A New Synthetic Method for α-Alkoxycarbonyl Iminium Salt and Its Reaction with Nucleophiles

Shimizu, Makoto; Itou, Hiroyuki; Miura, Megumi

doi:10.1021/ja042330f

Cited by 65 publications

(14 citation statements)

References 19 publications

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“…QBAs are highly reactive to reductants such as NaBH 4 and nicotinamide adenine dinucleotide (NADH), a biological reducing agent, and nucleophiles such as OH À , CN À , NH 3 , ROH and acetone, and are easily converted to their corresponding derivatives, such as dihydrosanguinarine, 6-hydroxydihydrosanguinarine (pseudobase or alkanolamine), aminal, bimolecular aminoacetals and 6-alkoxysanguinarine (pseudoalcoholate) (Eldin & Jencks, 1995;Nakanishi et al, 2000;Parenty, Smith, Pickering, Long, & Cronin, 2004;Shimizu, Itou, & Miura, 2005;Yoshida et al, 1999). On the other hand, the pseudobase, aminal and pseudoalcoholate of QBAs may be converted to their corresponding iminium ion form in an acidic condition.…”

Section: Introductionmentioning

confidence: 99%

Structural modification of sanguinarine and chelerythrine and their antibacterial activity

Miao

Yang

Zhou

et al. 2011

Natural Product Research

110

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In this study, five derivatives of sanguinarine (1) and chelerythrine (2) were prepared, with 1 and 2 as starting materials, by reduction, oxidation and nucleophilic addition to the iminium bond C=N+. The structures of all compounds were elucidated on account of their MS, ¹H-NMR and ¹³C-NMR data. The antibacterial activities of all compounds were screened, using Staphylococcus aureus, Escherichia coli, Aeromonas hydrophila and Pasteurella multocida as test bacteria. The minimum bacteriostatic concentration and minimum bactericidal concentration of the active compounds were determined by the turbidity method. The structure-activity relationships of 1 and 2 were discussed. The results showed that 1, 2 and their pseudoalcoholates were found to be potent inhibitors to S. aureus, E. coli and A. hydrophila, while the other derivatives were found to be inactive. The pseudoalcoholates might be the prodrugs of 1 and 2. The iminium bond in the molecules of 1 or 2 was the determinant for antibacterial activity, and the substituents at the 7 and 8 positions influenced the antibacterial activities of 1 and 2 against different bacteria.

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Section: Introductionmentioning

confidence: 99%

Structural modification of sanguinarine and chelerythrine and their antibacterial activity

Miao

Yang

Zhou

et al. 2011

Natural Product Research

110

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“…The highly polar iminium moiety easily reacts with biological reducing agents such as nicotinamide adenine dinucleotide (NADH), or nontarget nucleophiles in biological fluids to become the corresponding neutral nonactive phenanthridine derivatives. [16][17][18][19][20] Therefore, during the past ten years, a great deal of work had focused on improving the chemical stability of QBAs by structural modification. 16,21) Psoroptes cuniculi is an important veterinary ectoparasite in rabbits, goats, horses, sheep and so on.…”

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confidence: 99%

Structural Modification of Sanguinarine and Chelerythrine and Their <i>in Vitro</i> Acaricidal Activity against <i>Psoroptes cuniculi</i>

Miao

Yang

et al. 2012

Chem. Pharm. Bull.

