Total synthesis of the indole alkaloids dl-eburnamonine and dl-vincamine

Herrmann, J.; Cregge, Robert J.; Richman, Jack E.; KIECZYKOWSKI, G. R.; Normandin, S. N.; QUESADA, M. L.; Semmelhack, Carol L.; Poss, A. J.; Schlessinger, R. H.

doi:10.1021/ja00500a028

Cited by 40 publications

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“…It is known that reduction of the related compounds with NaBH 4 gives a mixture in which the trans isomer is in excess of the cis isomer. [38][39][40][41] In our system, trans isomer 20 was obtained as a sole product. Comparison of the optical rotation with that reported 42) showed that the product was (Ϫ)-epieburnamonine (20).…”

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confidence: 84%

“…Oxidation and methylation followed by removal of the Boc group under microwave irradiation afforded methyl ester 19, from which syntheses of eburnamonine, eburnamine and vincamine have been reported. [35][36][37] Methyl ester 19 was converted to epieburnamonine (20) through Bischler-Napieralski reaction and reduction with NaBH 4 . It is known that reduction of the related compounds with NaBH 4 gives a mixture in which the trans isomer is in excess of the cis isomer.…”

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confidence: 99%

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Toward General Access to the <i>Aspidosperma</i>-Type Terpenoid Indole Alkaloids: Synthesis of the Key 3,3-Disubstituted Piperidones through Enantioselective Intramolecular Heck-Type Reaction of Chloroformamides

Yasui

Takeda

Takemoto

2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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An enantioselective intramolecular Heck-type reaction of chloroformamides has been developed for the synthesis of 3,3-disubstituted piperidones. The desired piperidone was formed in the presence of a palladium catalyst, an optically active phosphoramidite ligand, K 3 PO 4 and Ag 3 PO 4 . The obtained piperidone was converted to epieburnamonine.Key words enantioselective reaction; total synthesis; terpenoid indole alkaloid Chem. Pharm. Bull. 56(11) 1567-1574 (2008) © 2008 Pharmaceutical Society of Japan * To whom correspondence should be addressed. e-mail: takemoto@pharm.kyoto-u.ac.jp under normal conditions (entries 1-3). However, lactam 9 was isolated in 60% yield when Ag 3 PO 4 was added to the reaction (entry 4). The combination of Pd 2 (dba) 3 and BINAP was also able to promote the cyclization in the presence of Ag 3 PO 4 (entry 5). Nolan's NHC catalyst was not effective (entry 6).With these results in hand, syntheses of each cis-trans isomer of alkenyl chloroformamide 2 were performed. Alkene (E)-4 was synthesized through hydroalumination as a key step (Fig. 5). 4-Pentyn-1-ol (10) was transformed into alcohol 11 through oxidation, acetalization, and hydroxymethylation using benzotriazolylmethanol (BtCH 2 OH). 22) Alcohol 11 was then subjected to the hydroalumination-iodination sequence 23,24) to give (Z)-iodo alkene 12, whose configuration was confirmed by NOE experiment. Ethylation by Suzuki coupling, followed by benzylation gave the desired alkene (E)-4.Change of the starting material afforded the alternative stereoisomer (Fig. 6). (Z)-Iodoalkene 14 was synthesized from 2-pentyn-1-ol (13) through hydroalumination and iodination. Since benzylation of the hydroxy group under either basic or acidic conditions competed with decomposition of the starting material, protection by THP group was carried out. The resultant THP ether 15 underwent Negishi coupling with 3,3-(dimethoxy)propylzinc chloride 16. 25) Selective hydrolysis of the THP ether and benzylation afforded the desired alkene (Z)-4.Alkenyl acetals (E)-4 and (Z)-4 were coupled with tryptamine 3 26) through hydrolysis and reductive amination to give amines (E)-17 and (Z)-17, respectively (Fig. 7). These compounds were converted to the corresponding chloroformamides (E)-2 and (Z)-2 by treating with triphosgene and Et 3 N.Before the enantioselective Heck-type reaction, a racemic reaction was attempted to find out a suitable palladium source ( Table 2). The cyclized product 1 was isolated after hydrolysis of the resultant enol ether. At the early stage, poor reproducibility was a serious problem. After several attempts, it was found that the activity of the catalyst is highly associated with the conditions used to mix palladium sources and ligands prior to the addition of chloroformamide 2. When [Pd(h 3 -C 3 H 5 )Cl] 2 was premixed with (p-tol) 3 P at 30°C for 30 min, the disappearance of 2 was slow and the yield was 30% after 24 h (entry 1). In contrast, the starting material disappeared in 3 h and yield reached 49% when premixing was performed at 40°C...

