Conversion of Ecgonidine methyl ester to Ecgonine methyl ester

most current information available to me centers on the synthesis of anhydroecgoine (Ecgonidine) from natural sources, ecgonine, tropinone enolate, cycloheptatriene carboxalic acid, or other methods.

due to regulations and licenses it is preferable to proceed directly to useful phenyltropanes in order to find a 'cocaine antagonist" to act as a addiction inhibitor. however most are ineffective, or have the same issues as the target compound.

some are useful in Alzheimer research or eye surgery.

recent advances have made it possible to use a "antibody approach' which means that newer examples will require mimicking the structure of the target compound as close as possible.

the phenyltropane class lack the offset oxygen side, and rather are attached directly.

as far as ive found the ethyl analouge has been expermetedwith useing H2 electrolyticly in ether. the refrence was missing however.

other reports that oxygenation, then hydrogenation occurs when ecgonine impurity's arise in experiments with anhydroecgonine. other references more common lt states that oxygenation gives rise to a final degradation product ( tropine or the cycloheptanone)

another method looking atthe structure may be to incorporate the missing oxygen side arm in the benzene ( a entantomer of benzaldhyde?)








[Edited on 5-12-2009 by cyclohexane]

Reference Information


Enantioselective Synthesis of Unnatural (S)-(+)-Cocaine
Jae Chol Lee, Kwangho Lee, and Jin Kun Cha
J. Org. Chem., 2000, 65 (15), pp 4773–4775




Introduction
Since Willsta¨ tter’s first synthesis of (R)-(-)-cocaine (1)
in 1923,1 a substantial amount of research has been
devoted to the synthesis and biosynthesis of cocaine, the
most prominent member of the tropane alkaloids isolated
from different plant sources.2 As cocaine abuse has
emerged as one of the serious societal problems, notoriety
is attached to cocaine. Development of antagonists and
partial agonists of cocaine, which could find use in the
treatment of cocaine abuse, has recently attracted considerable
attention.3 Herein we report a stereoselective
synthesis of (S)-(+)-cocaine (2), the unnatural enantiomer,
starting from the known and commercially available
tropinone (3). The underlying strategy would not
only provide access to enantiomerically pure analogues
of cocaine and other medicinally significant tropane
alkaloids, but also be of general utility in asymmetric
synthesis.

Attachment: Enantioselective Synthesis of Unnatural (S)-(+)-Cocaine.pdf (88kB)
This file has been downloaded 1668 times

i got that....learned about it here:


notice from that article and the paper you linked the it mentions the wrong entantomer of the
lithium reagent



Attachment: new coke from tropinone.pdf (425kB)
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[Edited on 7-12-2009 by cyclohexane]

Issue 1: "benzoyl methyl ecgonidine" <b>IS</b> cocaine. (see IUPAC name Fig 1B)

Issue 2: In order to go from methyl <b>ecgonidine</b> to <b>ecgonidine</b>, the molecule must be oxidized at carbon #3 (see Tropane numbering here) . HBr would add Markovnikov, but hydroboration proceeds in an anti-Markovnikov manner (see Wikipedia, Markovnikov's Rule, see Fig 1A). Hence, I suggested hydroboration followed by oxidation to give the C-3 alcohol <b>with retention of stereochemistry</b>. Do not forget that <b>both</b> C-2 and C-3 are pro-chiral, so we get two chiral centers when we oxidize, and two possiblepairs of diastereomers (see Fig 1A).

Issue 3: Now... what stereochemistry do we actually get? There's a fairly common issue in organic synthesis of "convex" versus "concave" attack of a nucleophile. Hopefully I've convinced you hydroboration (or an analogous reaction) is required. Generally, the "concave" attack is disfavored due to steric effects (i.e. bad 1,3-pseudodiaxial interaction with hydrogens at C-1 and C-3, and carbons C-6 and C-7). If convex attack is favored, the boron would be pointed "up" in the flat structure (Fig 1A) - this can consequently be seen in the "chair" structure (Fig 1B). The stereochemistry of the methyl ester is then set by hydride delivery to give the most stable <b>syn</b> product - with the ester pseudoequatorial.

If the boron is oxidized, the resulting alcohol is still "up", and benzoylation (Fig 1B) gives the misnomer "methyl benzoylecgonine", which is identical to cocaine.




[Edited on 7-12-2009 by Arrhenius]

Additionally, I have no idea what this means, but it's nonsense. Does cocaine penetrate the BBB? Yes, certainly. Do enantiomers of cocaine penetrate the BBB? I would say with the utmost certainty that they do.

As for "antibody approach" or "viral structure", I have no idea what this means. Are you're referring to a hapten?

P.S. - Tell your teacher to give me the bonus points

Any introductory organic textbook (I recommend Brown, Foote, Iverson or Vollhardt) will discuss hydroboration. No heating, perhaps cooling to 0ºC or lower. Borane (shown above) must be handled under inert atmosphere. Reaction would likely be complete within an hour or so.