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Sanguinarine (1) and chelerythrine (2) are two quaternary benzo[c]phenanthridine alkaloids (QBAs). Eighteen derivatives of 1 and 2 were synthesized by modification of C N bond and evaluated for their in vitro acaricidal activity against Psoroptes cuniculi, a mange mite. A new method was developed to prepare 6-alkoxy dihydro derivatives of 1 and 2 (1a-e, 2a-e). Among all the compounds, only 6-alkoxy dihydrosanguinarines (1a-e) showed significant acaricidal activity at 5.0 mg/mL and 1a possessed the strongest activity (50% lethal concentrations (LC 50 ) 339.70 0.75 mg/L, 50% lethal time (LT 50 ) 6.53 0.04 h), comparable with a standard drug ivermectin (LC 50 168.19 11.79 mg/L, LT 50 16.54 0.11 h). The iminium moiety in 1 and 2 was proven to be the determinant for their acaricidal properties. 6-Alkoxy dihydro derivatives (1a-e, 2a-e) were prodrugs of 1 and 2. Compared with 7,8-dimethoxy groups, 7,8-methylenedioxy group was able to significantly improve the bioactivity. The present results suggested that QBAs are promising candidates or lead compounds for the development of new isoquinoline acaricidal agents.Sanguinarine (1) and chelerythrine (2) (Fig. 1) belong to quaternary benzo[c] phenanthridine alkaloids (QBAs) and widely present in a number of plant species of the Fumariaceae, Papaveraceae, and Rutaceae families. 1) QBAs have given rise to a lot of attention because of their extensive bioactivities including antitumor, 2-4) antimicrobial, 5,6) anti-inflammatory, 7) antiviral 8) including anti-human immunodeficiency virus (HIV), 9) anti-platelet aggregation, 10) anti-angiogenesis 11) and anti-acetylcholinesterase. 12) Recently, QBAs were also found to have antiparasitic actions against Trichodina sp., 13) Dactylogyrus intermedius 14) and malaria. 15) However, the acaricidal activity of QBAs was not reported until now.Nevertheless, QBAs have the common drawback of low compatibility with physiological conditions. The highly polar iminium moiety easily reacts with biological reducing agents such as nicotinamide adenine dinucleotide (NADH), or nontarget nucleophiles in biological fluids to become the corresponding neutral nonactive phenanthridine derivatives. [16][17][18][19][20] Therefore, during the past ten years, a great deal of work had focused on improving the chemical stability of QBAs by structural modification. 16,21) Psoroptes cuniculi is an important veterinary ectoparasite in rabbits, goats, horses, sheep and so on. 22) It can cause intense pruritus, reduction of weight gain or even death of animals. 23,24) Therapy and control of both human scabies and animal mange are based mainly on the use of effective drugs and chemicals. However, many of the chemical acaracides have limitations such as resistance, 25,26) toxicity 27,28) and environmental damage. 27,28) Ivermectin is increasingly being used to treat human scabies and animal mange but often treatment failures, recrudescence and reinfection can occur. 29) These problem have lead to research efforts to discover new effective acaricides derived from some...

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“…[1] However, regioselective alkyl addition to 1 is problematic, since these conjugated umpolung compounds can react with organometallic reagents at three possible electrophilic centers: the imino carbon atom (path a to give 2), imino nitrogen atom (path b to give 3), and carbonyl carbon atom (path c to give 4). [3][4][5] Moreover, purification is laborious, since the obtained compounds often have similar chemical properties. [3][4][5] Moreover, purification is laborious, since the obtained compounds often have similar chemical properties.…”

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C‐Selective and Diastereoselective Alkyl Addition to β,γ‐Alkynyl‐α‐imino Esters with Zinc(II)ate Complexes

et al. 2015

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Since umpolung α-imino esters contain three electrophilic centers, regioselective alkyl addition with traditional organometallic reagents has been a serious problem in the practical synthesis of versatile chiral α-amino acid derivatives. An unusual C-alkyl addition to α-imino esters using a Grignard reagent (RMgX)-derived zinc(II)ate was developed. Zinc(II)ate complexes consist of a Lewis acidic [MgX](+) moiety, a nucleophilic [R3 Zn](-) moiety, and 2 [MgX2 ]. Therefore, the ionically separated [R3 Zn](-) selectively attacks the imino carbon atom ,which is most strongly activated by chelation of [MgX](+) . In particular, chiral β,γ-alkynyl-α-imino esters can strongly promote highly regio- and diastereoselective C-alkylation because of structural considerations, and the corresponding optically active α-quaternary amino acid derivatives are obtained within 5 minutes in high to excellent yields.

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A New Synthetic Method for α-Alkoxycarbonyl Iminium Salt and Its Reaction with Nucleophiles

Abstract: An iminium salt was easily prepared using the oxidation of amino ketene silyl acetal with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and the subsequent nucleophilic addition to this iminium species proceeded efficiently to afford alpha-amino esters in good yields.

Cited by 65 publications

References 19 publications

Structural modification of sanguinarine and chelerythrine and their antibacterial activity

Structural modification of sanguinarine and chelerythrine and their antibacterial activity

Structural Modification of Sanguinarine and Chelerythrine and Their <i>in Vitro</i> Acaricidal Activity against <i>Psoroptes cuniculi</i>

C‐Selective and Diastereoselective Alkyl Addition to β,γ‐Alkynyl‐α‐imino Esters with Zinc(II)ate Complexes

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