Sciencemadness Discussion Board

Important milestones in organic chemistry/organic synthesis

NiCoLi_BrLiNTe - 16-6-2013 at 09:40

I've been looking to step-up to some more difficult organic synthesis now that the academic year is over. To be honest most of the stuff I've been messing about with so far is relatively easys inorganic synthesis like P-toluene sulphonic acid. Anyway I've been looking through the literature for inspiration and came-up with the following idea. Firstly I've searched the forum and whilst there is loads of information on loads of different topics/areas, I couldn't find anything like what I'm proposing! Which is, rather than everyone searching through shit loads of irrelevant papers, we could start a thread containing links to articles of specific interest. I think it could be a useful resource! However I've (often) been wrong before.
Anyway I'll kick it off with a classic: Wohler's synthesis of urea, well actually its a reconstruction of his synth! Even if no one wants to do it, it's definitely worth reading through.

Also, I was thinking of putting Gate's total synthesis of morphine up as well, but i'm not sure if it's a good (ethical) thing to do? obviously it's impressive chemistry and a definite milestone in organic synthesis, but equally it has obvious abuse potential? I'd appreciate any opinions on this!

Sincerely,

NiK

Attachment: synthesis of urea.pdf (365kB)
This file has been downloaded 508 times


ScienceSquirrel - 16-6-2013 at 12:33

The discussion of total syntheses of morphine type alkaloids is allowed on this board because no one would ever take this route to make a controlled substance.
It is just too difficult and low yielding.
As far as l know all the companies that supply codeine, morphine, heroin, papaverine, etc to the pharmaceutical industry start from opium.

ScienceSquirrel - 16-6-2013 at 12:35

If I can make a nomination, Woodward's total synthesis of strychnine;

http://en.wikipedia.org/wiki/Strychnine_total_synthesis

aliced25 - 16-6-2013 at 18:55

There is a discussion on homoanisic acid with a view to the synthesis of dextromethorphan. Feel free to get involved in that, it is something I've become interested in. The best route I can see, is from methylation of Raspberry ketone to give the 4-(4-methoxyphenyl)-2-butanone, which should cleave with peroxide to give homoanisic acid.

Trying out various improvements, such as MW amide synthesis, N-methylation of the phenethylamine either before or after Birch Reduction, there are a number of interesting components. The potential for cyclization with other acids than those used in the past (polyphosphoric or HBr), even in the MW, yeah, there should be considerable amounts of interesting chemistry.

NiCoLi_BrLiNTe - 17-6-2013 at 03:51

It's amazing how they complete structure elucidation by synthesising the the molecule. I know that was how they proved molecular structure before x-ray diffraction and crystallography, by Strychnine is hideously complex. Where would you begin. I may be wrong, but I believe with Gate's total synthesis he began with the deconstruction of the complete product, breaking it down until he reached a relatively abundant starting material, 2,6-naphthalenediol. Then for the total synthesis he worked back from 2,6-naphthalenediol to the complete morphine molecule.
I've attached a paper which contains both Gates 1952 synthesis and K. C. Rice's 1985 total synthesis; as well as notes on other important occurrences in the sub-field.
Also, can anyone find the synthesis of Taxol? It's quite recent but I like to see it anyhow!
Ok, that pdf exceeds the 2MB limit - but heres the link:
http://www.springer.com/cda/content/document/cda_downloaddoc...

NiCoLi_BrLiNTe - 17-6-2013 at 03:52

Also thanks for the offer aliced25, I will have a look at the discussion you've mentioned. Although I'm afraid I won't be of much use!

NiK

kavu - 17-6-2013 at 06:30

In the olden days of total synthesis it was not so much based on retrosynthesis (formalized by Corey in 1995) but rather on known decomposition products. Some natural compounds might have been hydrolyzed for example to give compounds, few of which were previously known structures. Such modifications of somewhat closely related members of the same compound groups led to many of the great total syntheses of the past. This was also the case with the famous total synthesis of camphor by G. Komppa.

You might find the book series Classics in Total Synthesis by K. C. Nicolaou closely related to your interests. Nicolaou has also authored the book "Molecules That Changed The World", which doesn't require as much background in organic chemistry.

[Edited on 17-6-2013 by kavu]

NiCoLi_BrLiNTe - 17-6-2013 at 07:19

Thanks Kavu, I've just bought why chemical reactions happen, by J, Keeler and P, Wothers, it's aimed at chemistry students making the transition from A-Level to undergraduate but is still absolutely fascinating. I was already starting to look for something to read once i've finished it so I'll definitely check those two books out!
Thanks again,

NiK

Intergalactic_Captain - 18-6-2013 at 05:16

As nicol and alice noted, total synthesis has a fascinating history - even though now it's pretty much an esoteric adventure.

Woodward's strychnine synthesis was one of the first we studied in my favorite o-chem class. Think about it - 1954, the state of technology at the time was just barely at the point where the total stereochemistry of the target molecule could be deduced. It was regarded by my professor as one of the first proof-of-concept tests that, by working backwards and figuring out your building blocks, any natural product could be made in the lab.

Go back a few decades and all you had to work with was combustion gas analysis and x-ray crystallography, which coupled with characterization tests could give you a rudimentary idea of structure provided you had the chemical formula. At this point in time, total synthesis was more of a tool to elucidate structure than for production - If the optical rotation doesn't match, somethings wrong with your stereochemistry - And it was known then that getting the formula right doesn't mean crap if you don't know what the molecule "looks like."

Now throw yourself back to the 19th century - One of my favorite stories in chemistry is that of the creation of mauvine. The inventor was trying to create indigo in the lab - The science of the time was advanced only so far as combustion analysis, and he knew that indigo had exactly double the number of every atom as aniline - So the obvious answer was to condense two molecules of aniline into one of indigo... Long story short, chemistry doesn't work that way and he failed spectacularly, but accidentally created a cheap artificial purple dye and became wildly rich. A total failure on the synthetic front, but then again, at the time, he was only working with knowledge and logic that was state of the art...

...Not entirely certain where I was going with that, but I'll put my vote in for Woodward's strychnine syntheis - It's widely regarded as the beginning of modern total synthesis. And, just as a nod to UB, check out Tuffariello's synthesis of cocaine - rediculously impractical if you have ill intentions, but a lot of interesting chemistry and problem-solving.

paw_20 - 18-6-2013 at 10:53

No votes for the total synthesis of vitamin B12? Maybe not as elegant as the total synth of strychnine, but worth a mention.

NiCoLi_BrLiNTe - 19-6-2013 at 23:39

Paw, If you can find a link to that synth then you should post it. I was kind of hoping to get some ideas, an insight into what others thought was important and at the same time create a resource for anyone looking for some interesting reading or project ideas.

kavu - 20-6-2013 at 02:44

There's already a big synthesis archive of interesting targets, check http://www.synarchive.com/

NiCoLi_BrLiNTe - 20-6-2013 at 08:38

Nice one kavu, that will definitely be useful!