Sciencemadness Discussion Board

Tropane Chemistry

unome - 7-3-2010 at 22:45

Notice, I made no reference to Coca in the topic heading, this thread is not SPECIFICALLY about Peruvian Marching Powder, but about the bizarre chemistry, specifically under reduction, of tropin-x-ones...

Now, there have been many, many arguments about this, but the N-Methylamino group is, despite it's 'apparent' chirality, chiral after all - it can exist in either of two forms, but they are superimposable, thus it cannot be chiral - which way the methyl group points is, yet isn't chirality, for the simple fact is it's a tertiary amine, held in place rigidly on only two sides and inversion is going be toward whichever side it finds most attractive - numerous papers have dealt with the subject (most of which are way above my head) and they ignore it, so shall I:cool:).

Findlay's papers on the subject are instructive, pseudotropine and tropine (the two epimeric alcohols, one axial & the other equitorial) are both oxidised to tropinone, ie. a single isomer (see the difficulty? first citation HAS to be be to the most demonized tropane of all?)... Anyway, in one of his papers (the second attachment), he notes that natural ecgonine is 2-cis-carboxy-3-cishydroxytropane (and as cis and trans are a whole lot easier to deal with, that would make pseudoecgonine 2-trans-carboxy-3-cishydroxytropane...

That would mean that the relevant Alloecgonine and allopseudoecgonine would be 2-cis-carboxy-3-transhydroxytropane and 2-transcarboxy-3-transhydroxytropane

But the interesting thing here is that there are several papers on the reduction of both 2-tropinone and the 2-carbomethoxy-variant using sodium alcoholates to give the "natural" ecgonine and pseudoecgonine derivatives, which is interesting insofar as it would on one hand, appear to support Findlay's assertion that reduction by sodium amalgam in alcohol gives predominantly the "natural" (cis) epimeric alcohol (and hydrogenation gives the predominantly the "unnatural" (trans) variants), but on the other hand it flies directly in the face of his statement that even mild treatment with alkali alcoholates causes epimerization around C2... I mean, the papers to support his argument about epimerization, by showing that the longer the reaction proceeds, the lower the yields of the natural enantiomer (same configuration at the alcohol, the shift is at the carboxyl), but he reduces 2-CMT in sodium amalgam/alcohol over some considerable period (in what would have to be a seriously strongly basic solution) without complete inversion @C2?

So far as I remember, there is at least one paper stating that reduction of pre-resolved (-)2-CMT with sodium isopropylate (the last attachment) gives the 'natural' (thus the resolution must have involved the C2, as the Ketone at C3 would presumably be irrelevant prior to reduction, and therefore (-)-2-cis-Carbomethoxytropinone was reduced) and there is another article attached stating that sodium pentolate gives effectively the same result with 2-tropinone (IIRC, the second to last attachment).

Could anyone explain why such a result is possible? It just seems novel to me that using the alcoholate to effect reduction is rather novel, especially, where as here, it is apparently seriously enantiospecific (or should that be epimer-specific, it is the epimeric alcohols that are the reduction product).

Attachment: Findlay.3D.Structure.of.Cocaines.1.Cocaine.and.Pseudococaine.pdf (937kB)
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Attachment: Findlay.Note.3D.Structure.of.Cocaine.pdf (402kB)
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Attachment: Findlay.3D.Structure.of.Cocaines.2.Structure.of.Racemic.Pseudo.Allococaines.pdf (1.4MB)
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Attachment: Sinnema.etal.Configuration.all.4.Cocaines.NMR.pdf (1MB)
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Attachment: Carroll.Coleman.Lewin.13C.NMR.Study.Isomeric.Cocaines.pdf (911kB)
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Attachment: Bell.Archer.2.Tropinone.pdf (417kB)
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Attachment: Casale.etal.Base.Catalyzed.C2.Exchange.Epimerization.Cocaine.Analogues.pdf (806kB)
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[Edited on 8-3-2010 by unome]

JohnWW - 8-3-2010 at 00:24

As I remember, tropane, tropic acid, tropidene, tropinone, etc., and ultimately the tropylium carbocation, have 7-membered rings, and are usually derived from the degradation of atropine, the principal poisonous substance in deadly nightshade (belladonna), used in very small (nanogram) quantities as a muscle relaxant, which has a 7-membered aliphatic ring bridged by a tertiary N atom. Cocaine also has an aliphatic 7-membered ring, similarly bridged by a tertiary N atom, but there the resemblance ends.

Being illegal in many places (as part of the phoney "war/whore on drugs", run to enrich the CIA and the Mafia), it is much more difficult to get hold of cocaine to perform such degradation reactions. BTW, I wonder it there is any way that atropine could be economically converted to cocaine.

turd - 10-3-2010 at 05:13

Hi, umome, just send me 100 g of 2-cis-carboxymethyl-tropinone and I will tell you if it reduces to the "natural" isomer. :D:D

But seriously, is this reduction described in any of the papers you posted? I quickly skimmed over them and didn't see it. Would be interesting to compare the reaction conditions to those of the epimerization studies.

BTW, I wonder it there is any way that atropine could be economically converted to cocaine.

Probably not. Definitely not by me in any case. Without some racemate resolution the best you could theoretically get would be racemic cocaine (i.e. with half of the molecules havng the carboxy group on the 4- instead on the 2-position). And I doubt that the regioselectivity of the involved reactions is all that good, so total yield of the "good" stereoisomers would probably be quite low. The fact that carboxy group is to be in the thermodynamically unfavourable position and apparently tends to epimerize if you look wrongly at it doesn't make things better... :P

You would probably be more lucky trying to make some analogues: (+references therein)
But honestly, I wouldn't want to test them. Atropines being strong deliriants which are awful hard on the body and ecgonines being strong stimulants which are also hard on the body - I'm somewhat skeptical that there are nice things there. Of course very interesting nonetheless...

un0me2 - 18-8-2010 at 01:17

At least two of them deal with the chemistry of the reduction, catalytic hydrogenation & the hydrides give the wrong (equitorial isomer), whereas the alkoxide(s) are reported to give up to 95:5% pure axial isomer.

Not bad if it's true, as if one were to start with 2-CMT, the solubility of the enantiomers (@C-2) are used to separate the "natural" product from the unnatural one. As there is only 4 options in reality and two are taken out of the equation by the solvent separation, means that if such a selective reduction is available, that the natural form of methylecgonine should be pretty much pure after the reduction.

Globey - 18-8-2010 at 05:26

enolization wouldn't be taking place here and at any step AFAICT. There is possibility of mistakes in the literature, but that seems u unlikely here due to corroboration. I'm just using a simple cyclohexyl model to try and get a handle to begin to visualize what you are talking about, but it is far beyond me level of knowledge. Keep us updated please!

Globey - 18-8-2010 at 05:29

Quote: Originally posted by turd  
and ecgonines being strong stimulants which are also hard on the body

Indeed yes, and especially hard on the heart.