Quebrachamine synthesis

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... 

Quaternary ammonium compounds biocidal activity mechanism, 1, 401 toxicity, 1, 124 Quaternization heterocyclic compounds reviews, 1, 73 ( )-Quebrachamine synthesis, 1, 490 Queen substance synthesis, 1, 439 4, 777 Quercetin occurrence, 3, 878 pentamethyl ether photolysis, 3, 696 photooxidation, 3, 695 Quercetrin hydrolysis, 3, 878 Quinacetol sulfete as fungicide, 2, 514 Quinacridone, 2,9-dimethyl-, 1, 336 Quinacridone pigments, 1, 335-336 Quinacrlne... 

Other syntheses of the tetracyclic intermediates 434 and 436 that merit mention, and thus constitute additional formal syntheses of (-1-)-quebrachamine, have been contributed by Fuji et aL and by Asaoka and Takei. Fuji s approach (279) starts with the chiral lactone 446, which is readily available from 2-ethyl-5-valerolactone. Partial reduction to the aldehyde stage, followed by acetal formation, gave 447, which on condensation and reduction (lithium aluminum hydride) gave a mixture of C-3 epimers 434, the late intermediate in the (+)-quebrachamine synthesis (Scheme 41). 

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). 

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... 

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). 

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... 

The closure of a bond between positions 12 and 19, presumably involved in the natural synthesis of aspidospermine-type alkaloids from quebrachamine, has been shown (18) to occur during the zinc dust distillation of the latter when a compound IX was isolated whose mass spectrum was exactly comparable with that of the indolenine VII, except for the 30-unit shift in the indole-containing fragments (Table V). Substance IX has subsequently been found in nature (Section II, E). 

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). 

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... 

In view of the importance of vindoline (44) as a constituent of the oncolytic bisindole alkaloid vinblastine, methods for the synthesis of both vindorosine (43) and vindoline from members of the quebrachamine and vincadifformine groups have been extensively investigated. The first results... 

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). 

The enantioselective approach to quebrachamine adopted by Fuji and collaborators (Scheme 41) (279) has also been modified to afford a new synthesis of (-)-aspidospermidine (251). Here, the lactone 446 was converted by titanium trichloride into the lactone hemiacetal 485, which, after appropriate reduction and oxidation stages, gave the acetal acid 486. Condensation with tryptamine gave the tetracyclic lactam 487, which was then rearranged by means of trifluoromethanesulfonic acid to the pentacyclic indolenine lactam 488, reduction of which gave (-)-aspidospermidine (251) (Scheme SI). 

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

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

Recently, Takano and co-workers (221) have reported an improved synthesis of quebrachamine (82) and of 16-cyano-14,15-dehydroque-brachamine (485), an intermediate in the synthesis of tabersonine (28)... 

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