What you've mentioned - cocaine attached to a viral protein - technically is a hapten for cocaine. It's not cocaine, but <b>may</b> ellicit an antibody response that binds cocaine as well. That aside, it's a really crummy hapten for cocaine. Imagine the number of sites the antibody could bind to on the viral protein that don't involve the cocaine-like domain at all!! Basically, it may be a good cholera vaccine, and a crappy cocaine vaccine. See antibody screening for ELISA assays for more discussion of that. The problem - as I see it - with that approach is that insufflated drugs take a matter of seconds to reach the brain. This is far faster than an immune response. There's conflicting info on the net as to the status of the clinical trials of this vaccine. Clinicaltrials.gov says it's not yet recruiting for Phase II, but Dr. Kosten's website claims it's in Phase III. The end point of the study is urine tests negative for cocaine.... seems dicey to me, but I'm just some internet knucklehead.

You could cite personal communication with Svante Arrhenius. Your professor might laugh though.. that guy died a long time ago.

[Edited on 7-12-2009 by Arrhenius]

Quote: Originally posted by solo

Reference Information Enantioselective Synthesis of Unnatural (S)-(+)-Cocaine Jae Chol Lee, Kwangho Lee, and Jin Kun Cha J. Org. Chem., 2000, 65 (15), pp 4773–4775 Introduction Since Willsta¨ tter’s first synthesis of (R)-(-)-cocaine (1) in 1923,1 a substantial amount of research has been devoted to the synthesis and biosynthesis of cocaine, the most prominent member of the tropane alkaloids isolated from different plant sources.2 As cocaine abuse has emerged as one of the serious societal problems, notoriety is attached to cocaine. Development of antagonists and partial agonists of cocaine, which could find use in the treatment of cocaine abuse, has recently attracted considerable attention.3 Herein we report a stereoselective synthesis of (S)-(+)-cocaine (2), the unnatural enantiomer, starting from the known and commercially available tropinone (3). The underlying strategy would not only provide access to enantiomerically pure analogues of cocaine and other medicinally significant tropane alkaloids, but also be of general utility in asymmetric synthesis.

Am I the only one to have noticed this? That the paper uploaded by Solo describes the stereoselective reduction (97% ee) of the (+)-2-CMT directly to (+)(-)-Ecgonine methyl ester? It utilises Birch-conditions (instead of more facile reduction methods - nearly all of which lead preferentially to the (+/-)(+)-Pseudoecgonine(s)?*

There is an article (Cocaine Chemistry: A Review - attached) which shows the various routes and discusses how ironic it is that dissolving metal reductions are the ONLY way to attack that ketone stereospecifically, citing the very paper Solo uploaded.

It actually makes me wonder - in his other article, 'Concerning 2-Carbomethoxytropinone' Findlay provided a reaction scheme utilising the dimethyl ester of ketoglutaric acid, to give 2,4-dicarbomethoxytropinone which was then decarboxylated to give a mixture of (+/-)-2CMT... Can anyone think of a way to control which isomer we would get from the decarboxylation? I know of at least one patent which suggests that bakers yeast could do so with the N-methyl group being protected but it seems a little bit like a guesswork to me.

*See Findlay (On the 3D structures of Cocaine, etc. there are 3 papers attached) etc. on that point, but the majority of hydrogenation techniques and most hydrides lead to virtually pure pseudococaines...


Attachment: Cocaine.Chemistry.A.Review.pdf (425kB)
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Attachment: Findlay.3D.Structure.of.Cocaines.1.Cocaine.and.Pseudococaine.pdf (937kB)
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Attachment: Findlay.3D.Structure.of.Cocaines.2.Structure.of.Racemic.Pseudo.Allococaines.pdf (1.4MB)
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Attachment: Findlay.Note.3D.Structure.of.Cocaine.pdf (402kB)
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[Edited on 12-12-2009 by unome]

Attachment: Casale.etal.D.Labeled.Cocaine.pdf (313kB)
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Quote: Originally posted by Nicodem

Cyclohexane, for an antibody approach for the "vaccination" against small molecules to work, the active dose would have to be in the range of nanomoles. Even if the hapten approach would induce the creation of effective antibodies (which I have to agree with Arrhenius, is unlikely), cocaine users generally take 1 mmol cocaine or even more, so you would need to have at least 3/4 mmol of "anti-cocaine antibodies" vigilant in the body at any time to reduce the effects to subthreshold activity (this is a highly conservative estimate, also assuming all of the antibodies complexes with 1 or 2 cocaine molecules before these reach the DAT and NET transporters in the brain, which is obviously impossible). The molecular weight of antibodies is usually about 150 kDa, meaning you would have to have 150 g of these antibodies in your body for this thing to work! I did not read anything about this dr. Kosten, so I might be missing something, but at first glance this appears just as another fund-raising pseudoscientific hoax. Maybe some of our resident biochemists might take a look at this problem and explain why it might or might not be a hoax.