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Author: Subject: Conversion of Ecgonidine methyl ester to Ecgonine methyl ester
cyclohexane
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[*] posted on 5-12-2009 at 03:59
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?)






ecgoninemethylester.gif - 2kB anhydroecgoninemethylester.jpg - 2kB

[Edited on 5-12-2009 by cyclohexane]

coke.jpg - 5kBtabe.jpg - 22kB
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[*] posted on 5-12-2009 at 12:45


here is some references as i was asked.

Alkaloids of Darlingia ferruginea

IRC Bick, JW Gillard and H Leow

Abstract

Darlingia ferruginea J. F. Bailey contains the new tropane alkaloids ferrugine (2) and 3α-benzoyloxy-2α-hydroxybenzyltropane (4) as well as darlingine (1) and ferruginine (3), which also occur in D. darlingiana.

Australian Journal of Chemistry 32(11) 2537 - 2543

google gives this for the above but i cant acess it;
Catalytic Hydrogenation of Anhydroecgonine Ethyl Ester. A solution of anhydroecgonine ethyl ester (1 g) in ethanol (50 ml) was shaken with 10% Pd/C ...

next:

Design and synthesis of a cocaine-diamide hapten for vaccine development
Mitsuya Sakurai, Peter Wirsching* and Kim D. Janda*
The Scripps Research Institute, Departments of Molecular Biology and Chemistry and The Skaggs Institute of Chemical Biology 10550 North Torrey Pines Road, La Jolla, CA 92037, USA


Journal - Chemical Society, London, Volume 76, Part 1‎ - Page 555
Chemical Society (Great Britain) - Science - 1899
... ecgonine during the oxidation of anhydroecgonine. He holds that oxygen is
added first and that then hydration takes place

Supplement to Volumes 1 and 2‎ - Page 151
R H Manske, H. L. Holmes, R. G. Rodrigo - 1965
... new route to tropane derivatives, particularly to anhydroecgonine, has been
outlined (122). ... acid giving rise to (+)-anhydroecgonine, that is, ...

An introduction to the alkaloids‎ - Page 61
George Albert Swan - Science - 1967 - 326 pages
... esterification of which with methanolic hydrogen chloride gives back cocaine
. ... When anhydroecgonine is heated with hydrochloric acid at 280° it ...



The vegetable alkaloids: With particular reference to their chemical ...
By Amé Pictet, Henry Chalmers Biddle


The Alkaloids: Chemistry and Physiology, Volume 4‎ - Page 296
R. H. Manske - Medical - 1965
is formed from anhydroecgonine by the addition of one mole of hydrogen in the
presence of a catalyst. Since anhydroecgonine is readily ...
Limited preview

the picture is from:

kms.cm-uj.krakow.pl


The Alkaloids: Chemistry and Physiology, Volume 4‎ - Page 296
R. H. Manske - Medical - 1965
is formed from anhydroecgonine by the addition of one mole of hydrogen in the
presence of a catalyst. Since anhydroecgonine is readily ...
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[*] posted on 6-12-2009 at 11:45


come on people this is chemistry not cooking,
the only cook suitable route to anhydroecgonine
is to degrade cocaine....which they wouldn't do.

the other routes to anhydroecgonine involve shit like diazomethane/ diazoacetic acid and a 2000 psi hydrogen atmosphere with methylamine, or complex enolate routes that a cook would find pretty hard/impossible without a real university lab.

still tropione/ tropane chemistry is pretty interesting IMHO

i think the Fluro-grignard phenyltropane product would make a excellent
antidepressant if put into a microdelivery device.

and Atropine can save ones life should one be in a situation where older types of nerve gas are used...the kind
that crazy terrorists could get there hands on. the fact that pomegraent, soloniums and erythroloxyon plant species all unrelated make this same type of compound says something. its a complex structure to have arisen over and over independently.
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[*] posted on 6-12-2009 at 11:59


I don't think anyone here thinks this is a drug thread, but perhaps we just simply don't know much about this subject. Most of the time, drug threads get more replies here then this one has...


Quote:
the fact that pomegraent, soloniums and erythroloxyon plant species all unrelated make this same type of compound says something. its a complex structure to have arisen over and over independently.


That is actually a really interesting point that something this complex keeps reoccurring in plants completely unrelated. I think that is proof that it has a lot of uses.




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[*] posted on 6-12-2009 at 12:21


Firstly, I'll say BS to the whole antagonist crap. Most antagonists don't mimic substrate or ligand structure, and are allosteric in nature. If you want the alpha-beta unsaturated ester (ecgonidine) for making cocaine analogues, you might as well scrap the tropane ring and go for something simpler.

The problem is that your posts aren't making any sense.

