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StTimothy
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| Quote: | Originally posted by Sauron
Thanks, much appreciated and not just by me, I am sure.
If I had this sooner I would have saved a great deal of work on precursors and reagents. I came to the same conclusions but the hard way.
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Are you working on synthing 4-bromo-indole at the moment? Or a pyridine?
We never did talk about optimizing this synthesis. Nobody else seemed to pipe up with ideas. Have you had any yourself, Sauron, after reading J.
Wang's dissertation? If only the reduction with NaBH4/TFA or BH3/THF were higher yielding, and the N-methylation went to completion before degradation
of the methylene product...
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Sauron
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My interests lie with other than LA targets. So I don't have to worry about N-alkylation.
For those who do, it's the least of their problems.
Once with racemic LA in hand they still face resolution to the (+) isomer, avoidance of epimerization to iso-LA, and the amide coupling, which is very
lossy (Shulgin's method, only 20% yield.)
All of that looks very frustrating. But, I will simply sidestep it because no carboxylic acid function, no problem.
Sic gorgeamus a los subjectatus nunc.
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chemrox
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Please don't use rapidshare. I got error messages on both files stating that their donwload limits (10 each) had been exceeded. So many free
services available why use the MS of filesharing?
BTW: I had no difficulty with Sauron's pdf files.
[Edited on 23-1-2009 by chemrox]
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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Sauron
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Chemrox, would you like me to upload the complete Wang dissertation to 4hared for you?
It is <5 Mb.
Or, I can just post pages 102-to end That probably can go on forum directly.
[Edited on 24-1-2009 by Sauron]
Attachment: Wang Dissertation Part 2.pdf (1.8MB)
This file has been downloaded 1658 times
Sic gorgeamus a los subjectatus nunc.
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Sauron
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Pardon the double post but, it occured to me that vivi's post of first half of Wang dissertation was also on the accursed Rapidshare. So here that one
is, posted direct to forum hosting.
Reassemble these in Acrobat and you have the complete doctoral dissertation.
It was necessary to split pages through 101 into Part 1A and Part 1B
[Edited on 24-1-2009 by Sauron]
Attachment: Wang Dissertation Part 1A.pdf (1.1MB)
This file has been downloaded 1455 times
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Sauron
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The final part of first half
[Edited on 24-1-2009 by Sauron]
Attachment: Wang Dissertation Part 1B.pdf (1.8MB)
This file has been downloaded 1959 times
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Sandmeyer
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Sauron, thank you very much for posting Wang's dissertation.
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Sauron
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You're welcome.
Sic gorgeamus a los subjectatus nunc.
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StTimothy
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From looking at page 60 of Mr. Wang's dissertation, it looks like the 3-chloro-isocinchomeronic acid can also be made using POCl3 or phosgene (as
grind noted).
Woohoo! You mentioned you found about half a dozen ways to POCl3, Sauron? I'd rather make that than SOCl2.
StTimothy
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Sauron
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Phosgene, oh joy oh joy!
Makes SOCl2 look like after shave lotion.
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Pryta
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A Reported “New Synthesis of Lysergic Acid” Yields Only The Derailment Product: Methyl 5-Methoxy-4,5-dihydroindolo[4,3-f,g]quinoline-9-carboxylate
Nichols et al (2011)
DOI: 10.1021/ol203048q
Abstract
Attachment: drdave.pdf (191kB)
This file has been downloaded 1528 times
[Edited on 1-1-2012 by Pryta]
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CuReUS
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Quote: Originally posted by Sauron  |
The W-H is such a splendid example of the power of retrosynth and the disconnection approach. It is shockingly simple compared to the Woodward, or the
Julia, or any of the other prior methods except the 1884 one which also proceeds from 4-bromoindole, but involves a 4+2 cycloaddition and a pain in
the ass removal of a TMS PG. I talked about it upthread.
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where is the 1884 paper? I couldn't find it
| Quote: Originally posted by Sauron |
Once with racemic LA in hand they still face resolution to the (+) isomer, avoidance of epimerization to iso-LA, and the amide coupling, which is very
lossy (Shulgin's method, only 20% yield.)
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the amide coupling by shulgin's method(using POCl3) gives 66% yield
https://www.erowid.org/library/books_online/tihkal/tihkal26....
| Quote: | | The earliest syntheses of LSD involved the used of an azide intermediate (the original Hofmann process, 1955), mixed anhydrides with trifluoroacetic
anhydride (1956) or sulfuric anhydride (SO3-DMF on the lithium salt, 1959), with the peptide condensation agent N,N'-carbonyldiimidazole (1960), or
with the acid chloride as the active intermediate with POCl3, PCl5 or thionyl chloride (1963) or just phosphorus oxychloride (1973). Most methods are
faulted due to excessive moisture sensitivity, generation of side-products, or epimerization or inversion at the 8-position carbon to form d-iso-LSD.
The POCl3 procedure is clean and fast, and is the preferred process today for the synthesis of a wide variety of substituted lysergamides.
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In the synthesis of aspartame,The COOH of aspartic acid is activated by first esterifying it with 2,4,6-trichlorophenol and then reacting it with
phenylalanine methyl ester to form the amide in 96% yield.
maybe the same thing could be done here,instead of using POCl3 or other chlorinating agents ?
would the use of picric acid instead of the trichlorophenol give a better yield of the amide ? As picric acid is more strongly electron withdrawing
and hence a better leaving group ?
