Cularine alkaloids synthesis

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. 

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. 

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. 

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). 

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-... 

Suau, R., Rico-Gomez, R., Souto-Bachiller, F.A., Rodriguez-Rodriguez, L.A., and Ruiz, M.L., Efficient photoinduced electron transfer in papaverine N-oxide regioselective intramolecular hydroxylation of papaverine as an alternative disconnection for the synthesis of cularine alkaloids. 

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. 

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). 

Bhacca NS, Craig JC, Manske RHF, Roy SK, Shamma M, Slusarchyk WA (1966) The configuration and conformation of cularine. Tetrahedron 22 1467-1475 Birch AJ, Jackson AH, Shanon PVR, Stewart GW (1975) Phenol oxidation. Part IV. Synthesis and novel ring opening of spirocyclic dienones related to the benzylisoquinoline alkaloid cularine, J. Chem Soc Perkin 1 2492-2501... 

Jackson AH, Stewart GW, Charnock GA, Martin JA (1974) Phenol oxidation, part III. Synthesis of the benzylisoquinoline alkaloid cularine. J Chem Soc Perkin 1 1911-1920 Kametani T, Fukumoto K (1963) Cularine and related compounds Part VI. A total synthesis of ( )-cuJiarine. J Chem Soc 4289-4 296... 

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