Of quebrachamine

An efficient synthesis of ( )-quebrachamine is based on the construction of a suitable precursor via ring cleavage of an a-diketone monothioketal (810) (80JCS(P1)457). This monothioketal, available from 4-ethoxycarbonylcyclohexanone ethylene ketal, was fragmented to the dithianyl half ester (811) with sodium hydride in the presence of water. Reaction of (811) with tryptamine and DCC provided an amide which was converted to the stereoisomeric lactams (812) on hydrolysis of the dithiane function. Reduction of either the a- or /3-ethyl isomer with lithium aluminum hydride followed by conversion of the derived amino alcohol to its mesylate produced the amorphous quaternary salt (813). On reduction with sodium in liquid ammonia, the isomeric salts provided ( )-quebrachamine (814 Scheme 190). 

Full details of the syntheses93" of quebrachamine and tabersonine by Takano et al. have now been published.936... 

The first enantioselective synthesis94 of (+)-quebrachamine (146) has also been contributed by Takano s group, and in principle is an elegant adaptation of the Kutney route, the required aldehydo-acid (147) [with (5) configuration at the future C-20] being prepared from the lactone (148), itself obtained from l-glutamic acid. Alkylation of the anions from both (148) and (149) proceeded... 

The X-ray crystal structure determination of quebrachamine reveals that the conformation adopted by the molecule is one in which the lone electrons on Nb are sterically shielded by other atoms if this conformation is preferred in solution, the reluctance of quebrachamine to form quaternary salts is explained.114 This conclusion agrees with that derived from 13C n.m.r. spectroscopy,us which in turn is consistent with deductions made earlier on the basis of 3H n.m.r. spectroscopy. 

A summary of Takano s recent synthesis of ( )-quebrachamine (200), mentioned in last year s Report,22h is now accessible.122 The critical stages leading to a mixture of (206) and its epimer are outlined in Scheme 20 the remaining stages were carried out according to established methods. 

New synthetic work in this area includes a description of the synthesis of dihydrocleavamine122 and an ingenious, brief synthesis of desethylibogamine.138 Takano s synthesis of ( )-20aH-dihydrocleavamine (231) involves an appropriate modification of the synthesis of ( )-quebrachamine, reported simultaneously. The essential starting material (232) was converted into (231) by the route outlined for the synthesis of quebrachamine in Scheme 20. 

The known pentacyclic lactam (219), prepared from 2-hydroxytryptamine and dimethyl 4-ethyl-4-formylpimelate, has been used in an improved synthesis of ( )-quebrachamine.106a Conversion of (219) into the thiolactam, acetylation to (220), desulphurization, and hydrolysis yielded 1,2-dehydroaspidospermidine (221), which on reduction gave ( )-quebrachamine (222) (Scheme 31). A new synthesis of the tetracyclic amino-alcohols (223) constitutes another formal synthesis of quebrachamine.1066... 

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... 

Figure 8 shows the analytical base-line separation of quebrachamine antipodes by inclusion chromatography on B-cyclodextrin polymers. 

Figure 8. Baseline resolution of (+)-quebrachamine (2 mg) and (-)-quebrachamine (2 mg) on 6-cyclodextrin polymer (1.6x85 cm, pH 6.8 phosphate buffer, flow rate 50 ml/h, 20 °C).

Reduction of cleavamine gave a dihydro derivative, mp 136°-138°, which is a C-ethyl isomer of quebrachamine, and, in fact, their IR-spectra... 

The Vinca minor alkaloids vincadine (II-A) and vincaminoreine (II-B) are the 3-carbomethoxy- and 3-carbomethoxy-Aa-methyl derivatives, respectively, of ( + )-quebrachamine (10a). The same plant also contains ( + )-indolic-A-methylquebrachamine (10b). 

The determination of the structure of quebrachamine (I) followed on that of aspidospermine (II), and was indeed suggested at the time that this latter structure was published (11, 12, 13, 14). In work prior to this, Witkop and his co.-workers were able to show that the two alkaloids were related, since both gave on zinc dust distillation a mixture from which... 

An examination of the NMR-spectrum of quebrachamine (I) (17) showed the absence of an a-hydrogen on the indole nucleus and confirmed the absence of an V-methy] group. 

Mass Spectra of Quebrachamine (I), 17-Methoxyquebrachamine (VIII), and 19-Deuterio-17-Methoxyquebrachamine (19d-VIII)... 

The total synthesis of ( + )-quebrachamine has been achieved by a modification of the route used for the synthesis of aspidospermine (Section II,C ref. 27a). Condensation of the intermediate XXX-J with phenyl hydrazine gave dl-IX which on borohydride reduction yielded (+ )-quebrachamine (I). 

The indolenine corresponding to aspidospermidine was also isolated (28,51a). It was denominated Alkaloid 280A [later named 1,2-dehydro-aspidospermidine (51)] and has structure IX. This compound had previously been obtained by the zinc dust distillation of quebrachamine (18, Section II, B) and was subsequently found in R. stricta (51). It is... 

