- Concise catalytic asymmetric total synthesis of biologically active tropane alkaloids
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A general strategy for the total asymmetric synthesis of valuable tropane alkaloids by catalytic stereoselective transformations is disclosed. The power of this approach is exemplified by the concise catalytic enantioselective total syntheses of (+)-methylecgonine, (-)-cocaine and (+)-cocaine as well as the first catalytic asymmetric total syntheses of a cocaine C-1 derivative and (+)-ferruginine starting from 5-oxo-protected-α,β-unsaturated enals using only two and three column chromatographic purification steps, respectively. Copyright
- Cordova, Armando,Lin, Shuangzheng,Tseggai, Abrehet
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p. 1363 - 1372
(2012/06/18)
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- Total synthesis of (-)-cocaine and (-)-ferruginine
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Total synthesis of tropane alkaloids (-)-cocaine and (-)-ferruginine were accomplished in nine steps each and in 55% and 46% overall yields, respectively, starting from the known Betti base derivative (+)-(7aR,10R,12S)-10-(1H- benzotriazol-1-yl)-7a,8,9,10-tetrahydro-12-phenyl-12H-naphtho[1,2-e]pyrrolo[2, 1-b][1,3]oxazine. In this novel route, RCM reaction and 1,3-dipolar cycloaddition were employed as key steps for the enantioselective construction of tropane skeleton and the regioselective introduction of 3-bromo-2-isoxazoline ring as masked cis-2,3-disubstituents. To obtain the desired precursor (2S,5R)-2-allyl-5-vinylpyrrolidine for RCM reaction, we developed a general and practical method for the preparation of enantiopure cis-2,5-disubstituted pyrrolidines bearing alkene- and/or alkyne-containing substituents. We also offered two highly efficient pathways for the conversion of the 3-bromo-2-isoxazoline ring into the desired cis-2,3-disubstituted groups in (-)-cocaine and (-)-ferruginine.
- Cheng, Guolin,Wang, Xinyan,Zhu, Rui,Shao, Changwei,Xu, Jimin,Hu, Yuefei
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p. 2694 - 2700
(2011/06/20)
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- Facile and enantiospecific syntheses of (6 S,7 R)-6-chloro-7-BENZYLOXY-, (7 S)-halo-, and (7 S)-hydroxy-cocaine and natural (-)-cocaine from d -(-)-ribose
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First syntheses of C6,7 and C7 enantiopure cocaine analogues were achieved from d-(-)-ribose via a trans-acetonide controlled endo-selective intramolecular nitrone-alkene cycloaddition (INAC) as the key step. This synthetic scheme allows practical preparation of cocaine analogues for bioevaluation as potential candidates for the treatment of cocaine addiction and as potential conjugates for immunotherapy.
- Shing, Tony K. M.,So, King H.
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p. 2916 - 2919
(2011/07/31)
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- Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same
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Hapten-carrier conjugates capable of eliciting anti-hapten antibodies in vivo are disclosed. Methods of preparing the hapten-carrier conjugates and therapeutic compositions are also disclosed. Where the hapten is a drug of abuse, a therapeutic composition containing the hapten-carrier conjugate is particularly useful in the treatment of drug addiction, more particularly, cocaine addiction. Passive immunization using antibodies raised against conjugates of the instant invention is also disclosed. The therapeutic composition is suitable for co-therapy with other conventional drugs.
