Syntheses and Cardiovascular Activity of Stereoisomers and Derivatives of Eburnane Alkaloids

Czibula, László; Nemes, András; Visky, György; M, Farkas; Szombathelyi, Zsolt; Kárpáti, E; Sohar, P.; Kessel, Martin; Kreidl, J.

doi:10.1002/jlac.199319930140

Cited by 29 publications

(32 citation statements)

References 24 publications

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“…[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: 73%

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

2008

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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: 73%

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

2008

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“…General procedures followed during the course of the work detailed herein were similar to those reported elsewhere. 4,8 IR spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer using KBr pellets. NMR spectra were recorded on a Varian VNMRS-400 spectrometer (400 MHz for 1 H detection).…”

Section: Methodsmentioning

confidence: 99%

“…The precipitated crystals were separated, washed with water, then suspended in a mixture of EtOH/water 2:1 (110 mL) to yield 19. 4 (±)-cis-Ethyl-1-ethyl-9-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine-1-(2'-hydroxyimino)-propionate (18). To 17 (6 g, 13 mmol) in EtOH (100 mL) a solution of potassium hydroxide (0.9 g, 16 mmol) in water (9 mL) was added and stirred for 3 h at 25-30 o C.…”

Section: Methodsmentioning

confidence: 99%

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Synthesis of metabolites of cis and trans apovincamine derivatives

Nemes¹,

Szántay²,

Czibula³

et al. 2008

Arkivoc

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“…Since then, it has become a reference compound in the pharmacological research of cognitive deficits caused by hypoxia and ischaemia [3]. The medicinal use of vincamine, vinpocetine, vinburnine, brovincane and further ebumane derivatives has inspired continual synthetic efforts to produce related compounds of cis-D/E ring anellation (i.e., 3a-H, 16a-ethyl: (3S, 16S) configuration), and recently, those of trans-D/E ring anellation [4,5].…”

Section: Introductionmentioning

confidence: 99%

Capillary electrophoresis separation of vinpocetine and related compounds: Prediction of electrophoretic mobilities in partly aqueous media

et al. 2000

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Offord's equation, a relationship between electrophoretic mobility and charge, size and shape of peptides, has been extended to quantitate the electrophoretic mobility of vinca alkaloids. Partly aqueous protonation constants and the derived theoretical mobilities have been proven to be able to predict experimental electrophoretic mobilities. In practice, seven vincamine derivatives of very low water-solubility were separated by capillary electrophoresis. Buffer total concentration, apparent pH and methanol content, the three most important parameters of the running buffer, were used in triangular resolution mapping to characterize separation. Even though electrophoresis is well known to slow down in partly aqueous media, under our optimized circumstances a baseline separation was achieved within 8 min in each case.

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Syntheses and Cardiovascular Activity of Stereoisomers and Derivatives of Eburnane Alkaloids

Cited by 29 publications

References 24 publications

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

Synthesis of metabolites of cis and trans apovincamine derivatives

Capillary electrophoresis separation of vinpocetine and related compounds: Prediction of electrophoretic mobilities in partly aqueous media

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