The spectrum of quebrachamine (220) thus shows predominant fission of bonds in ring C. Dependent on the localization of the charge,... 

The structure of quebrachamine was proved by comparing its mass spectrum with that of methoxyquebrachamine synthesized from deacetylaspidospermine via its dehydro product.104... 

Hydrolysis of thioacetals. Exposure of the thioacetal 1 to excess methyl iodide in aqueous acetonitrile at reflux results in formation of the lactam 2, an intermediate in the synthesis of quebrachamine. This transformation invoives initiai hydrolysis of 1 to an aldehyde intermediate (4,341), followed by an Hl-catalyzed Pictet-Spengler... 

Several new sources of quebrachamine (5) (10-16) and, particularly, voaphylline (conoflorine, 6) (15,17-34) have been found in recent years. Other known alkaloids encountered in recent extractions include vincadine (7) (35,36), 14,15-didehydro-epivincadine (8) (37), rhazidine (9) (38), and 12-methoxyvoaphylline (10) (39-41). New alkaloids include quebrachamine hydroxyindolenine (strictanol, 11), which has been found in the fruits (42) and leaves (43) of R. stricta, and voaphylline hydroxyindolenine (12), for which five sources have been reported (20,22,27,34,44). In common with many other hydroxyindolenine derivatives of easily oxidized alkaloids, these may well prove to be artifacts of the extraction process. Ervayunine (13), the enantiomer of voaphylline, occurs in the roots of Ervatamia yunnanensis... 

Aspidochibine (23), which has so far only been isolated from cell-suspension cultures of A. quebrachoblanco Schlecht (55), rather than intact plants, is the product of the oxidation of quebrachamine at C-3, C-5, and C-14, followed by lactone formation between a carboxyl group generated at C-5 and a hydroxyl group at C-14. Structure 23 indicates the relative stereochemistry of aspidochibine. The absolute configuration is presently unknown. 

The first enantioselective synthesis of (+)-quebrachamine was also developed by Takano and his collaborators (275), and in principle is an elegant adaptation of the Kutney route, the required aldehydo-acid 430, with the... 

In a subsequent communication, Takano et al. (276) reported an alternative synthesis of (+)-quebrachamine from the lactone 433, together with a synthesis of (-)-quebrachamine (5) from the same lactone, which was achieved by reversing the roles of C-2 and C-4. The new synthesis of (+)-quebrachamine essentially involved an alternative route for the conversion of the tetracyclic lactam 436 into the familiar tetracyclic aminoalcohols... 

Yet another synthesis of the aldehydo-acid 430 by Takano s group (277) constitutes a further formal synthesis of ( )-quebrachamine. Here, butyro-nitrile was bisalkylated by allyl bromide, and the product converted into the iodolactone 441 by reaction with iodine in mild aqueous alkali. Hydrolysis then gave the corresponding alcohol, which on further hydrolysis and... 

The approaches to quebrachamine adopted by other workers were rather different. Pakrashi and his collaborators (281) developed a synthesis via the known pentacyclic lactam 453 (prepared from 2-hydroxytryptamine and dimethyl 4-ethyl-4-formylpimelate) and 1,2-didehydroaspidospermid-ine (27), the final stage being simply the reduction of 27 by means of potassium borohydride, as in the last stage of the original synthesis of quebrachamine by Stork and Dolfini (Scheme 43). 

Ban s synthesis of quebrachamine (5) (282-284) (Scheme 44) was readily modified to afford syntheses of several aspidospermidine derivatives. Thus, angular alkylation of the tetracyclic lactam 478, followed by appropriate reduction and cyclization stages, afforded ( )-lV-acetylaspidospermidine (26), whereas acylation at the future C-20 by means of oxalic ester provided a route to ( )-deoxylimapodine (479) and ( )-N-acetylaspidoalbidine (480). ( )-Deoxyaspidodispermine (481) was obtained by C-20 hydroxyla-tion of 478 by means of oxygen and LDA, followed by reduction and cyclization stages (4,282-284). 

A synthesis " (Scheme 16) of (+)-quebrachamine (102) employs the cyclic enamine (103) which, after introduction of an acetic ester side chain by enamine... 

The reaction was also applied to thcAspidosperma alkaloids. Thus oxidation of (—)-quebrachamine (4) with mercuric acetate followed by reduction with lithium aluminum hydride gives (+)-aspidospermidine (5). 

Takarro et al. have extended their enantioselective synthesis to the preparation of both enantiomers of quebrachamine from a single... 

The simplest of all Aspidosperma alkaloids is quebrachamine (82), having only one stereochemical center and no carbomethoxy group. A number of syntheses of quebrachamine have been discussed previously in these volumes (see, e.g., Volume XI, p. 277). 

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