Cularine synthesis

Shimanouchi H, Sasada Y, Honda T, Kametani T (1973) Crystal and molecular structure and absolute stereochemistry of cularine methiodide. J Chem Soc Perkin 11 1226-1230 Shono T, Miyamoto T, Mizukami M, Hamaguchi H (1981) Electrojreductive synthesis of 1-(bromobenzyl)-isoquinoline derivatives and its application to cularine synthesis. Tetrahedron... 

Secocularine (228) and secocularidine (229) were synthesized by Hofmann degradation of the corresponding cularine and cularidine methiodides, respectively (181). Both secocularidine (229) and norsecocularine (230) were transformed to secocularine (228) by O- and N-methylation, respectively (181,182). Total synthesis of noyaine (231) was achieved by Ullmann condensation of 8-hydroxy-7-methoxy-2-methyltetrahydroisoquinoIine (232) with 6-bromoveratric acid methyl ester followed by oxidation of the intermediate 233 (183) (Scheme 35). 

Rodrigues,]. A. R. Abramovitch, R. A. de Sousa,]. D. F. Leiva, G. C. Diastereoselective Synthesis of Cularine Alkaloids via Enium Ions and an Easy Entry to Isoquinolines by Aza-Wittig Electrocyclic Ring Closure.]. Org. Chan. 2004, 69, 2920-2928. 

Jackson et al. (22) reported the biomimetic total synthesis of ( )-cularine (67) itself (Scheme 11). Benzyolation of isoquinoline 68 in the presence of potassium cyanide gave Reissert compound 69, the anion of which was alkylated with 3-benzyloxy-4-methoxybenzyl chloride, resulting in intermediate 70. After al-... 

In the reaction of the electroreduetively generated anion with substituted benzyl bromides, a bromine atom on the aromatic nucleus of the benzyl bromide is completely inert. This method has been used in the synthesis of cularine 59 40). 

The major application of the alkylation of Reissert compounds (2) via 26 to 27 and then hydrolysis to 28 has been in the field of alkaloid synthesis. Thus, the Reissert alkylation scheme has been used in the synthesis of amurensine and isoamurensine, caseadine methyl ether, cularine, - ... 

A synthesis of 7,8-dioxygenated isoquinolines (found in cularine alkaloids) requires o-metallation of the Af-protected -phenylethylamine. The primary amine is protected by reaction with two equivalents of trimethylsilyl chloride. Phenylhydroxylamine and the allenic nitrile (53.7) react in boiling ethanol over 48 h to give a high yield of 4-aminoquinoline—an important intermediate for the synthesis of some antimalarial drugs. 

C(14) or C(10)-to-nitrogen bonding arrangement. The position of the acetoxy-group in (316 R = Ac) and thus the hydroxy-group in cancentrine was determined by examination of their n.m.r. spectra and by n.o.e. measurements. Cancentrine is a unique dimeric alkaloid constructed from morphine and cularine subunits and represents a formidable challenge for biogenetic-type synthesis. 

A synthesis of ( + )-cularine (61) (mp 119°) by oxidative coupling of the diphenolic benzylisoquinoline (59) has been achieved. The oxidant was potassium ferricyanide in a two-phase system (8% ammonium acetate-chloroform) and gave the phenolic product (60) (mp 126°) in 7% yield. Methylation with diazomethane completed the synthesis. The compound 59 was prepared as its dibenzyl derivative by a mild variant of the Pomerantz-Fritsch synthesis 76). 

Synthesis of ( )-cularicine (114) by the established route uia (115) has been recorded. Details have appeared of synthetic studies on cularine, including the successful phenolic oxidative coupling route employing the new variant of the Pomerantz-Fritsch cyclization to obtain 8-benzyloxy-7-methoxy-isoquinoline and the Reissert method for introducing the benzyl substituent. ... 

Kametani et al. (544,545) and other workers (546-561) endeavored to carry out the synthesis of cularine alkaloids by phenolic oxidation (bio-genetic type of synthesis) of the corresponding derivatives of laudanosine. The paper (549) describes the synthesis of these bases via the 6-ethoxycar-bamido-3,4-dihydroisoquinolines, which were converted to 6-amino-isoquinoline. By Ullmann reaction it gives the compound 52 and ( )-cularine (51) (Scheme 18). Cularine-type alkaloids were also synthesized by the intramolecular Ullmann reaction of 7,8-disubstituted isoquinoline obtained by the usual Bischler-Napieralski reaction from the phenolic bromoamide (pathway a) (544, 548). However, in the papers referred to (557,558,561), the rings A, C, and D were formed first (pathway b), and only then was the ring formed during the synthesis of cularine. 

The ORD curve of the product of partial synthesis, the curve of the hydrogenolytic product 53, and the ORD curve of (S)-romneine or (5)-laudanosine were identical. Cularine was therefore assigned the (S) configuration, which was confirmed by X-ray analysis (563, 564). 

