Author Topic: Yeast reduction of P2P to (d)-phenyl-2-propanol? (Read 241 times)

no1uno · « **on:** March 19, 2012, 11:41:22 AM »

Ok, the nomenclature I have to think about for a bit, but I was trying to work out a way to resolve, recycle, etc. (that is if one had to do so) the wrong isomer of MA. All roads really do lead to P2P in that regard.

But we know that yeast can reduce the ketone involved and we also know we can brominate the alcohol, which should/would give the relevant (for the sake of argument) (d)-Phenyl-2-bromopropane ONLY.

So the question is, why isn't that being done, yeah, yeast reductions look painful to implement, but they are being used in undergraduate courses nowadays. Bromination of the alcohol - there is a paper on that somewhere on this board - shouldn't be too difficult to imagine, nor should alkylation of Methylamine using the same. In fact neither of the two steps (bromination or alkylation) should 'realistically' fuck up the chirality of the single isomer alcohol.

salat · « **Reply #1 on:** March 19, 2012, 01:18:14 PM »

It was in use in at least one lab that got busted- see attached paper (2nd one down). The first paper is the scientific paper on the method. Consider that a lot of the early hive chemistry was based on early 20th century chemistry there's a heck of a timelag. Even so it was quite a lot of work by a lot of talented and untalented people to translate laboratory techniques into something that could be done by nonchemists in a home lab.

I just downloaded a bunch of papers on lignin chemistry from the wood pulping industry. That is exactly what industry is attempting to do with byproducts from papermaking. Many of the reactions are enzymatically based. ACS has a special topic area with lots of interesting papers.

Salat

no1uno · « **Reply #2 on:** March 19, 2012, 03:00:29 PM »

Yeah, we aren't discussing l-pac, but the reduction of P2P itself to P2Pol, then bromination of that to P2BrP.

The attached paper demonstrates that the P2Pol's can be used to produce a stereospecific outcome - ie (r)-/(s)-P2Pol (nb (r)=L & (s)=D confusing ain't it?) gives the relevant (r)- or (s)-P2BrP, reaction of that with Methylamine would give the relevant (r)- or (s)-MA.

But the yeast reduction should give a single isomeric P-2-Pol, that is the trick I'm working toward

marakov · « **Reply #3 on:** March 19, 2012, 09:34:54 PM »

Quote from: marakov on March 19, 2012, 09:29:04 PM

Quote from: no1uno on March 19, 2012, 11:41:22 AM
Ok, the nomenclature I have to think about for a bit, but I was trying to work out a way to resolve, recycle, etc. (that is if one had to do so) the wrong isomer of MA. All roads really do lead to P2P in that regard.

It has been done. A chemist would isolate the isomer via tartarate salt, degrade the isomerised product to the alcohol or ketone and proceed from there. It is time consuming to put it mildly. There is information on the rhodium archive about this process. Look up ephedrine degradation to Benzyl Methyl Ketone. It will put you in the right path. The chemistry is related.

Quote from: no1uno on March 19, 2012, 11:41:22 AM
But we know that yeast can reduce the ketone involved and we also know we can brominate the alcohol, which should/would give the relevant (for the sake of argument) (d)-Phenyl-2-bromopropane ONLY.

So the question is, why isn't that being done, yeah, yeast reductions look painful to implement, but they are being used in undergraduate courses nowadays.

When working with yeast the biggest problem is the solvent volumes required to even bench scale reactions to proceed in acceptable yield. What is typically done is that yeast are produced and then lysis is performed to separate the enzymes from the yeast cells. It usually involves a mild base and a centrifuge. The enzymes are then used in place of the yeast allowing the chemist to use smaller solvent volumes which makes the process scalable.

Quote from: no1uno on March 19, 2012, 11:41:22 AM
Bromination of the alcohol - there is a paper on that somewhere on this board - shouldn't be too difficult to imagine, nor should alkylation of Methylamine using the same. In fact neither of the two steps (bromination or alkylation) should 'realistically' fuck up the chirality of the single isomer alcohol.

Bromination can be done via NaBr/KBr or with Br2. You are correct that there is plenty of information of this available.

Note: Marakov was unable to find proof for the comment below:
See these two subjects in relation to reductive alkylation for information about chilarity.
NaBH4 versus Al/Hg and Stereospecific synthesis using bromopropiophenone.
It is some related.

no1uno · « **Reply #4 on:** March 19, 2012, 11:48:28 PM »

Is there a paper on that Marakov? I've read most of the papers on the preparation of ephedrine/cathinones from bromopropiophenone and there is a definite issue with the reduction of the ketone in that series - even between hydrides and Platinum/other reductions. But it seems improbable that they would reduce a carbonyl group on the second carbon on the chain the same way, as all arguments I've seen concentrate on the restricted access to the benzylic carbon being the primary cause of chirality, whereas yeasts effect is due to a very different mechanism (also, if it were possible to 'easily' introduce chirality on this particular substrate chemically it would surely have been done before now - perhaps even when Walden et al were playing around with inversions?)

But if there is a way to avoid resolution and recycling then it should be taken, if nothing else racemic product automatically lets LE know what is being used/done which is rarely a good thing.

marakov · « **Reply #5 on:** March 20, 2012, 07:07:55 PM »

Saw paper on system for isolating via metal tartarate salts in two phase system using a hydrocarbon. It was written up almost as a process and didn't look as time consuming as I remember resolution to be and now I can't seem to find it.
This will have to be for now.

