Oxidation, bisbenzylisoquinolines

Tetrandine-2 -N-a-oxide (bisbenzylisoquinoline) Stephania tetrandra (Menispermaceae) ACE [70]... 

The title compounds, isolated from Berberis buxifolia Lam. (Berberidaceae), are the most recently reported of the eight known bisbenzylisoquinoline /V-oxide alkaloids. They are noteworthy in being the first N-oxides of this group to have their complete stereochemistry assigned by NMR NOEDS studies (see Section VI,A,2,b). Unfortunately, the first report (59) was based on an incorrect assignment due to overlap of the NMe and aliphatic signals of calafatine (88, Section... 

In contrast, reaction of tertiary bisbenzylisoquinolines with common oxidants leads first to an enamine (not necessarily isolable), which is easily cleaved to an... 

Ceric ammonium nitrate appears to be a valuable reagent for dehydrogenation of bisbenzylisoquinoline alkaloids. For example, oxidation of tetrandrine (48) with 8 mol of this reagent in buffered HOAc, followed by NaBH4 reduction of the intermediate imine 381, gave a 95% yield of diamine 382, as well as the crystalline diol 383. Similarly successful results were obtained with heman-dezine (24a) and O-methylmicranthine (384), the latter demonstrating that this procedure is compatible with secondary amino groups. Berbamine (364),... 

The first elucidation of the nitrogen stereochemistry of a bisbenzylisoquinoline N-oxide alkaloid (see calafatine N-oxides, Section H,C,10) was made possible by NOEDS. A procedure was developed that systematically interconnects all protons, allowing complete structure determination (54). A previous attempt to prove the stereochemistry of the epimeric calafatine N-oxides had given an erroneous result due to inadequate decoupling data (59). 

Ultraviolet (UV) spectrophotometry has been a valuable tool in bisbenzylisoquinoline alkaloid research. One example is its use in the identification of a newly isolated sample of pennsylvanine (317). In order to rule out the isomer, thalidoxine (429a), the alkaloid was oxidized (as its O-acetate) and the resulting 430 was examined by UV spectrophotometry under neutral and basic conditions. The data unequivocally confirmed structure 430, and hence 317 for the alkaloid (209). 

All bisbenzylisoquinoline alkaloids from Berberidaceae have either (1/ , l S) or (IS, 1 R) configurations. The extra oxygen function of the C ring of thalibrun-ine (Section II,A,4), calafatine (Section II,C,9), and related alkaloids apparently arises from secondary oxidation ortho or para to the diphenyl ether linkage (57). A scheme for the biosynthesis of pakistanine (see Section II,C,52), kalashine (Section II,C,52), and related alkaloids from either a pakistanamine (Section II,B,6) or valdiberine (Section II,C, 142) precursor has been suggested (62) (see Section II,C,52). 

On the basis of in vitro oxidation of simple benzylisoquinoline quaternary salts with Oz/Cu+, it was proposed that secobisbenzylisoquinoline alkaloids could be derived by singlet oxygen oxidation of bisbenzylisoquinolines, specifically, bal-... 

Among the species of Stephania, the presence of bisbenzylisoquinoline alkaloids in Stephania suberosa Forman has been confirmed. Five new bisbenzylisoquinoline alkaloids have been isolated from the tuberous roots of Stephania suberosa. In addition to the known (+)-cepharanthine (16, R = Me), which was isolated as the major alkaloid in this plant, the new alkaloids are characterized as (+)-2-norcepharanthine (16, R = H), (+)-cepharanthine 2 -/3-Af-oxide (17), (+)-stephasubine (18), (+)-norstephasubine (19), and stephasubimine (20) (18). The last three compounds are relatively rare examples of bisbenzylisoquinolines incorporating an aromatic isoquinoline moiety. 

Barton and Cohen 10) and Erdtman and Wachtmeister 11) have related the concept of free radical coupling of phenols to the biogenesis of natural products, and suggested that bisbenzylisoquinoline alkaloids are formed by this reaction from benzylisoquinoline units. The mechanism of the reaction consists of generation of the resonance-stabilized phenoxy free radical by one-electron oxidation of the phenoxy anion, followed by coupling and tautomerization to form hydroxylated diphenyls or diphenyl ethers. Intermolecular coupling may involve any... 

The only bisbenzylisoquinoline alkaloids whose structures preclude the simple oxidative pairing mode of synthesis are those containing three diphenyl ether linkages (trilobine, isotrilobine, menisarine, normenis-arine, and micranthine). However, Barton and Cohen (10) have proposed a mechanism for the formation of the dibenzo-p-dioxin system of these alkaloids which comprises phenoxy free-radical coupling with a subsequent migration reaction. 

Hydroxythalidasine-2a-Ar-Oxide (94), C39H4409N2 (684.3046), [a]D -11° (c 0.4, MeOH), was isolated as an amorphous solid along with eight other bisbenzylisoquinoline alkaloids from... 

Oxidation of bisbenzylisoquinoline alkaloids with potassium permanganate has been found to be controllable enough to permit fission of only one of the two benzylisoquinoline systems. In this way the O-acetyl derivatives of the isomeric alkaloids tiliacorine and dinklacorine have been oxidised to the aldehydo-isoquinolones (67, R =Me, R =Ac) and (67, R =Ac,R =Me) respectively (Shamma and J.E. Foy, J.org.Chem., 1976, 1293 ... 

Products of such oxidative fission of bisbenzylisoquinolines with one, two and three diphenyl ether linkages have been found to be natural products forming a small sub-group of secobisbenzylisoquinoline alkaloids. Those so far identified are karakoramine (68), jhelumine (69, R=H), chenabine (69, R=Me), sindamine (70), punjabine (73, R =H, R =CH0) and gilgi-tine (73, R =H, R =C00Me), isolated from Berberis lycium (J.E. Leet et al.. Heterocycles, 1982, J9, 2355 1983, 425),... 

These structures have been deduced from spectroscopic data and confirmed by the preparation of key alkaloids by the oxidation of known bisbenzylisoquinolines and by interconversions. Baluchistanamine and sindamine have been obtained by oxidation of the isomeric alkaloids oxyacanthine and berbamine, secocepharanthine from cepharanthine and 0-methylpunjabine from... 

This could occur to provide a free hydroxy-group necessary for phenol oxidative coupling within a bisbenzylisoquinoline precursor. This would mean that isoboldine (44) is not a normal intermediate in the biosynthesis of thalicarpine (41). 

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