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confidence: 84%

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confidence: 99%

Toward General Access to the <i>Aspidosperma</i>-Type Terpenoid Indole Alkaloids: Synthesis of the Key 3,3-Disubstituted Piperidones through Enantioselective Intramolecular Heck-Type Reaction of Chloroformamides

Yasui

Takeda

Takemoto

2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Oxidative cleavage of the allyl group furnishes carboxylic acid 20 , which undergoes Fischer indole synthesis with concomitant esterification to afford indole 21 . Though Bischler–Napieralski cyclization to iminium perchlorate 22 proceeds smoothly, we were disappointed to observe the diastereoselective hydrogenation conditions described by Schlessinger [12f] fail to deliver any reduced products [19] . After further optimization, we discovered that heterogeneous hydrogenation in DMF [20] with subsequent addition of DBU promotes diastereoselective hydrogenation and lactamization in one pot, completing the synthesis of eburnamonine ( 8 ) in five steps from lactam 10 and ten steps from commercially available material.…”

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confidence: 99%

The Enantioselective Synthesis of Eburnamonine, Eucophylline, and 16′‐epi‐Leucophyllidine

et al. 2021

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“…-MS (130°C): M + = 298 ME (16%), 297 (8), 223 (7). 185 (13), 184 (loo), 169 (6), 168 (7), 156 (11). C,,H,,N,O (298.4) Ber.…”

Section: I2cp-ethylmentioning

confidence: 99%

Reaktionen an Indolderivaten, XLVI¹⁾ Ein stereoselektiver Zugang zu Isoeburnamonin

Bölsing

Winterfeldt

1981

Chem. Ber.

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Die interessanten physiologischen W i r k~n g e n~l ' ,~' der Alkaloide vorn Typ des Eburnarnonins (1) haben dazu gefuhrt, da8 neben Totalsynthesen der Naturstoffe5-") auch die Strukturvariationen dieses Alkaloidtyps studiert wurden 1 2 * 1 3 i 1 4 ). Fii r uns bot sich die Moglichkeit zur strukturellen Variation unter Einhaltung der in den Alkaloiden auftretenden relativen Konfiguration, als wir bei synthetischen Studien in dieser Reihe die konfigurative Stabilitat des Ketolactarns 3 untersuchten. Ein unerwartet effizienter Epirnerisierungsprozefl eroffnete dabei einen Zugang zu Isoeburnarnonin (2), iiber den wir in dieser Mitteilung berichten.Die Darstellung der Verbindung 3 durch nucleophile Ringoffnung eines Cyclopropan-Zwischenprodukts wurde kiirzlich von uns beschrieben Is). Hier sei nur noch einma1 erwahnt, dal3 3 aus einer protenenkatalysierten (KF, Eisessig) Cyclisierungsreaktion hervorgeht. Dabei wurde stets bereits begleitende Isornerisierung zu 4 registriert. Zwar konnte 4 zunachst nur in au8erst geringer Menge bei chrornatographischen Auftrennungen von Restrnutterlaugen entdeckt werden, doch loste dieses angesichts belegter und zweifelsfreier konfigurativer Einheitlichkeit des Ausgangsmaterials irnrnerhin den Verdacht aus, da8 4 durch protonenkatalysierte Epirnerisierung entstanden sein konnte und rnoglicherweise die therrnodynarnisch stabile Konfiguration reprasentiert .In der Tat iiberfiihrt rnehrtagiges Erhitzen in Eisessig unter Stickstoff das Ketolactarn 3 in guter chernischer Ausbeute und rnit ausgezeichneter Stereoselektivitat in die Isoverbindung 4 rnit cis-Anordnung von H und Ethyl an C-3 und C-17 (Alkaloiddhlweise s. 1 bzw. 2). Diese eindeutige Bevorzugung der Konfiguration 4 ist bernerkenswert, beruht sie doch, wie ein Studiurn der wahrscheinlichsten Konforrnationen 3' und 4' lehrt, leChem. Ber. 114(1981)

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Total synthesis of the indole alkaloids dl-eburnamonine and dl-vincamine

Cited by 40 publications

References 1 publication

Toward General Access to the <i>Aspidosperma</i>-Type Terpenoid Indole Alkaloids: Synthesis of the Key 3,3-Disubstituted Piperidones through Enantioselective Intramolecular Heck-Type Reaction of Chloroformamides

Toward General Access to the <i>Aspidosperma</i>-Type Terpenoid Indole Alkaloids: Synthesis of the Key 3,3-Disubstituted Piperidones through Enantioselective Intramolecular Heck-Type Reaction of Chloroformamides

The Enantioselective Synthesis of Eburnamonine, Eucophylline, and 16′‐epi‐Leucophyllidine

Reaktionen an Indolderivaten, XLVI¹⁾ Ein stereoselektiver Zugang zu Isoeburnamonin

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Total synthesis of the indole alkaloids dl-eburnamonine and dl-vincamine

Cited by 40 publications

References 1 publication

Toward General Access to the <i>Aspidosperma</i>-Type Terpenoid Indole Alkaloids: Synthesis of the Key 3,3-Disubstituted Piperidones through Enantioselective Intramolecular Heck-Type Reaction of Chloroformamides

Toward General Access to the <i>Aspidosperma</i>-Type Terpenoid Indole Alkaloids: Synthesis of the Key 3,3-Disubstituted Piperidones through Enantioselective Intramolecular Heck-Type Reaction of Chloroformamides

The Enantioselective Synthesis of Eburnamonine, Eucophylline, and 16′‐epi‐Leucophyllidine

Reaktionen an Indolderivaten, XLVI1) Ein stereoselektiver Zugang zu Isoeburnamonin

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Reaktionen an Indolderivaten, XLVI¹⁾ Ein stereoselektiver Zugang zu Isoeburnamonin