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Author: Subject: Decided on a goal - chloramphenicol.
PirateDocBrown
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[*] posted on 9-2-2017 at 20:51
Decided on a goal - chloramphenicol.


I have been watching NurdRage's total synthesis on pyrimethamine with great interest and admiration. Chemplayer, Dougslab, and several others as well.

I decided to do something similar, and document it for online video.

I have zero experience making videos, I don't even own a camera that's not part of my phone (yet), but hey, life is a learning experience.

But I do know chemistry, and have started to create a lab.

But what to make in it? Well, I read some books, the "1632" series, where an entire town is moved back in time. They had limited resources, but realized that antibiotics were one of the defining technologies of the modern era. They decided to make chloramphenicol, bootstrapping from 17th century technology.

This would be a highly useful skill in the event of a catastrophe that leads to a post-apocalyptic world. So why not perfect it?

I've sketched a total synthesis from mostly OTC sources, and am looking for just a few more pieces of the puzzle.

The lab still needs work, a fume hood must be built, and the vacuum pump situation needs to be resolved. I continue to find OTC chemicals.

And of course, I need to learn how to do video production. I'm looking at a time horizon of at least a year or two to begin publication.

I welcome input.
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[*] posted on 9-2-2017 at 21:28


This looks like a challenge.


It is way out of my league but I will follow with interest.
As for videography, it sounds like you and I are in the same place: building a lab, buying a camera, learning the ropes in the field of editing and posting some stuff online. My target date is September. I have a growing number of projects in mind.

More power to you!
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PirateDocBrown
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[*] posted on 10-2-2017 at 02:11


Well, I'm going to aim at racemic synthesis at first, and worry about stereochemistry after.

The starting point would be p-nitro acetophenone. The final reaction would be the amide addition of the dichloroacetate.

Both of those materials, of course, would have to be made from simpler ones.

Now, characterization of intermediates as I go will also be a challenge, as I completely lack analytical instruments.
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PirateDocBrown
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[*] posted on 10-2-2017 at 02:25


The first step would be halogenation of the terminal methane of the p-NO2 acetophenone. This would be followed by replacement of the halogen to create a primary amine. This would need to be protected, by amide formation, then the alpha methyl hydroxy group could be added from formaldehyde. Then the original carbonyl can be reduced, but under mild conditions, as you don't want a reaction with the nitro. The protective amide can then be hydrolyzed, and replaced with the dichloroacetate.

When working out the enantomeric resolution, you create an intermediate with another chiral compound, after the carbonyl reduction (since that creates your final chiral center), but before the final amide condensation. Then once resolved, complete the synthesis as before.

But, baby steps.
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DJF90
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[*] posted on 10-2-2017 at 04:44


Quote: Originally posted by PirateDocBrown  
Well, I'm going to aim at racemic synthesis at first, and worry about stereochemistry after.


Its not just absolute stereochemistry you've got to deal with, but also relative stereochemistry. You're going to have to make sure those two stereogenic centres are (R,R) or (S,S) whilst avoiding the (R,S) and (S,R) diastereomers, just to acheive a racemic mixture!

How did you come up with p-nitroacetophenone as a starting material? This doen't seem particularly easy to access (seeing how it also needs to be prepared), and there are likely other beneficial disconnections you could make in order to streamline the synthesis if you're open minded about starting materials (obviously/ideally they'll be OTC or at least available to yourself)

[Edited on 10-2-2017 by DJF90]
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PirateDocBrown
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[*] posted on 10-2-2017 at 06:40


Yes, in my previous post I do refer to enantiomeric resolution. But I'm going to concern myself with getting to the endpoint, before moving on to which of the 4 enantiomers are selected for.

As for p-NAP, nitros are pretty sturdy functional groups, so long as you don't expose them to strong reducing environments.

Carbonyls, of course, are the normal jumping off points for most syntheses.