Furthermore, the following compounds were synthetically prepared racemic cheilanthifoline (58c) (47), kikemanine (58d) (129), canadine (58e), berberine (59a) (590, 614), tetrahydropalmatine (58g) (475), sinac-tine (58h), cavidine (68d) (616,617), nandinine (58i) (590, 614, 615), capaurine (58p) (618), capaurimine (58o) (128, 618a), xylopinine (60c) (610, 615, 619), O-methylcaseanadine (62b) (70, 620), thalictricavine (68b), and corydaline (68h) (615). Xylopinine (60c) and some other alkaloids were synthesized by benzoylation of 1-alkyl-3,4-dihydroisoquinolines followed by photocyclization. This method provides a useful route to the synthesis of other protoberberine alkaloids (619). It is also applicable to the synthesis of cularine (51) and spirobenzyltetrahydroisoquinoline alkaloids (188). Xylopinine was also synthesized from the corresponding enamide under benzyne reaction conditions (615). Kametani etal. summarized their findings on the synthesis of these alkaloids and described the formation of protoberberines by debenzylation and photolysis of tetrahydroisoquinolines (622, 623). The total stereospecific synthesis of racemic ophiocarpine (70a) from the 3,4-dihydroisoquinoline derivative by Mannich cyclization was also described (624). 

Sarcocapnine (14) was the first natural 7,4, 5 -substituted cularine alkaloid isolated 18). Its UV spectrum is independent of the pH of the solution. In the H-NMR spectrum, the presence of three methoxy groups (4.02, 3.82, and 3.82 ppm) reveals its nonphenolic nature. The two AB quartets account for the four aromatic protons and not only indicate the 4, 5 -substitution at the D ring but also readily differentiate the spectrum from that of the isomeric cularine (11). Total synthesis of 14 has already been described 39, 40). 

Secocularine (28), isolated as an amorphous substance (crystallized as perchlorate) shows a characteristic UV spectrum (220, 235, 296, and 320 nm). The substitution pattern has been established from the H-NMR spectrum, which shows two singlets (6.68 and 6.92 ppm) and an AB quartet with a normal ortho coupling constant (8.3 Hz) (25). Confirmation of the structure has been obtained by synthesis. Hofmann degradation of cularine methiodide (49) with refluxing sodium hydroxide solution produces material of unknown structure (52). The same reaction, when carried out with sodium ethoxide, gives an 83% yield of a mixture of compounds 50 and 28 (25). 

Two general approaches have been used for synthesis of cularines. One involves the formation of the diaryl ether linkage at the initial stages and subsequent formation of the B and C rings. The other approach begins with the synthesis of appropriately substituted benzylisoquinolines and reserves construction of the oxepine ring as the last step. 

The interesting approach developed by Kametani et al. (53, 54) for the synthesis of ( )-cularine (11) and ( )-cularimine (3) forms the tetracyclic system in a single step by cyclization of dicarboxylic acid 58 to key lactone 59 by poly-phosphoric acid. This has now been applied to a synthesis of phenolic cularidine... 

An alternative synthesis has been used by Jackson and co-workers to synthesize ( )-cularine (11) (62, 6J). Remarkable improvement in the synthesis of the required ( )-crassifoline (75) is obtained by alkylating the Reissert compound 74, easily prepared from 0-vanillin by a small modification of the Pomerantz-Fritsch cyclization. 

Taking advantage of the Reissert approach to the synthesis of 7,8-disubstituted benzylisoquinolines, followed by Ullmann cyclization, Castedo et al. have carried out convergent synthesis of several cularine alkaloids and obtained excellent yields (48). As depicted in Scheme 4, condensation of Reissert compound 74 with benzylchlorides 78 under phase-transfer conditions and hydrolysis gives benzylisoquinolines (79). N-Methylation, reduction, and deprotection give 80, which, after Ullmann reaction, produced the following alkaloids ( )-cularine (11) from 80a (91% yield), ( )-sarcocapnine (14) from 80b (86%), and O-methyl cularicine (81) from 80c (83%). 

Nucleophilic aromatic substitution, based on an intramolecular attack of the phenoxide ion in the benzyne intermediate 87 (generated by dimsyl sodium treatment of 86), has been used by Castedo et al. (66) in a versatile synthesis of cularine alkaloids. However, N-attack competes with 0-attack in all instances to give dibenzopyrrocoline derivates (88), together with tetradehydrocularines (89). The main value of this approach is the easy conversion of 89 to norcularines, by catalitic hydrogenation to cularines, by quatemization with methyl iodide fol-... 

The phenolic base cularicine has been prepared by a synthesis which closely parallels the original synthesis of cularine. However, variations in the scheme were introduced to accommodate the sensitivity of the required phenol protecting group to Lewis acid. ... 

Another synthesis (2) of cularine, specifically via cularimine, has also been reported. The dicarboxylic acid III, obtained by two different routes from isovanillin and veratraldehyde, was lactonized to IV (X = O) by heating with polyphosphoric acid this was convertible into the lactam IV (X = NH mp 216°) by treating with alcoholic ammonia. Reduction of the latter with lithium aluminum hydride followed by chromatography on alumina gave a base showing an IR-ketonic band. Clemmensen reduction generated d -cularimine (mp 128°) which was convertible into d(-cularine by methylation. 

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