Benzylisoquinoline alkaloids synthesis

Benzylamine, o-chloro-N-(cyanomethyl)-N-methyl-isoindole synthesis from, 4, 323 Benzylisoquinoline alkaloids synthesis, 1, 446 Benzynes... 

Whereas the Annonaceae are characterized primarily by benzylisoquinoline alkaloids, two pyrrolidine alkaloids have recently been found in species belonging to this family. Squamolone (29) was isolated from Annona squamosa L. by Chinese workers in 1962 (68). Despite careful spectroscopic investigation and a total synthesis (Eq. 1), squamolone was assigned the incorrect diazepine formula 30. The correct structural formula (29) was later established by an unambiguous synthesis of 30 (Eq. 2). Compounds 29 and 30 proved to have very similar spectroscopic properties, which could justify the early confusion (69). 

The synthesis of the basic skeleton of 1-benzylisoquinoline alkaloids has been reported by Uff et al. 15) starting from isoquinoline and benzyl chloride (Scheme 5). The preparation of Reissert compound iV-benzyl-l-cyano-l,2-di-hydroisoquinoline (4) was performed in a dichloromethane-water two-phase system with potassium cyanide and benzoyl chloride in about 64-69% yield. The deprotonation of 4 with sodium hydride in dimethylformamide solution, the subsequent alkylation with benzyl chloride, and the final alkaline hydrolysis could be performed as a one-pot reaction sequence to supply 1-benzylisoquinoline (25) in an overall yield of 75-84%. 

The mammalian alkaloids are formed from aromatic amino acids and their metabolically derived amines by reaction with carbonyl substrates at physiological pH. The reaction is catalyzed by acid and is commonly referred to as the Pictet-Spengler cyclization (I0a,b,II). Winterstein and Trier in 1910 proposed that the Pictet-Spengler reaction might be of significance in the biosynthesis of benzylisoquinoline alkaloids in plants (5a). The carbonyl compounds participating in the Pictet-Spengler synthesis of mammalian alkaloids are aldehydes and a-keto acids, which are produced... 

Of phenolic oxidations using vanadium compounds, intramolecular oxidative phenolcoupling reactions are quite attractive from the viewpoint of natural products synthesis. A number of benzylisoquinoline alkaloids, lignans and neolignans are well known to be produced, in a key step, by oxidative radical coupling of open phenolic precursors. 

Application of LTA-mediated hydroxylation to the synthesis of spiro-benzylisoquinoline alkaloids has been reported by Blasko et al. 128. 2,3,9-Trimethoxy- and 9-methoxy-2,3-methylenedioxy- IO-hydroxy-8-keto-spirobenzylisoquinolines (457 and 458) underwent acetoxylation at C-13 on treatment of LTA in AcOH to afford the corresponding 5yn-13-... 

One new benzylisoquinoline alkaloid, cinnamolaurine, obtained from Cin-namonium species, has recently been reported. It is l-(4-hydroxybenzyl)-6,7-methylenedioxy-2-methyltetrahydroisoquinoline, and its structure has been confirmed by synthesis. ... 

The following four new total syntheses of dimeric benzylisoquinoline alkaloids have been reported (—), (— )-00-dimethylcurine (288 R = Me),274 O-methyl-thalicberine (323 R = Me),275 ( )-0-methyltiliacorine (331),276 and ( )-obaberine (286 R1 = R2 = R3 = Me).277 The synthesis of O-methylthalic-berine, the first reported example of the bisbenzylisoquinoline alkaloids, is... 

The alkaloids of the narcotine type can also be synthesized from benz[d]indeno(l,2-f ]azepine (133a) (698) (Scheme 45). Moreover, compound 133a forms a key substance for the synthesis of the tetrahydro-protoberberine (58), protopine (101), rhoeadane (154), and spiroben-zylisoquinoline (191) ring skeletons. The compounds 133a and 133b arise also by rearrangement from the spirobenzylisoquinoline, protoberberine, and 1-benzoylisoquinoline skeletons. Therefore, it is assumed that even in the plants it plays a key role in the formation and interconversion of the benzylisoquinoline alkaloids with 17 carbon atoms in the skeleton (Scheme 45). 

Diphenyl selenoxide has been advocated for the oxidation of catechols to ortho-quinones in the synthesis of benzylisoquinoline alkaloids. ... 

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... 

The first chapter, by Barbosa-Filho, da-Cunha, and Gray, describes in great detail the tremendous volume of research that has been conducted in recent years on the alkaloids of the Menispermaceae, a family which produces a wide structural range of benzylisoquinoline alkaloids. The second chapter is a very special collaborative effort by three Japanese chemistry groups led by Somei, Murakami, and Ninomiya discussing the recent developments on the synthesis of the ergot alkaloids. Finally, Skaltsounis, Mitaku, and Tillequin discuss the diverse acridone alkaloids from the perspectives of their isolation, distribution, synthesis, and biological properties. 

Schrittwieser JH, Resch V, Wallner S, Lienhart W-D, Sattler JH, Resch J, Macheroux P, Rroutil W. Biocatal ftic organic synthesis of optically pure (S)-scoulerine and berbine and benzylisoquinoline alkaloids. J. Org. Chem. 2011 76 6703 6714. 

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 total synthesis of pavinane alkaloid platycerine (89) (Scheme 14) has been accomplished successfully (26) via 1-benzylisoquinoline derivative 91 obtained from Reissert intermediate 90. Quatemarization of 91 with methyl iodide followed by lithium aluminum hydride reduction supplied 1,2-dihydroisoquinoline 92, which on treatment with a 7 5 mixture of formic acid and phosphorous acid gave ( )-platycerine (89) in 60-70% yield. 

The synthesis of a number of bisbenzylisoquinoline alkaloids by direct dimerization of a phenolic benzylisoquinoline monomer is an extremely attractive... 

H. Guinaudeau, M. Leboeuf, and A. Cave, J. Nat. Prod. 42, 133 (1979). Dimeric aporphine-benzylisoquinoline and aporphine-pavine alkaloids. Tabulates physical properties, sources, and references to synthesis of 28 alkaloids. 

The benzylisoquinolines represent one of the largest group of plant alkaloids (146,147), and catecholic representatives occur in mammalian tissues and fluids. The best known is tetrahydropapaveroline, shown in Fig. 22 as the (5) enantiomer TIQ 75a. Racemic material is often referred to as THP (160,161). The synthesis of TIQ 75a as well as that of the plant alkaloid (5)-N -bisnorreticuline (77a) is shown in Fig. 22. (5)-Tetrahydropapaverine (74a), on treatment with concentrated hydroiodic acid at 125 C, afforded TIQ 75a, which was fully characterized as its hydrochloride (156). TIQ 77a, possibly an intermediate in the plant biosynthesis of (5)-norreticuline (78a) and derived TIQs, and possibly mammalian morphine as well, was prepared from the benzyl-protected TIQ 76a. Deblocking was achieved over Pd catalyst and hydrogen in the presence of hydrochloric acid, leading directly to the hydrochloride salt of TIQ 77a... 

Because benzylisoquinolines have been available synthetically (in racemic form) for decades, there is quite a bit of chemistry known regarding their use as key intermediates in the synthesis of a number of more complex isoquinoline alkaloids. The asymmetric synthesis of benzylisoquinolines has been used to complete total synthesis of representative members of several of these alkaloid classes. As shown in Figure 6, the protoberberine alkaloid norcoralydine, the aporphine alkaloid ocoteine, the isopavine alkaloid reframoline and the morphinan 0-methylflavinantine have been made available in optically active form for the first time (except by isolation or resolution) using this approach. 

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