Update:

I checked again and was unable to find the information to proof. I do remember seeing a paper to that effect but I must take back what I said about the stereospecific reduction until I can provide proof of my claim.

Tungsten. · « **Reply #6 on:** April 05, 2012, 07:36:48 PM »

Wouldn't P2BrP + NH3 or H2NMe lead to polymerization (probably more-so with NH3 than H2NMe) ? You might have to find a way of protecting the nitrogen...

carl_nnabis · « **Reply #7 on:** June 12, 2012, 05:36:24 PM »

i think this topic is drowning here it is so damned interesting, so how far has your research come yet? I would more likely do this with some phenylacetone this is definitely the best thing one can do with it!
But instead bromination or maybe this and then iodine via finkelstein swap better tosylation with tosylchloride, easier added to an alcohol and i´ve read a 100x or 1000x better leaving group, this would be a so much cleaner and better way from phenylacetone to d-MA.
p-Tosylchloride is cheap and nonsuspicious too, its a waste product of saccharin production. I think it can be bought without any trouble, and the p-toluene sulfonic acid can be recovered from ones own nontoxic waste it has some interesting uses.
Polymerization is also more unlikely to happen with this leaving group I think.
The reduction is similiar to the one phenylethylamin and tryptamin decarboxylated from the corresponding amino acid undergo to tryptophol and phenylethanol or that one from nitroalkene to nitroalkane, just charming like any biosynthesis is!
i would really love to see something like this happen one day
racemic product was never something that has given me the same godmode feeling because of side effects, a god has not huge dilated pupils nor sweaty hands

it felt only like a more potent better version of standard racemic amp, somewhat boring over times, not the same for both, the primary and secondary amine, if they were in pure eutomeric forms.

atara · « **Reply #8 on:** June 13, 2012, 02:05:34 AM »

My understanding is that the SN2 halogenation of an alcohol with HBr generates a reliable steric inversion, that is, a conversion cleanly to the opposite isomer. The subsequent reaction with methylamine gives a second inversion, restoring the original [desired] chirality... the Finkelstein reaction allows the chirality to switch multiple times and thus gives a racemic product, so is undesirable for the purposes of chiral purity.

If what is to be recycled is the laevomethamphetamine, perhaps... an anhydrous route will save a little pain along the way? N-bromosuccinimide or N-chlorosuccinimide should generate cleanly the bromamine/chloramine which can undergo dehydrohalogenation to the P2P-imine without hydrolysis... reduction then gives a racemate. A review of N-haloamine chemistry, including formation and dehydrohalogenation reactions, is attached. I am hopeful that this could be made into a one-pot reaction.

Sure, it isn't pure, but hey... isomeric resolution is in this case much easier than enantioselective synthesis, I'd argue.

carl_nnabis · « **Reply #9 on:** June 16, 2012, 11:54:00 PM »

I cannot believe what a little gem this whole thing here is and it seems really like no one except no1 has realised how beautiful, elegant and clean this is!

sooo...
first atara, tosylation is as an ester a similiar SN2 reaction like a halogenation is, so that should apply here too.

then, what we need is S-Phenyl-2-propanol (or d-P2Pol, S-P2Pol, your choice), and thats fortunately what we get (mostly

) according to this here:
hxxp://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv7p0215

this will get the same chirality back after the ester/halogen swap, one will end with desired S-MA....

it seems that no1 has invented a fantastic way to synthesize d-MA without unwanted products, and even without the need of ephedrine... and even more fantastic, even without the need of mercury or another toxic reagent....

You definitely have earned a lot of respect, this is really beautiful!
Even l-PAC can be somehow made in this manner, as the varying of conditions
changes the isomeric output... see attached paper...

carl_nnabis · « **Reply #10 on:** June 17, 2012, 12:01:07 AM »

And, to add, someone who is in the need to separate isomers of said product, has the ability to produce P2P and how to aminate it...

but think of someone who knows of this whole topic, has access to TsCl, etc?

I think anybody who is smart enough to make P2P and racemic product, is also smart enough to do this whole process using d-P2Pol...
Thus avoiding at least nasty mercury... and of course unwantend byproduct

you should not say "just recycling of unwanted l-methamphetamine" because i know several people who actually would only for that purpose consider to make P2P... there is still really a lot to discover

Author Topic: Yeast reduction of P2P to (d)-phenyl-2-propanol? (Read 241 times)

no1uno

Yeast reduction of P2P to (d)-phenyl-2-propanol?

salat

Re: Yeast reduction of P2P to (d)-phenyl-2-propanol?

no1uno

Re: Yeast reduction of P2P to (d)-phenyl-2-propanol?

marakov

Re: Yeast reduction of P2P to (d)-phenyl-2-propanol?

no1uno

Re: Yeast reduction of P2P to (d)-phenyl-2-propanol?

marakov

Re: Yeast reduction of P2P to (d)-phenyl-2-propanol?

Tungsten.

Re: Yeast reduction of P2P to (d)-phenyl-2-propanol?

carl_nnabis

Re: Yeast reduction of P2P to (d)-phenyl-2-propanol?

atara

Re: Yeast reduction of P2P to (d)-phenyl-2-propanol?

carl_nnabis

Re: Yeast reduction of P2P to (d)-phenyl-2-propanol?

carl_nnabis

Re: Yeast reduction of P2P to (d)-phenyl-2-propanol?