Benzylisoquinoline-aporphine alkaloids

A survey of the H NMR spectra of the benzylisoquinoline-aporphine alkaloids [60]—[65] enables assignment of some of the methoxyl proton resonances. The lowest frequency methoxyl proton signals at ca. 8 3-58 are characteristic of a 7 -methoxyl function, and the 10-methoxyl protons are found to absorb to higher frequency of 8 3-90. (52) This latter shift is also shown in the spectrum of fetedine [66] the aromatic proton signals of which are completely resolved at 220 MHz. (53) In the... 

At least SO genera including some 7S species are known to be alkaloidal benzylisoquinolines, aporphines, berberines, and a variety of other N-containing compounds arc found throughout the family. Recent reviews of some of these constituents are available (Cave et al., 1989 Waterman, 1985 Zhong and Xie, 1988). The following record of positive alkaloid tests was obtained from 240 samples comprising 155 species. 

Barton and Cohen (48) were the first to suggest the seminal idea that dienones could be intermediates in the biosynthesis of aporphine alkaloids from benzylisoquinolines, since such dienones could rearrange to the aporphine nucleus either through a dienone-phenol or a dienol-benzene rearrangement as shown in the scheme on the following page. 

The interesting alkaloid hernandaline (XCVI), which is intermediate between aporphines and benzylisoquinoline-aporphine dimers has been found in the related H. ovigera L. (33b). 

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. 

Thalifaboramine is but one of over 16 new aporphine-benzylisoquinoline dimeric alkaloids that have been isolated from Thalictrum faberi Ulbr., and the crude basic fraction, as well as most of the new alkaloids, including thalifaboramine (79), have demonstrated cytotoxic effects against the P-388 carcinoma cell [133],... 

Thalifarazine (10), C40H4iOlN2 (682.3254), [a]D +72° (c 0.06, MeOH), was isolated along with eleven other aporphine-benzylisoquinoline dimeric alkaloids from an extract (EtOH) of the whole plant of T. cultratum Wall, in 1986 [2,4], The UV spectrum of this phenolic alkaloid was similar to those of other aporphine-benzylisoquinoline dimers and displayed maxima at 228 nm (log e 4.70), 270 (shX4.29), 283 (4.38), 297 (shX4.25), and 310 (shX4.02)while the CD spectrum... 

The antimicrobial activity of aporphine alkaloids in general has been tested and oxoaporphines were the most active [108]. Some of these alkaloids are found to be toxic for mammalian cells in tissue cultures [109]. In another study of antimicrobial activity of fourteen benzylisoquinoline alkaloids, two oxoaporphines isolated from species of South American Menispermaceae, lysicamine (10) and O-methylmoschatoline (homomoschatoline) (11), had activity against cocci and gram positive bacilli, including Mycobacterium phlei [110]. 

New alkaloids reported in the period under review include thalsimidine, which is 5-0-desmethylthalsimine, from Thalictrum simplex, espinine (45 R = H) and espinidine (45 R = Me), from Berberis laurina penduline, which is an optical isomer of pycnamine, from Cocculus pendulus," coclobine (46), from Cocculus trilobus, and the mixed benzylisoquinoline-aporphine base... 

Alternative approaches to aporphine alkaloids using benzyne intermediates have been reported.113-118 For example, treatment of the readily available bromo-benzylisoquinoline derivative (98 X = Br, Y = H) with potassium amide gave the corresponding amino-compound (98 X = H, Y = NH2), which upon... 

In an eady attempt to understand the genesis of alkaloids from amino acids it was postulated (56) that intramolecular phenolic coupling should lead from benzylisoquinoline bases such as laudanosine (77, R = CH3), before it was completely methylated, to aporphine bases such as isothebaine (81). For example, between a benzylisoquinoline derived from laudanosoline (77, R = H), such as orientaline (82), and an aporphine alkaloid such as isothebaine (81), there should be a proaporphine alkaloid such as orientalinone (83) (56). The isolation of 83 lent credence to the hypothesis. Indeed, the fragile nature of 83 (it readily undeigoes the dienone—phenol rearrangement on acid treatment) required unusual skill in obtaining it from total plant extract. 

Shortly after Barton and Cohen 30, 31, 35) and Erdtman and Wacht-naeister (137) put forward the hypothesis that the cyclohexadienone compounds, which are formed by phenolic oxidation (26, 38, 40,154, 275, 353, 445) from the corresponding benzylisoquinoline bases, are the precursors of the aporphine alkaloids, these structures were recognized in some known alkaloids (mecambrine) or they were isolated. At present we know a large number of proaporphinesf (100) (Tables Va-Vc). Many of... 

The reduction with borohydride and the acid-catalyzed dienone-phenol/dienol-benzene rearrangements leave the center of chirality at C-6a intact. Consequently, the absolute configuration of this center can be intercorrelated with that of the benzylisoquinoline, proaporphine, and aporphine alkaloids (Schemes 1, 2, and 20). 

In practice a particular aporphine alkaloid may be derived a priori from a number of diphenolic benzylisoquinoline precursors either by direct coupling or through the genesis of a dienone intermediate as seen above. Thus in the study of the superficially simple alkaloid boldine (79), a number of benzylisoquinoline precursors had to be tested. Experiments were carried out with labelled samples of ( )-norprotosinomenine (83), ( )-nororientaline (84), ( )-4 -o-methyl-... 

The term aporphinoids covers aporphines and their close biogenetic precursors, the proaporphines. Alkaloids derived from relatively straightforward biological transformations of proaporphines or of aporphines are also encompassed, so that proaporphine-benzylisoquinolines, aporphine-benzylisoquinolines, aporphine-pavines, oxoaporphines, dioxoaporphines, aristolactams, and aristolochic acids, as well as phenanthrenes, will be discussed. Azafluoranthenes are also included within the scope of aporphinoids for reasons which will become clear toward the end of the present chapter. 

Further studies of the synthesis of the aporphine alkaloids were carried out to find simpler procedures and to increase the yields. The most frequently applied methods are the Bischler-Napieralski reaction (91, 408, 408a, 449, 450), the Pschorr cyclization (451, 452), and the photocy-clization of various benzylisoquinoline precursors (416a, 453,454) (Scheme 10). 

Spectrophotometric studies of two types of aporphine alkaloid and of benzylisoquinolines isolated from Peumus boldus have been published. ... 

The aporphine alkaloids (I) are derivable from the benzylisoquinolines by the abstraction of two hydrogens in such a manner that the two benzene nuclei now form part of a 9,10-dihydrophenanthrene. Since the bio-... 

Species belonging to the section Stenocraspedontae are characterized by the presence of benzylisoquinoline alkaloids, for example, E. oregana Greene contains escholamine (33) as the major alkaloid. Eschscholtzia lobbii Greene appears to be exceptional since neither pavine nor benzylisoquinoline alkaloids have been detected therein. The presence of aporphine alkaloids is characteristic for all the species. 

New investigation of bisbenzylisoquinoline biosynthesis is welcome (see ref. 32 also this Report, p. 16). Although aporphine alkaloids are the simplest developments of the benzylisoquinoline skeleton, their biosynthesis need not, as several examples show, be simple. It has, however, been found that the biosynthesis of boldine and isocorydine is straightforward. Further detail has been repor-ted on the biosynthesis of Erythrina alkaloids, which were established to be modified benzylisoquinolines some time ago. Further detail on the biosynthesis of morphine (23) and related alkaloids continues to be published. Of particular R. B. Herbert, in ref. 9, p. 11. 

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