Lavendamycin methyl ester

Fig. 9 Synthesis of lavendamycin methyl ester by Kende and Ebetino... 

The Pictet-Spengler reaction has also seen much use in the synthesis of lavendamycin methyl ester. Both Hibino [31] and Behforouz [32] used it as a key step in their syntheses of this molecule (Fig. 10). In Hibino s synthesis, /i-methyltryptophan ethyl ester 27 was condensed with quinoline aldehyde 28 to give the corresponding lelrahydro- -carbohnc, which was aromatized by heating with palladium on carbon in xylenes, giving /1-carboline 29 in 75% yield. A five-step sequence (which included conversion to the methyl ester for easier comparison with known compounds) yielded bromoquinone 24 in 27% yield for the five steps. This completed Hibino s formal total synthesis of lavendamycin methyl ester, since this was the same intermediate used in Kende s synthesis. 

Behforouz s synthesis employed more highly substituted quinoline aldehyde 30, which, when condensed with ester 21, produced /3-carboline 31 without need of a separate oxidation step. Selective hydrolysis of the acetamide group then provided lavendamycin methyl ester in high yield. A few years later, Behforouz and coworkers reported an improved synthesis of 30, thus boosting the overall yield of their lavendamycin synthesis [33]. 

One of the earliest syntheses of lavendamycin methyl ester, however, did not employ either the Pictet-Spengler or the Bischler-Napieralski reactions for construction of the /J-carboline ring system. Instead, a palladium-promoted ring closure of aryl pyridine 36 (Fig. 12) was used to prepare /1-carboline 37 by Boger and coworkers [35]. Unfortunately, stoichiometric palladium was found to be necessary, in this case 1.5 equivalents of the tetrakis(triphenylphosphine)palladium(0) being used. Friedlander condensation with aldehyde 38 in the presence of benzyltrimethylammonium hydrox-... 

Treatment of 131 with sodium azide, to replace the bromine with an azide, followed by reduction to the amino group with Na2S204 afforded the desired lavendamycin methyl ester (132). It was reported that conversion of the ester 132 to lavendamycin using conventional methods produced low yields (55). 

Scheme 13. Total synthesis of lavendamycin methyl ester (132) (55,56).

In 1993, Behforouz et al. reported their highly concise, five-step, and overall high-yield (33%) synthesis of lavendamycin methyl ester (132)... 

Six-membered heterocyclic systems which have been synthesised by similar methods include l,6-methano[10]annulenopyridines (214) from (213), y-carblines (215), lavendamycin methyl ester,a range of functionalised 2,3-dihydropyrido[3 ,2 4,5]thieno[3,2-d]pyrimidines (216), and the quinazolino[3,4-a]perimidine derivatives (e.g. 218) from 1,2-dihydro-properimidine azide (217). The previously unreported 4-methylene-4H-3,l-benzozazine ring (219) has been prepared from o-azidoacetophenone and the zwitterionic heteropolycyclic uracils (220) have been synthesised by a three-component reaction of iminophosphorane, isocyanate, and substituted pyridine. ... 

After structural elucidation of lavendamycin (81TL4595), the proposed structure (243) was confirmed by total synthesis of its methyl ester (84H91, 84TL923 85H261). Another total synthesis of its methyl ester was based on the Friedlander condensation for the A-B part, and this part was connected with a )J-carboline moiety (85JOC5790). Moreover, several syntheses of... 

The synthetic plan devised for lavendamycin (40) by Kende and Ebetino was based on Bischler-Napieralski reaction. The key synthon (42) representing the AB fragment, was obtained by a straightforward preparation from 8-meth-oxyquinaldic acid (41) by sequential nitration at C-5 and bromination at C-7. Subsequent coupling reaction of 42 and P-methyltryptophan (43) formed the amide 44 which was cyclised to the pentacyclic intermediate (45) as present in the skeleton of lavendamycin. The desired functionalisations of ring A in 45 to obtain the methyl ester of 40 are summarised in Scheme 5. 

In 2011, Nissen and Detert [9] reported a partially intramolecular [2+2+2] aromatization for the synthesis of lavendamycin (Scheme 9.4). Lavendamydn is an antitumor antibiotic produced by Straptomyces lavendulae. Both Rh and Ru catalyses were used for this [2+2+2] cycloaddition of a 1,6-diyne and an electron-deficient nitrile. What was interesting was the observation that the symmetrical adduct was always preferred with Rh catalysis, and when Ru catalysis was employed, only the desired unsymmetrical p-carboline product was obtained. The pentacyclic core of lavendamycin was then converted to lavendamydn methyl ester via a sequence of functional group manipulations. 

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