Nitros do direct to the meta position, so to make it, I would have to start out with a substituted benzene, in this case, acetophenone, then add the nitro, and then resolve the para isomer.
[Edited on 2/10/17 by PirateDocBrown]

[Edited on 2/10/17 by PirateDocBrown]

[Edited on 2/10/17 by PirateDocBrown]
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[*] posted on 10-2-2017 at 07:05


You won't easily be able to get p-nitrobenzaldehyde from p-nitrophenol. (You could oxidize p-nitrotoluene to the aldehyde.)

From p-nitrobenzaldehyde, you could react it with a vinyl Grignard, and then functionalize the double bond. If I have time, I could plan a diastereoselective synthetic route.




As below, so above.
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PirateDocBrown
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[*] posted on 10-2-2017 at 07:07


Yes, that's what I'm now looking into.
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CuReUS
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[*] posted on 10-2-2017 at 10:05


what about this route ?
1.Claisen-schmidt reaction between p-nitrobenzaldehyde and acetaldehyde to give p-nitrocinnamaldehyde
2.reduction of p-nitrocinnamaldehyde to p-nitrocinnamylalcohol using NaBH4 or MPV
3.epoxidation of the double bond of p-nitrocinnamylalcohol
4.reaction of epoxide with NH3
5.amidation of the compound obtained from the previous step with dichloroacetic acid to give chloramphenicol
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[*] posted on 10-2-2017 at 12:16


Sounds like a fun but very challenging project! I look forward to seeing how it goes.

I do feel that it is necessary to point out, however, that oxidation of nitrotoluenes to nitrobenzaldehydes might not be as trivial as it seems. There are several possible routes, but most are not very amateur-friendly, and the ones that are are not very well documented.




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Hexavalent
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[*] posted on 10-2-2017 at 15:51


Quote: Originally posted by PirateDocBrown  
Yes, in my previous post I do refer to enantiomeric resolution. But I'm going to concern myself with getting to the endpoint, before moving on to which of the 4 enantiomers are selected for.


These four species are diastereomers of one another, not enantiomers.

I think you're missing DJF90's point; you need to control the relative stereochemistries of your two chiral centres. Otherwise, you will have a mixture of four products, with two different sets of physical properties between them. I'm not familiar with this molecule and so I'm not sure how much these properties vary (and hence how easy it will be to separate the two pairs of enantiomers ((R,R)/(S,S) and (R,S)/(S,R)) from the mixture).

In any case, potentially having to discard 75 % of your final product (in order to achieve a single enantiomer) seems like a very wasteful approach to what is already a challenging synthesis.

How do you propose to determine/characterise the absolute and relative stereochemistries during your synthesis? The ideal solution would of course be X-ray crystallography but this is clearly impractical in an amateur environment.

[Edited on 10-2-2017 by Hexavalent]




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[*] posted on 10-2-2017 at 16:50


Good luck! This certainly looks like a tough but very interesting challenge!

Lots of awesome potential chemistry here - nitration, hydroxymethylation, Delepine reaction...

A quick google came up with an interesting paper (http://www.ptfarm.pl/pub/File/Acta_Poloniae/2000/3/213.pdf) which also describes the synthesis of some analogues: thiamphenicol, azidamphenicol, perchlorylamphenicol (holy cow), so there might also be lots of viable analogue options to consider and hence some variants of starting ketones / aldehydes possible.




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PirateDocBrown
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[*] posted on 10-2-2017 at 18:21


Good questions have been raised, meaning I'm going to have to do some more research and likely modeling.

Controlling stereospecificity is usually unique to each problem, so I'm going to have to look for ways to do that here, OTC.

First task, as I said, will be mastering the racemic sysnthesis

[Edited on 2/11/17 by PirateDocBrown]
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[*] posted on 10-2-2017 at 20:30


Pirate:

You may find some of the chemistry in these two patents useful.

AvB

Attachment: phenylserine prep US2816915A.pdf (554kB)
This file has been downloaded 189 times

Attachment: phenylserine prep DE1938513B1.pdf (644kB)
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