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- Two-carbon bridge substituted cocaines: Enantioselective synthesis, attribution of the absolute configuration and biological activity of novel 6- and 7-methoxylated cocaines
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In an effort to learn more about the general structure-activity relationships of cocaine with the aim to elucidate those structural features that might confer antagonistic properties to such analogues, we describe herein our synthetic efforts to prepare two-carbon bridge functionalized (methoxylated and hydroxylated) analogues. Our approach makes use of a modification of the classical Willstatter synthesis of cocaine: Mannich type cyclization of acetonedicarboxylic acid monomethyl ester with methylamine hydrochloride and 2-methoxysuccindialdehyde in a citrate buffer solution afforded the 6- and 7-substituted 2-carbomethoxy-3-tropinones 3a,b and 4a,b in approximate yields of 64%. Reduction of the (±)-tropinone derivatives was performed with sodium amalgam in a sulfuric acid solution to afford a mixture of (±)-methoxyecgonine and (±)-methoxypseudoecgonine derivatives 5, 11 and 6, 7, 12, 13. Benzoylation of these alcohols yielded the desired cocaine and pseudococaine-like compounds 8, 14 and 9, 10, 15, 16. Additionally, we show that enzymatic hydrolysis of these cocaine analogues using pig liver esterase (PLE) affords a practical means for achieving their chemical resolution. The enantiomers of the methoxycocaine analogues were also prepared starting from chiral (±)- and(-)-6-methoxytropinone. All new analogues were examined for their ability to displace [3H]mazindol binding and to inhibit high-affinity uptake of [3H]dopamine into striatal nerve ending (synaptosomes). It appeared evident that methoxylation of the cocaine two-carbon bridge provides compounds of particular interest: the K(i) for the binding of the methoxypseudococaines is about two to four times smaller than the K(i) for inhibition of dopamine uptake, thus enabling these compounds capable of countering the effects of cocaine to some extent.
- Simoni, Daniele,Roberti, Marinella,Andrisano, Vincenza,Manferdini, Monica,Rondanin, Riccardo,Invidiata, Francesco Paolo
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p. 275 - 287
(2007/10/03)
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- Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same
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Hapten-carrier conjugates capable of eliciting anti-hapten antibodies in vivo are disclosed. Methods of preparing the hapten-carrier conjugates and therapeutic compositions are also disclosed. Where the hapten is a drug of abuse, a therapeutic composition containing the hapten-carrier conjugate is particularly useful in the treatment of drug addiction, more particularly, cocaine addiction. Passive immunization using antibodies raised against conjugates of the instant invention is also disclosed. The therapeutic composition is suitable for co-therapy with other conventional drugs.
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- Enantiospecific Synthesis of Natural (-)-Cocaine and Unnatural (+)-Cocaine from D- And L-Glutamic Acid
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Natural (-)-cocaine and unnatural (+)-cocaine have been synthesized enantiospecifically from D-and L-glutamic acid, respectively. The axial-equatorial substitutents were introduced by a stereo-and regiospecific dipolar cycloaddition to the corresponding (1R,5S)- and (1S,5R)-N-BOC-nortropenes with (ethoxycarbonyl)formonitrile N-oxide. A sequence of subsequent stereochemically controlled transformations converted the fused isoxazoline to the requisite β-hydroxy ester. Synthesis of the key intermediate N-BOC-nortropenes involved construction of the 8-azabicyclo[3.2.1]octane framework by Dieckmann condensation of cis-5-substituted D- and L-proline esters. For comparison, (1R,5S)-N-BOC-nortropene also was derived by degradation from natural cocaine. The cis-5-substituted D- and L-proline esters were obtained by sulfide contraction and subsequent catalytic hydrogenation to induce stereospecifically the C-5 stereochemistry from D- and L-thiopyroglutamate, which in turn were prepared from D- and L-glutamic acids, respectively.
- Lin, Ronghui,Castells, Josep,Rapoport, Henry
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p. 4069 - 4078
(2007/10/03)
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- A PLE-based resolution of cocaine, pseudococaine, and 6-and 7-methoxylated cocaine analogues
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The enzymatic hydrolysis of racemic cocaine and cocaine analogues using pig liver esterase (PLE) is shown to afford a practical means for achieving their chemical resolution. This reaction was found to proceed not only with good enantioselectivity, but with an interesting chemoselectivity as well.
- Kozikowski,Simoni,Baraldi,Lampronti,Manfredini
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p. 441 - 444
(2007/10/03)
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- Cocaine analogs
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Bioactive cocaine analogs of the general formulae: STR1 are provided wherein X' is H or (C1 -C5)alkyl, X is H, halo, alkyl, alkoxy, perfluoroalkyl, nitro, alkoxycarbonyl, dialkoxyphosphonyl, acyl, perfluoroacyl, azido (substituted)silyl or (substituted)thio, and Y is H, halo, nitro, amino or (substituted)amino, alkoxycarbonyl, carboxy, alkyl or alkoxy; and the pharmaceutically acceptable salts thereof.
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- Local anaesthetic salts of chondroitinsulfate compounds
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Water-soluble local anaesthetic compounds having sustained effect are prepared by reacting a chondroitin derivative with a basic local anaesthetic compound.
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