Quote:

<b>Conversion of Ecgonidine methyl ester to Ecgonine methyl ester</b>

Your title says you want to make an oxygenated intermediate required to synthesize cocaine.

Quote:

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.


So now you want to go from the beta hydroxy ester to the alkene (stupid simple reaction... beta elimination of acetylecgonine)?? Which is it?

<b>What, <b>exactly</b>, are you asking or proposing?</b> It seems to me that you're asking for help coming up with a precursor to monoamine reuptake inhibitors, and yes, that would thus qualify as cooking. Why? Because you don't seem to have a working knowledge of basic chemistry, and haven't proposed any ideas of your own.

The (other) transformation you want to do from Ecgonidine to Ecgonine is likely possible through hydroboration-oxidation. You may get a mixture of undesired diastereomers.

Let us know how it works out.
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[*] posted on 6-12-2009 at 14:58


cooking would be making cocaine directly from tropinone.

as did Cha in 2000-in a totally stereo and entantomer specific fashion-thereby avoiding all those
problems of earlier routes.

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

still all the resources i can find avoid ecgonine due to license issues
and the producers of anhydroecgonine start from benzoylmethylecgonine.

to date no one has ever published going from anhydroecgonine to ecgonine.
but with this new antibody approach even if the substance was cocaine it would be rendered inert
due to additional viral structure and not being able to pass the BBB.

anhydroecgonine is more available however and the license requirements are not so high.
this process would be great for research.

but yes, my chemist training is not very high tho in the next program plan on taking o-chem,
this is part of a research paper iam doing for biology 2 actually.

i cant cite non-existent sources for the anhydroecgonine-ecgonine back conversion. the ecgonine-BM ester of E-->antibody compound is already published.

ive read everything from willstatter in 1928 up threw preobrazhinski,clark,lewis..ect up to 2003

i assumed the back converting would be very simple and easy to source a process.....but i cant find anything
in all that....so iam going to hopefully figure out how it would be done, and put that in the paper...hopefully getting some bonus points in the process for a new chemical process.

i know i got to bust that extra bond, with a hydrogen at one site and a OH on the other right?

"The (other) transformation you want to do from Ecgonidine to Ecgonine is likely possible through hydroboration-oxidation. You may get a mixture of undesired diastereomers."

so form a intermediate with HBr, then oxidize it?
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[*] posted on 6-12-2009 at 15:52


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)
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[*] posted on 6-12-2009 at 17:23


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 :P



Attachment: new coke from tropinone.pdf (425kB)
This file has been downloaded 2086 times

[Edited on 7-12-2009 by cyclohexane]
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[*] posted on 6-12-2009 at 17:33


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.


cocaine synth.gif - 24kB

[Edited on 7-12-2009 by Arrhenius]
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[*] posted on 6-12-2009 at 17:51


Quote:

to date no one has ever published going from anhydroecgonine to ecgonine. but with this new antibody approach even if the substance was cocaine it would be rendered inert due to additional viral structure and not being able to pass the BBB.


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 :P
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[*] posted on 6-12-2009 at 19:15


no that hapten doesn't work too well.

the cocaine is attached to a inactive cholera toxin protein.
antibodies are generated for both the cholera and the cocaine....no getting high for at least 2 months
(prolonged further by a booster shot).

the antibodies bind and result in it not crossing the BBB. i mentioned that i response to the cookery contention.

its being developed by Dr.Tom Kosten at the Baylor college of medicine.

if successful then a meth version will follow.

the trials going pretty well however.....

still it looks like that method will fit the bill. after the boron/ excess hydrogen is expelled follow the usual process with benzoyl chloride or perhaps benzoic anhydride. ( was higher yielding in the old days)



a alternate maybe to form benzoylecgoinine first, the methylate it in ether with diazomethane. that process is from a forensics journal and very high yielding and fast....tho dangerous too.

you know where i can read more about this hydroboration? i should put in any driving catalysts, heat,temp,ect ect in.

i will cite you as the source if you wish....tho it'll be a funny looking reference,lol
actually i might have to look on my refrence handbook how to do that....MLA hasn't kept up with the times
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[*] posted on 6-12-2009 at 19:45


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. :D

[Edited on 7-12-2009 by Arrhenius]
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[*] posted on 7-12-2009 at 11:26


lol ill cite you some how..or the guy that discovered that and mercury poisoning.

i think the new format for website sourcing is silly...and looks poor. add date+website was accessed in case of changes? unless the reader was running a search spider on your topic from the get go it would not matter....

so i almost always find if i can thru cross referencing the website's source of the info,and then cite that itself.

looks so much better then the weblink version.

