Quebrachamine

Synthesis This is part of Kutney s quebrachamine synthesis (J. Amer. Chem. Soc., 1966, 3656). He foimd that if X = OEt, both C-N bond-forming operations could be... 

Quebracho bark was first examined by Fraude, who isolated aspidospermine, and later by Hesse, who obtained quebrachine (yohimbine) and four other bases, aspidosamine, aspidospermatine, m.p. 162°, [a]n — 72-3°, hypoquebrachine and quebrachamine, of which the last has been confirmed by other workers the first and third, according to Ewins, are possibly decomposition products of aspidospermine. In the course of an investigation of this alkaloid Ewins isolated two unnamed bases. One of these, m.p. 149-150°, is probably quebrachamine the other crystallises from ethjd acetate in octahedra, m.p. 176-7°. 

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. 

Alkylation of enamines with epoxides or acetoxybromoalkanes provided intermediates for cyclic enol ethers (668) and branched chain sugars were obtained by enamine alkylation (669). Sodium enolates of vinylogous amides underwent carbon and nitrogen methylation (570), while vicinal endiamines formed bis-quaternary amonium salts (647). Reactions of enamines with a cyclopropenyl cation gave alkylated imonium products (57/), and 2-benzylidene-3-methylbenzothiazoline was shown to undergo enamine alkylation and acylation (572). A cyclic enamine was alkylated with methylbromoacetate and the product reduced with sodium borohydride to the key intermediate in a synthesis of the quebrachamine skeleton (57i). 

The addition of (Z)-3-(alkylamino)-2-butenoic acid esters to nitroalkenes derived from open-chain sugars gave a 50 50 mixture of diastereomeric products 32. The reaction of chiral 2-sub-stituted l-(2-nitroethenyl)pyrrolidines with zinc enolates of 3-substituted tetrahydro-2//-pyran-2-oncs in 1,2-dimethoxyethane at — 78 °C afforded the corresponding 3,3-disubstituted products in 82-96% ee via an addition-elimination process33. The stereochemical course of the reaction was determined by chemical correlation of (S)-( )-3-ethyltetrahydro-3-(2-ni-troethenyl)-2//-pyran-2-one with ( + )-quebrachamine. 

Scheme 10.12 gives some examples of enantioselective cyclopropanations. Entry 1 uses the W.s-/-butyloxazoline (BOX) catalyst. The catalytic cyclopropanation in Entry 2 achieves both stereo- and enantioselectivity. The electronic effect of the catalysts (see p. 926) directs the alkoxy-substituted ring trans to the ester substituent (87 13 ratio), and very high enantioselectivity was observed. Entry 3 also used the /-butyl -BOX catalyst. The product was used in an enantioselective synthesis of the alkaloid quebrachamine. Entry 4 is an example of enantioselective methylene transfer using the tartrate-derived dioxaborolane catalyst (see p. 920). Entry 5 used the Rh2[5(X)-MePY]4... 

The 5 configuration of the induced quaternary center of (35 )-3-ethyl-tetrahydro-3-(ni-troethenyl)-2//-pyran-2-one was determined by conversion into (+ )-quebrachamine while the (SS J-S-methyl derivative w as converted into (-i-)-podocarpic acid23. 

The 9-membered ring present in quebrachamine has also been established using the fragmentation strategy [93],... 

A-Acyliminium ions are versatile intermediates for synthesis of nitrogenous compounds, particularly alkaloids [154]. The conjugate system is very electrophilic such that it can be intercepted by various donors including carbonyl compounds and jt-systems. In comparison with a,p-unsaturated ketones the replacement of the a-carbon with a nitrogen atom accentuates the reactivity of these species. Ingenious applications of the JV-acyliminium ions include service to synthesis of corydaline [155], lycoramine [156], quebrachamine [157], and ajmaline [158], to name a very few. 

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). 

C(20), C(14) configuration. Since velbanamine, like quebrachamine, adopts the 16/ -substitution type of conformation shown in [445], the conformational identity of [448] and [449] also shows the cis relationship between 14-H and 16-H, permitting assignment of stereochemistry to pandoline. (268) Other 13C NMR data on pandoline derivatives are available. (269)... 

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... 

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. 

Epivincadine (198) adopts a conformation in which the lone electrons on Nb and the substituent at C-17 are axially disposed to ring D. Owing to steric crowding, its C-16 epimer, i.e. (+)-vincadine, cannot adopt this conformation, and instead adopts an alternative conformation (199) of the nine-membered ring, in which the lone electrons on Nb and the substituent at C-17 are still axial to ring D. Quebrachamine (200) appears to adopt this same conformation, in which approach... 

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).

Voacangine has been subjected to the action of cyanogen bromide (11) and has yielded three compounds the major product, an indole, C23H28N303Br, mp 203°-204°, [ ]D —92° minor products, an indole, C23H28N3C>3Br, mp 238°-240°, [a]D +46°, and an indolenine ( ), C23H27N303, mp 175°-176°, [a]D —34°. The first two compounds were probably normal von Braun products, one of which may be convertible into iV-cyanoapoibogai ne (XXIX).The formation of the indolenine would be a consequence of the nucleophilic reactivity of the indole at C-9 and another example (quebrachamine and cyanogen bromide) is reported in the same paper. 

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

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