Dibenzopyrrocolines

Oxidation products from tetrahydropapaveroline with potassium ferricyanide were reinvestigated by Mak and Brossi 21), who confirmed structure 28 for the initial product. Air oxidation of 29 gave after acetylation a product with the same physical properties reported by Harley-Mason, but its mass spectrum showed a parent ion at m e 900 and molecular composition C48H40N2O16, suggesting it to be a dehydro dimer of 12. The H-NMR spectrum of the dimer showed that the double bonds at the 5,6 positions were intact. The point of dimerization was determined by comparing the multiplicities of carbons in the C-NMR spectra of the dimer and dibenzopyrrocoline models. For monomeric compounds the peak ascribed to C-12 in compound 11 was a triplet and a doublet in 12, but a singlet in the dimer. Thus, the products from oxidation of 28 had structures 31 and 32 rather than 29 and 30, respectively. 

The aromatic dibenzopyrrocoline dimer 33 was obtained by Hess etal. (22) by electrochemical oxidation of papaverine at a platinum anode in methanolic so-... 

Lead tetraacetate in acetic acid oxidizes phenolic 1-benzylisoquinolines to p-quinol acetates which usually rearrange to aporphines in trifluoroacetic acid (25). However, Blasko et al. (24) recently reported that lead tetraacetate oxidized ( )-A -norlaudanosine (34) to dibenzopyrrocoline 35 in 16% yield. 

Oxidative coupling of (5)-(-)-laudanosoline (5) with horseradish peroxidase in the presence of hydrogen peroxide, studied by Brossi et al. (27), afforded dibenzopyrrocoline (—)-6 in 81% yield, and conversion to (5)-(—)-0-meth-ylcryptaustoline (14) by methylation provided additional proof for the absolute configuration of this and related alkaloids. Enzyme specificity in the C— coupling reaction was demonstrated with similar oxidation of (/ )-(—)-laudanosoline methiodide, which afforded an aporphine converted by O-meth-ylation to (R)-(-)-glaucine. 

Dibenzopyrrocolines have been prepared by intramolecular addition of benzyne intermediates and by nucleophilic substitutions, as shown in Scheme 6 with the synthesis of ( )-cryptowoline (2) and the related dehydro base 39 by Bennington and Morin (7). ( )-6 -Bromotetrahydroisoquinoline 37, prepared by standard procedures, when heated with copper powder in dimethylformamide afforded dibenzopyrrocoline 38 in low yield, and 39 was formed when 37 was allowed to react with potassium amide in liquid ammonia. Compound 39 was converted to ( )-cryptowoline iodide (2) by hydrogenolysis of O-benzyl ether 39 and quartemization with methyl iodide. 

The benzyne route to dibenzopyrrocoline alkaloids with the 1-benzyltetrahy-droisoquinolines (40) listed in Table II was investigated by Kametani et al. (28), Kessar et al. (29), and Gibson and Ahmed (31). Secondary amines protected as 7-0-benzyl ethers, affording unstable tetrahydro intermediates with benzyl ether functions difficult to deprotect, were less favored than the corresponding N-methyl-substituted analogs, affording the desired quartemary alkaloids directly. 

When potassium amide, with added potassium metal in liquid ammonia, was substituted in the benzyne reaction, further cleavage of C—bonds of the intermediate dibenzopyrrocolines was often observed. The indoline 41 (32) and... 

The parent dibenzopyrrocoline 3 was prepared by von Braun and Nelles (37) from 1-benzylisoquinoline when heated with copper powder at elevated temperatures. The product obtained was a yellow, weakly basic solid, melting at 238°C and reduced to a tetrahydro derivative by tin and hydrochloric acid. However, no structure was assigned to this product. 

Ninomiya et al. (38) synthesized dibenzopyrrocolines by enamine pho-tocyclization. In model studies designed to determine the feasibility of the photochemical reaction, an ether solution of the enamine 44a was irradiated at room temperature, and tetrahydrodibenzopyrrocoline 45a and a dehydro derivative (46) were obtained in 10 and 20% yield, respectively. The more abundant compound 46 was reduced to 45a by tin and hydrochloric acid. 

Following the successful demonstration of an enamine photocyclization, Ninomiya synthesized ( )-cryptaustoline iodide from 44b. Irradiation of isopropyl ether 44b gave a mixture of dibenzopyrrocolines 45b and 45c in 12 and 11% yield, respectively. The isopropyl ether group in 45c was selectively hydrolyzed by hydrobromic acid, and the resulting phenolic compound was converted to cryptaustoline iodide with methyl iodide. An attempt to photocyclize an O-benzyl ether analog of 44b was less satisfactory. 

Members of the tetracyclic dibenzopyrrocoline alkaloid family can be prepared by the intramolecular ring closure of l-(o-halobcnzyl)-tetrahydroisoquinoline derivatives. (3.38.)47 The analogous transformation of dihydroisoquinolines (3.39.) proceeds probably through the isomeric enamine form obtained by the tautomeric shift of the double bond 48 The palladium-carbene catalyst system applied in these reactions was also effective in the preparation of indoline, indolizidine and pyrrolizidine derivatives 49... 

Aporphines synthesized via benzyne intermediates obtained from treatment of appropriately substituted 6-methoxy-7-hydroxy-2 -halo-N-methyltetrahydro-benzylisoquinolines with KNH2 in liquid ammonia include N-methylcaaverine (1-hydroxy-2-methoxyaporphine), thaliporphine and domestidne. The upper limit on the yields by this route appears to be 24%, a by-product being the corresponding dibenzopyrrocoline salt resulting from cyclization on nitrogen. ... 

---