Cocaine Homolog Questions

[PrimoPyro]

Hi.  

Look at these for a second:



They are both cocaine homologs, the one on the right is really cocaine, the one on the left is a proposed structure that has a few slight variations.

They are:

1.The six-membered piperidine portion of the bicyclic ring has been shortened to 5 members, making it a pyrrolidine ring. This changes the relative positioning of the two ring substituents, the methyl carboxylate, and the benzoate relative to the nitrogen. Before, the benzoate was para, and the methyl carboxylate was meta. Now, they can both be said to be "metapara" as the nitrogen is between both of them, visually, when depicted as a 5 membered ring.

2.In the tropine portion of the ring, the ethyl bridge now has a double bond, making it an ethylene bridge.

What I would like to know/have opinions on, is: would the activity of this homolog be very different than cocaine itself? Do you think potency would decrease with these two changes? If the double bond is a problem, what about the same questions for the saturated version of this five-membered homolog? Is the six-carbon ring skeleton vital to cocaine's action and potency?

I know there are a number of cocaine analogs that have been synthesized, some stronger, some weaker, but I have never seen either of these. I am interested in these, most especially the unsaturated compund, because I can think of a novel method for its preparation that I have never seen before.  

Also, is the N-methyl in these cocaine analogs vital to its function and potency? The unmethylated analog would be tens of times easier to produce than the N-methylated version.

Thanks for your answers/opinions.  

                                                  PrimoPyro

[Rhodium]

I believe this is what's known about cocaine analogs:

https://www.thevespiary.org/rhodium/Rhodium/pdf/cocaineanalogs.pdf

As you can see, there are several N-substituents that "works".

[PrimoPyro]

Thanks Rhodium.  

I wonder how one would prepare N-methyl pyrrole?

1.Diels-Alder reaction between pyrrole (or N-methyl pyrrole) and maleic anhydride affords the bicyclic structure with a dicarboxylic anhydride at the positions that become the above mentioned substituents.

2.Reaction with NaOH and NaOCl changes the anhydride to the 1-amino-2-carboxylic acid.

3.The methyl ester of the carboxylic acid is made.

4.The amine is converted to the diazonium chloride, and then changed into the alcohol.

5.The benzoate ester is prepared.

Heh, my original idea was wrong haha, and I had to modify it as I wrote this. I had the oxygen on the wrong side of the carbonyl in my first idea.  

I originally wanted to make the carboxyl into a benzoate (haha, foolish error like I said, oxygen on wrong side in my mental image, oops) then react the diazonium chloride with cuprous cyanide to form the nitrile, and then react the nitrile with methanol in aqueous HCl to form the methul ester from the nitrile. heh, error error error, now its not as good a synth as I thought it was originally.

Oh well.....its still "different."

                                                   PrimoPyro

[PrimoPyro]

In the synthesis of cocaine from succindialdehyde, methylamine, and acetonedicarboxylic acid, the intermediate cyclic dicarboxylic acid it produced before decarboxylating to tropinone.

Is it possible to to prepare a half ester of this dicarboxylic acid before decarboxylating? With one of the acyl functions protected as an ester, one carboxyl can be selectively chewed off the molecule. If the methyl ester was specifically prepared, then after the monodecarboxylation, and reduction of the ketone to the alcohol, one would have methyl ecgonine right off, instead of totally decarboxylating the ring, then re-adding the carboxyl and forming the methyl ester.

Now just form your benzoate, gas it, and eat it.  

Also, can succindialdehyde be made from ozonolysis of 1,5-hexadiene, or the cyclic version of this?

                                                  PrimoPyro

[Rhodium]

I don't think you make 1-Methyl-pyrrole (CAS No 764-01-2), you buy it. $20/100ml from Aldrich.

If you react acetonedicarboxylic acid anhydride (beta-ketoglutarate) with methanol, you get  acetonedicarboxylic acid monomethyl ester. If you use that in the Robinson tropinone synthesis, the product is racemic 2-carbomethoxy-tropinone. After resolving that and keeping the desired optical isomer, you reduce the ketone with a reducing agent that preferentially gives pseudotropine and as little tropine as possible (that is axial or equatorial placement of the OH). Now you separate these isomers, and benzoylate the isolated pseudotropine to get (-)-Cocaine (all other isomers are inactive).

[PrimoPyro]

I thought that the Robinson tropinone synthesis required the free dicarboxylic acid? This is the only reason I did not propose this exact procedure initially.

If the half ester works, that is fantastic.  

[Rhodium]

The only thing required is the carboxyl function, or other EWG, like nitro/cyano etc.

[PrimoPyro]

Therefore, beta-oxo-butyronitrile could be used to procure the tropinone ring with a 2-nitrile instead of a carboxyl?

Alcoholysis of the nitrile would give the methyl ester. Then reduce the ketone to ecgonine methyl ester.  

I like this one even better. I wonder how common the beta-oxo-butyronitrile is?

[Rhodium]

You need an EWG in both ends, adjacent to the keto group in the middle. This to easier make the enols and "acidify" the alpha protons.

[Tricky]

In original Robinson Tropinon synthesis used simple acetone instead acetondicarboxylic acid. AFAIK, it also calls Willschtetter Synthesis.
But now I can't give any references about it, because I don't remember there I've seen it  
Matrix... may tricks?

[PrimoPyro]

...it might work using a mega-strong basic catalyst like LDA to promote enol tautomerization over keto toutomerization.