General approach for the synthesis of ajmaline-related alkaloids. Enantiospecific total synthesis of (-)-suaveoline, (-)-raumacline, and (-)-Nb-methylraumacline

Fu, Xiaoyong; Cook, James M.

doi:10.1021/jo00055a019

Cited by 55 publications

(36 citation statements)

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“…We found that more catalyst (10% Pd/C, 1:1 w / w ) and longer reaction time (4 days, 50 psi H 2 ) increased the amount of 11 to 50%. It was reported that N -methylation was observed in hydrogenolysis of benzyl group in an alkaloid synthesis (40–42). The proposed mechanism is that the catalyst of palladium (40) or other precious metals such as ruthenium (43) and iridium (44) can oxidize the adsorbed alcohol to the corresponding aldehyde, which can be trapped by free amine and then be reduced by hydrogen to N -alkylated products.…”

Section: Resultsmentioning

confidence: 99%

Bisethylnorspermine Lipopolyamine as Potential Delivery Vector for Combination Drug/Gene Anticancer Therapies

Dong

et al. 2010

Pharm Res

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Purpose To design novel synthetic gene delivery system in which the carrier molecule functions dually as a carrier and a cytotoxic agent targeting dysregulated polyamine metabolism in cancer. Methods Bisethylnorspermine (BENSpm) lipopolyamine was synthesized and its toxicity evaluated by MTS assay in MCF-7 and MCF-10A cells. Transfection activity was determined using luciferase plasmid DNA. Results Asymmetrical lipid analogue of polyamine anticancer drug BENSpm was synthesized using nucleophilic ring opening of azetidinium ion. The synthesized LipoBENSpm showed cytotoxicity comparable to that of parent BENSpm in human breast cancer cell line MCF-7 but mediated 3–4 orders magnitude higher transfection activity. Importantly, cytostatic activity of BENSpm, typically in a low µM range, falls within a relevant and typical concentration range required for efficient gene delivery. Conclusions These findings make gene delivery vectors based on BENSpm promising candidates for combination drug/gene approaches to the treatment of cancer.

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Section: Resultsmentioning

confidence: 99%

Bisethylnorspermine Lipopolyamine as Potential Delivery Vector for Combination Drug/Gene Anticancer Therapies

Dong

et al. 2010

Pharm Res

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“…The new amino acid Choi was prepared from both 22 and 23 . Debenzylation of 23 was sluggish, and the secondary amine 25 was accompanied by N ‐alkylation products from the alcohol used as solvent 24. However, 23 was easily converted to the N ‐Boc compound 26 in 95 % yield by catalytic, hydrogenolytic debenzylation in the presence of (Boc) 2 O.…”

Section: Resultsmentioning

confidence: 99%

First Total Syntheses of Aeruginosin 298-A and Aeruginosin 298-B, Based on a Stereocontrolled Route to the New Amino Acid 6-Hydroxyoctahydroindole-2-carboxylic Acid

et al. 2001

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The first total syntheses of aeruginosin 298-A (1) and aeruginosin 298-B (3) are described. The syntheses of the alternative putative structures 2 and 4 were also accomplished. The key common strategic element is the stereo-controlled synthesis of (2S,3aS,6R,7aS)-6-hydroxyoctahydroindole-2-carboxylic acid (L-Choi, 5) from L-tyrosine. The synthesis of this new bicyclic alpha-amino acid, which is the core of aeruginosins, involves Birch reduction of O-methyl-L-tyrosine (6) and aminocyclization of the resulting dihydroanisole 7 in acid medium, followed by N-benzylation to give the diastereoisomers 12 and 13. Upon acid treatment with HCl-MeOH, the last two produce an equilibrium mixture in which the endo isomer 13 significantly predominates. Hydrogenation of 13 in the presence of (Boc)2O gives 16, which on reduction with LS-Selectride furnishes the alcohol 22, a protected L-Choi. Successive couplings of 22 with D-leucine, protected (R)-(4-hydroxyphenyl)lactic acid, and L-arginine fragments, followed by reduction to the argininol level and a deprotection end step complete the synthetic sequence to produce aeruginosin 298-A (1). Spectral comparison showed that peptide 2, with the structure previously proposed for aeruginosin 298-A, was different from the natural product. However, synthetic 1 was found to be identical to the isolated natural sample of aeruginosin 298-A. These results unequivocally establish that the absolute stereochemistry of aeruginosin 298-A, formerly assigned incorrectly, is D-Hpla-D-Leu-L-Choi-L-Argol, as shown by structure 1. Aeruginosin 298-B was also synthesized and shown to be a mixture of rotamers of D-Hpla-D-Leu-L-ChoiNH2 (3), rather than an epimeric mixture of 3 and the L-Leu-incorporating 4.

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“…21,30 This synthesis has much in common with Cook's earlier synthesis of suaveoline. 31 From the N1-unsubstituted tetracyclic ketone 32, the synthesis proceeded as per the ajmaline synthesis in Section 2.3.2. Cook and co-workers opted to use the sarpagan C16-configured oxyanion-Cope product, although, in this instance, the configurations of C15, C16 and C20 are of less concern, since all are ultimately incorporated into the pyridine ring.…”

Section: Pyridine Formation: Norsuaveolinementioning

confidence: 99%

Recent advances in the chemistry of macroline, sarpagine and ajmaline-related indole alkaloids

Lewis

2006

Tetrahedron

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General approach for the synthesis of ajmaline-related alkaloids. Enantiospecific total synthesis of (-)-suaveoline, (-)-raumacline, and (-)-Nb-methylraumacline

Cited by 55 publications

References 0 publications

Bisethylnorspermine Lipopolyamine as Potential Delivery Vector for Combination Drug/Gene Anticancer Therapies

Bisethylnorspermine Lipopolyamine as Potential Delivery Vector for Combination Drug/Gene Anticancer Therapies

First Total Syntheses of Aeruginosin 298-A and Aeruginosin 298-B, Based on a Stereocontrolled Route to the New Amino Acid 6-Hydroxyoctahydroindole-2-carboxylic Acid

Recent advances in the chemistry of macroline, sarpagine and ajmaline-related indole alkaloids

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