lol i know that perhaps my questions answer is so obvious ta real chemist that its not really a new process
and thats why it was never included,
but on the other hand alot of those old books and references make big deal of putting stuff in like
the hydrolysis of tropinone /atropine with hcl acid or barium hydroxide. those seem a lot simpler then what
you have told me,

so if this is new we should name it after you as the inventor....lol the Arrhenius ecgonine synthesis ;p

on a side note wikipedia suggests that a larger borohydogen is sometimes better to work with,
i this case the large size could hinder things?

wiki mentions :

Because dimerization happens instantaneously, it is not possible to isolate pure borane. However, when diborane is treated with an ether or amine, a stable complex is formed, as the lone pair from the Lewis basic oxygen or nitrogen atom is donated to the borane. These complexes act chemically like borane.
Solutions of BH3 complexes in THF or diethyl ether are commercially available and more easily handled than diborane gas, and so are the more common form found in laboratories. For simplicity in illustration, borane will be used instead of the borane-ether complex in this article.

A widely used hydroboration reagent is 9-BBN which has just one hydrogen at boron and the same applies for catecholborane.

that 9-BBN looks huge however...prob not usable. cool shape to it tho.


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[*] posted on 7-12-2009 at 13:23


Arrhenius, the addition of BH3 on alkenes is an electrophilic addition. You depicted it as a 1,4-conjugate nucleophilic addition which is plain wrong because BH3 does not even have a lone electron pair at the boron - on the contrary, it even has the so called vacant orbital which makes it electrophilic (which you correctly show in its interaction with the oxygen of the carbonyl group). The reaction would therefore follow the rules for electrophilic addition (the attack of BH3 on the most nucleophilic carbon of the alkene double bond), meaning you would get mostly the wrong regioisomer. Additionaly, since electrophilic additions on alkenes work best the more nucleophilic the alkene is, you also have the potential problem of a slow reaction which might cause the borane reduction of the ester to compete (an otherwise quite slow reaction). In the view of the major BH3 addition product having the -BH2 and carbonyl group in a vicinal relationship, the intramolecular attack among the two seem pretty much unavoidable, reducing the ester group (kind of like in the mechanism of carboxylic acid reduction with BH3 where an intramolecular attack of the hydride reduces it). This could be avoided by employing 9-BBN instead of borane, but the wrong regioselectivity can not be avoided.

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.
Also, I for one, find your apologetic approach highly annoying. So why don't you just cut all the cocaine antagonists crap and stick to the chemistry? The moment you will show a drug cook attitude the thread will be locked anyway, regardless of your excuses, but if you will stick to the chemistry with a scientific attitude (without all that as-seen-in-the-article-introduction ideological bullshit), the thread will stay active.




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[*] posted on 7-12-2009 at 13:55



from what ive read about hapten is didnt work very well....and in certine cases ( not in this contex) experiments have resulted in a total crash of the immune system.

Dr.Kosten held this out as a new approach,
and was featured in this months copy of Discover Magazine-i assume they make some effort to check the validity of the their articles as they are a science magazine.

i tried to give a sampling at the start of why this topic is interesting, and valid for legitimate reasons.

the ester can be generated later, if that would help simplify the reaction.

would this make a mix of the S and R forms? if so there is a process using different forms of tartrate to separate the two....

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[*] posted on 7-12-2009 at 15:54


my college is a jr. one and skimped on journal database access....iam lucky to get chemistry abstracts....were more orientated to land management and environment / law enforcement in wilderness.

a couple of my citations would givea clue i thought...but i cant see them.

that Australian reference had the ethyl ester being hydrogenated in ether with Pd/c.

my theory was that this might work on the methyl ester,
but i cant see what they were really trying to do or any pictures of what part of the structure they trying to hydrogenate.

the other google book reference had the entire anhydrecgonine page "not part of the preview" but the next page had the end of the prior pages paragraph on it.
that said something to the effect of "1 mole hydrogen with appropriate catalyst"

iam guessing here that hitting the ecgonine with elemental hydrogen would yeild lots of wrong entantomers,ect.

ill tryto make some journal requests, but no luck yet....
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[*] posted on 7-12-2009 at 17:19


Thanks Nicodem - valid points. If hydroboration of an alpha-beta unsaturated ester is impossible, then I suppose reduction, hydroboration and re-oxidation is in order. Saponify, hit with excess borane, workup with peroxide and hope the nitrogen isn't oxidized too. Re-oxidize to methyl ester with MnO2, NaCN in MeOH.

Cyclohexane: If things work at all, this would give a mix of (R,R), (R,S), (S,S) and (S,R). Personally, I think there will be atleast a slight steric preference for (R,S) - as shown above. Hydrogenation of the ester will give dihydroecgonidine (no double bond). Whether things are a methyl- or ethyl ester has really no effect. The ester R group is chopped off extremely rapidly by esterases to give the free carboxylic acid. In this manner, cocaine might be thought of as pro-drug.