BTW,where did sauron go ? he seems to be an eccentric genius,if you ask me
[Edited on 15-6-2015 by CuReUS]
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clearly_not_atara
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I unfortunately must report a drawback of the Wang-Hendrickson method: it doesn't work.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265357/
Ho hum. I did come up with this though:
http://imgur.com/LubChBn
The radical allylation is described here but it's all guesswork anyway.
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CuReUS
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the same article was posted just above my post.
did you really come up with that .Its so beautiful.You have my respect.
but I have a few questions
1.when you are adding NaCN to vinyl acetone,itsn't there a chance of a michael reaction instead of adding to the carbonyl ?
2.in the diazotisation step,the indole N will react with HNO2 to form nitroso,unless its protected first
3.are you sure that trimethyl ether(I don't even know what to call it) formed from the carboxylic acid will survive that far.It looks extremely
fragile(I always dreamed about them,but I never thought it was actually possible to make them)
4.what chemical to you use to make the 13th compound(to make the 3-indole acetonitrile ?).I can't see it,its too blurred
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zed
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Sauron? He was a highly valued member.
Alas, he was excessively abusive, and he was invited to reform himself, or leave.
At least, that is my take on what happened.
So, after all this time.....Wang-Hendrickson doesn't work?
Fiddlesticks!
[Edited on 16-6-2015 by zed]
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clearly_not_atara
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| Quote: Originally posted by CuReUS |
the same article was posted just above my post.[/rquote]
Blast! :p
| Quote: | | did you really come up with that.Its so beautiful.You have my respect.
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._. thank you! i'm flattered. i was trying to mimic the biosynthetic pathway where dimethylallyltryptophan synthase creates 4-prenyltryptophan. after
a little fucking about i realized it made way more sense to start with the 4-prenylindole and then attach the aminoethyl-groups.
[rquote=409397&author=CuReUS]
1.when you are adding NaCN to vinyl acetone,itsn't there a chance of a michael reaction instead of adding to the carbonyl ? |
cyanide substitutes for sulfonic acid after the bisulfite adduct is formed. The alkene is no longer a Michael acceptor at that point.
| Quote: | | 2.in the diazotisation step,the indole N will react with HNO2 to form nitroso,unless its protected first |
Oh. Yeah... hm. You can maybe protect it by deprotonating/benzylating, or try to use 1:1 molar NOCl / NOBF4 instead of HNO2 -- the aniline should
still react much faster than the indole with a nitrosylator. Or something.
| Quote: | | 3.are you sure that trimethyl ether(I don't even know what to call it) formed from the carboxylic acid will survive that far.It looks extremely
fragile(I always dreamed about them,but I never thought it was actually possible to make them) |
http://en.wikipedia.org/wiki/Orthoester#As_a_protecting_grou...
They are stable in basic or oxidizing conditions but decompose in acids. I managed to not use any acids for the phase where it's the protecting group.
In fact OBO perhaps isn't necessary since a nitrile will react with an alcohol to a trialkyl orthoester in the right conditions.
| Quote: | 4.what chemical to you use to make the 13th compound(to make the 3-indole acetonitrile ?).I can't see it,its too blurred
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Formaldehyde cyanohydrin. Cyanohydrins react as weak electrophiles and indole is generally pretty
activated, but you might need a catalyst. However, formaldehyde cyanohydrin reacts so readily with ordinary indole that usually the product
is bis(indol-3-yl)methane, and in this case I'm hoping that the bulky substituents (sterics) and EWG on the indole make that path unfavorable.
Anywho, imgur's resize made it harder to read; http://postimg.org/image/ipmoslquh/ is better.
[Edited on 16-6-2015 by clearly_not_atara]
[Edited on 16-6-2015 by clearly_not_atara]
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CuReUS
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| Quote: | | Oh. Yeah... hm. You can maybe protect it by deprotonating/benzylating |
I already thought of that.The problem is,you reduce both the nitro groups is one step
(3>>4) using adam's catalyst.So you don't get an intermediate where only the indole N is present which you can protect.What you put on the
indole,gets put on the NH2 as well.But the use of the reagents in a molar ratio might work.
| Quote: | | They are stable in basic or oxidizing conditions but decompose in acids. I managed to not use any acids for the phase where it's the protecting group
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forgive me if I sound paranoid,but what about the 2 moles of HBr formed in the dehydrohalogenation step.(11>>12) ?. Could that destroy of the
ortho ester(I know it probably wouldn't,but you never can be 100% sure when it comes to organic chemistry)
BTW,I just read the article reporting the failure of the W-H reaction.I was shocked that it was so recent(2011)
I thought all research on LSD for medical or any other purpose was strictly banned in the 70's itself
these guys are coolly claiming their "interest in hallucinogenic compounds"
[Edited on 17-6-2015 by CuReUS]
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CuReUS
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atara,if you want to couple compound 5 and compound 9,why don't you use other reactions rather than going by the diazonium route?.there are many good
coupling reactions.then the problem of N protection won't arise.
during diazotising,are you first making the flouro derivative and then coupling or doing the whole thing in one pot.If it is one pot,the HF could
destroy the ortho ester.
also I just realised,the bromination step(10-11) is going to cause a lot of trouble
https://www.erowid.org/archive/rhodium/chemistry/5-br-indole...
| Quote: | | i was trying to mimic the biosynthetic pathway where dimethylallyltryptophan synthase creates 4-prenyltryptophan |
shouldn't one try to mimic the boisynthesis of ergotamine instead ?
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