Cleavamine

After the stmcture and absolute stereochemistry of cleavamine (111), C22H24N2, was estabUshed, its synthesis was shortly completed and impetus to unravel the stmcture of the dimeric bases (22) was bolstered (77). Again, the fragment, now only slightly modified from that originally present in secologanin (102), is readily seen in catharanthine (107). 

The key step in syntheses of if/-quebrachamine (122-127) and if/-dihydro-cleavamine (12S) is the oxidation of tertiary amines with mercuric acetate to cyclic imonium salts, which give rise to an intramolecular electrophilic attack on an indole. 

Extensive biotransformation studies have been conducted with the As-pidosperma alkaloid vindoline, but much less work has been done with monomeric Iboga and dimeric alkaloids from this plant. The long-standing interest in this group of compounds stems from the clinical importance of the dimeric alkaloids vincristine and vinblastine, both of which have been used for more than 2 decades in the treatment of cancer. Few mammalian metabolites of dimeric Catharanthus alkaloids have been characterized. Thus the potential role of alkaloid metabolism in mechanism of action or dose-limiting toxicities remains unknown. The fact that little information existed about the metabolic fate of representative Aspidosperma and Iboga alkaloids and Vinca dimers prompted detailed microbial, mammalian enzymatic, and chemical studies with such compounds as vindoline, cleavamine, catharanthine, and their derivatives. Patterns of metabolism observed with the monomeric alkaloids would be expected to occur with the dimeric compounds. 

Scheme 19. Oxidation of cleavamine by Polyporus anceps laccase. 

Cleavamine Intramolecular cyclization Polyporus anceps laccase 171... 

Cleavage products, 10 569 Cleavage reaction, in phenol manufacture, 25 749-750 Cleavage tests, 2 514 (+)-Cleavamine, 2 98 Clenbuterol, 23 14-15 Clentiazem, 5 121... 

A similar strategy was reported soon after by Atta-ur-Rahman for the synthesis of 16 -epianhydrovinblastine (Scheme 5) (27). Reductive cleavage of catharanthine (21) provided a mixture of epimeric carbomethoxy-cleavamines (22) which, without separation, was transformed to a mix-... 

While the coupling of vindoline to catharanthine N-oxide proceeds (particularly at low temperature) with high C-16 -C-14 PARF stereoselectivity, this result can be influenced by structural modifications which either increase the stability of the intermediate, cleavamine-derived cation... 

A similar sequence was used for generation and coupling of the indoloa-zacyclodecane 117, obtained from the tetrahydrocarbazole 118 (Scheme 32). Here, however, C-16 -C-14 PREF as well as PARF products (119) were produced in the chloroindoline alkene coupling reaction, while the corresponding nine-membered ring D-seco cleavamine gave only the PREF product (see also Scheme 7). 

A quantitive, spontaneous cyclization of the 16-carbomethoxy C-20-C-21 unsaturated cleavamine to coronaridine (HO) and the general failure of dehydrosecodine to serve as a synthetic precursor of catharanthine (see Ref. HI for literature review) suggest, however, that the Iboga alkaloids may be preferably assigned a biogenetic origin based on cleavamine cyclizations rather than on a dehydrosecodine. 

The final phase of our syntheses of vinblastine and analogous compounds required closure of the piperidine ring in the seco cleavamine part of the indole-indoline compounds 162 and 163. We had originally studied this reaction with the simple indolic C-16 and C-20 unsubstituted C-16 epimeric carbomethoxy seco cleavamines 164 and 165 and found that on cyclization they produced, through conformations 166 and 167, almost exclusively quaternary salts 168 and 169, which on debenzylation gave... 

When the corresponding seco cleavamines with a C-16 10-vindolinyl... 

The sensitivity of the three types of antimicrotubule activity by VBL to modification at a single site on the cleavamine moiety poses an obvious question Can the cleavamine moiety act alone to exert afunctional attack at this target The answer is no. The 20 -deoxy and epideoxy carbometh-... 

In the course of our synthetic efforts, we discovered a new, unnatural conformational isomer of the VBL piperidine ring (see Chapter 2, this volume, for details). This compound is inactive with the microtubule system in vitro and is poorly cytotoxic to cultured tumor cells (Fig. 5b). Therefore, the functional determinism of the C-20 position of VBL-like molecules mediates reactions, as yet unknown, that are dependent on the binary alkaloid structure and on the natural stereochemical configuration at C-16 and C-14 as well as on the conformation of the cleavamine moiety. 

Cyclodehydration. A key step in a recent synthesis of cleavamine (3) involves the cyclization of 1 to 2, which was accomplished with PPE. Cyclization with poly phosphoric acid gave 2 in 12% yield. This cyclization with PPE is unsuccessful with substrates lacking the Ai,5-double bond. 

The solution conformation of the azacyclononane ring in queb-rachamine [441], 16a-carbomethoxyquebrachamine [442], 16/ -carbo-methoxyquebrachamine [443], and related systems is of interest in view of its presence in the medicinally important alkaloids of the vincaleuko-blastine type. Conformations [444] and [445] have been assigned to [442] and [443] respectively, and cleavamine [446] has been shown to adopt a conformation analogous to [442]. In the 16/ -carbomethoxy series the difference in chemical shift between the C(21) methylene... 

A plot of the residual couplings (/R) of the C(16) methylene resonance of cleavamine [446] against the position of the decoupling... 

On the basis of their 13C n.m.r. spectra, and in particular on the similarity of the C-5 and C-6 resonances, the 7-chloroindolenine derivatives of the cleavamines and quebrachamines have been concluded to have the same stereochemistry at C-7 as voaphylline hydroxyindolenine, whose configuration is known 14,15-dehydroquebrachamine 7-chloroindolenine thus has the stereochemistry shown in (125).88... 

Reference has been made above to the determination of the stereochemistry at C-7 of cleavamine 7-chloroindolenine.88... 

Earlier investigations had shown that the coupling of 7-chloroindolenine derivatives of velbanamine, cleavamine, and their relatives invariably gives products having the undesired (16 R) configuration, presumably because the intermediate ion, e.g. (219), is attacked by nucleophile at its less hindered face. 

A new photochemical conditions with catalytic quantities of P-lapachone have been recently reported [140]. The P-lapachone acts as photosensitizer to promote selective C16-C21 bond cleavage of catharanthine (65) yielding 21a-cyano-16a-(methoxycarbonyl) cleavamine (66) quantitatively, Fig. (13). 

Catharanthine—Ibogamine-Cleavamine Group. Catharanthine is one of the alkaloids produced in suspension cultures of the 200 GW cell line of Catharanthus roseus, 2a and ibogamine has been found in the stem and root bark of Hazunta modesta var. modesta subvar. montana.62 Four Ervatamia species have been shown to contain several alkaloids of this group.64 Thus, E. orientalis (R. Brown) Domin contains voacangine, conopharyngine, pandine, and pandoline, E. daemeliana... 

New synthetic work in this area includes syntheses of desethyldihydro-cleavamine (desethylquebrachamine),119" 20crH- and 20/IH-dihydrocleavamine,1196 and cleavamine.119" Takano s route to the dihydrocleavamines119ft is essentially an adaptation of his earlier synthesis of quebrachamine,119d while the synthesis of (-t-)-cleavamine (254) by Imanishi et al. consists in essence of a brief route to the unsaturated keto-lactam (255), which affords ( )-cleavamine and a hydroxy-cleavamine (256) (major product) on reduction (Scheme 35).119c... 

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