Hitting ecgonidine with H2 will do nothing without a catalyst. If you use H2 and palladium you'll get dihydroecgonidine as I just mentioned. And no, I highly doubt you could separate enantiomers here using tartaric acid. Generally this only works for chiral amines. Do keep in mind that it would be racemic, not just a pair of enantiomers.

I'm still not clear on what exactly you're hoping to show/learn here.

[Edited on 8-12-2009 by Arrhenius]
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[*] posted on 11-12-2009 at 17:36


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.:cool:

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)
This file has been downloaded 2944 times

Attachment: Findlay.3D.Structure.of.Cocaines.1.Cocaine.and.Pseudococaine.pdf (937kB)
This file has been downloaded 1288 times

Attachment: Findlay.3D.Structure.of.Cocaines.2.Structure.of.Racemic.Pseudo.Allococaines.pdf (1.4MB)
This file has been downloaded 1197 times

Attachment: Findlay.Note.3D.Structure.of.Cocaine.pdf (402kB)
This file has been downloaded 733 times

[Edited on 12-12-2009 by unome]

Attachment: Casale.etal.D.Labeled.Cocaine.pdf (313kB)
This file has been downloaded 862 times

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[*] posted on 11-10-2011 at 07:37


ECGONINE

C9H15NO3, a cycloheptane derivative with a nitrogen bridge. It is obtained by hydrolysing cocaine with acids or alkalis, and crystallizes with one molecule of water, the crystals melting at 198° to 199° C. It is laevo-rotatory, and on warming with alkalis gives iso-ecgonine, which is dextro-rotatory. It is a tertiary base, and has also the properties of an acid and an alcohol. When boiled with caustic baryta it gives methyl-amine. It is the carboxylic acid corresponding to tropine, for it yields the same products on oxidation, and by treatment with phosphorus pentachloride is converted into anhydroecgonine, C9H13NO2, which, when heated to 280° C. with hydrochloric acid, splits out carbon dioxide and yields tropidine, C8H13N.

Anhydroecgonine melts at 235° C., and has an acid and a basic character. It is an unsaturated compound, and on oxidation with potassium permanganate gives succinic acid. It is apparently a tropidine monocarboxylic acid, for on exhaustive methylation it yields cycloheptatriene-1.3.5-carboxylic acid-7. Sodium in amyl alcohol solution reduces it to hydroecgonidine C9H15NO2, while moderate oxidation by potassium permanganate converts it into norecgonine. The presence of the heptamethylene ring in these compounds is shown by the production of suberone by the exhaustive methylation, &c., of hydroecgonidine ethyl ester
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Dr.Bob
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[*] posted on 11-10-2011 at 09:35


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.


Since someone else bumped this zombie thread, I couldn't help myself... I just attended a lecture on a similar research project by a different researcher.

There are a number of vaccine approaches for anti-drugs of abuse in progress. As it turns out, some of the approaches DO in fact work to some degree. Since mosts drugs cross freely back and forth on the BBB, any process that binds them will shift the equilibrium to remove some of the drug from the brain, as well as to lower the Cmax, lengthen the Tmax, and blunt the peak brain levels. Would this stop drug abuse, maybe, maybe not, but the NIH and its child agencies have funded a great deal of work in that area. The MWs and such are not quite as bad as your math shows, but the antibodies do recycle and their activation causes them to be cloned, just like any other immune response with antibodies.

I will agree that many of the approaches are long shots, but they are being funded by our own government, so they are not completely a "fund-raising pseudoscientific hoax" anymore than most other government funded research. (I'll leave that to the voters to decide.)

Bob

http://www.bcm.edu/news/packages/kosten/

(Oct. 5, 2009) -- A cocaine vaccine that recruits the immune system to help block the drug's euphoric effects proved effective in 38 percent of subjects who received the vaccine, said a Baylor College of Medicine researcher who led the study.
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[*] posted on 14-3-2013 at 06:07


Reference Information


Concise Catalytic Asymmetric Total Synthesis of Biologically
Active Tropane Alkaloids

Armando Crdova,a,b,c,* Shuangzheng Lin,
Adv. Synth. Catal.
2012, 354, 1363 – 1372
DOI: 10.1002/adsc.201100917


Abstract
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-a,b-unsaturated enals using only two and three column chromatographic purification steps, respectively.

Attachment: Concise Catalytic Asymmetric Total Synthesis of Biologically Active Tropane Alkaloids.pdf (472kB)
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[Edited on 14-3-2013 by solo]




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