntheses.76,77 In the latter reaction, use of a-formylphenyl-acetic esters for the non-nitrogen-containing component appears to be advantageous.77 An interesting sequence of reactions (43)—>—>(44) (Scheme 4) has apparently been applied to the synthesis of papaverine [44 R = 3,4-(MeO)2-C6H3CH2 ] and related alkaloids.78 An attempt to convert ( )-reticuline (37 R = H) into a morphinandienone-type alkaloid by enzymic oxidation with... 

The major alkaloids of the bark of species T.O.H., 13077, were identified as (+ )-l-(4-hydroxylbenzyl)-6,7-methylenedioxy-l,2,3,4-tet-rahydroisoquinoline (noroinnamolaurine), (— )-cinnamolaurine, ( + )-reticuline, and + )-corydine. The structure of noroinnamolaurine was elucidated by spectroscopic methods and confirmed by conversion into cinnamolaurine and by a synthesis of its racemate (49). 

Eventual biosynthetic postulations and revelations have led several groups over the years to approach the synthesis of morphine as does Nature, choosing to adopt a biomimetic phenolic oxidative coupling as the key step. Unfortunately, the in vitro oxidation of reticuline derivatives to salutaridines tends to proceed with poor regiocontrol and in low yield, despite employment of a variety of novel reagents. This of course... 

Studies aimed at the synthesis of morphine. 3. Synthesis of (,+-.)-salutaridine via phenolic oxidative coupling of (.+-.)-reticuline... 

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