Sciencemadness Discussion Board

The Wang-Hendrickson Synthesis

Sauron - 29-12-2008 at 10:29

This recent (2004) and elegantly simple total synthesis of racemic lysergic acid appears confusing at first because the publication in Org.Letters. 6, p 3-5 was cluttered with aspects of the experiments which failed.

The authors quite admirably expressed the untention to essay prep of alkyl-substituted versions of the lysergic skeleton which would not readily lend themselves to "reverse engineering" to psychedelics.

In that light I would like to open discussion of the key elements of this synthesis, without the clutter of fits and starts. I am slso interested in any improvements which may have come to light in the subsequent 5 years.

A. Key Precursors

There are only two. 4-bromoindole, and pyridine-2.5-dicarboxylic acid. I do not care for the authors' route to the indole since thallium (III) triflate is both toxic and obscenely expensive. The Leimgruber-Batcho indole synthesis is the better way. For the isocinchomeronic acid, see the paper from Bull Chem Soc Japan I posted in the pyridine dicarboxylic acid thread.

the bromoindole is converted by the sequence KH, t-BuLi, B(nBuO)3 to 4-indoleboronic acid. This is compound 8 in the original prep.

The acid is oxidized with Na2WO4 (aq) and 30% H2O2 to the N-oxide and reacted with SOCl2 to give compound 7, 3-chloro-2,5-pyridinedicarboxylic acid dimethyl ester.

B. Putting the Tetracycle Together

Compounds 7 and 8 are then coupled to form the diester 9a.

9a is reduced to the hydroxymethyl 9b and on to the formyl 9c and is then couples to form the tetracycle 10 which has a hydroxyl group in need of removal. That manipulation gives dihydro compound 11 which when N-alkylated and selectively reduced yields racemic lysergic acid ethyl ester.

The final few steps are done without isolation due to the instability of the intermediates.

The arsenal of reducing agents employed includes BH3-THF, NaBH4, Ca or Ba borohydride, KH and Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium. ) Most or all of these one can prepare himself, with varying degrees of difficulty. NaBH4 is very mundane. The alkiline-earth borohydrides, less so. Neither Merck nor Brauer says boo about them and neither does Paquette. Aldrich has Ca(BH4)2 but not the barium. Maybe Inorg.Syn. will shed some light.

The Pd-PPh3 comples is rather easilyu made from PdCl2.



One had best be adept at lithiation, or they will never get to the indole-4-boronic acid precursor. Solvents need scrupulous drying and purification. All that being said, the skillset required is not a very unusual one. TLC will suffice for following reactions. There is no specially arcane equipment called for. N2 and argon are not exotic atmospheres.

I see why zed's 14-year old niece likes this route to LA when she can't get Swiss ergotamine tartrate.

I have the Org.Lett paper but sans supporting daye (experimental, refs). Those fortunately are in Rhodium/Erowid. I will convert that to pdf and post it here.



[Edited on 30-12-2008 by Sauron]

Attachment: Binder1.pdf (93kB)
This file has been downloaded 1587 times

StTimothy - 1-1-2009 at 04:08

Sauron,
I'm glad to see your interest in this total synthesis. I'm a relative newbie when it comes to organic chemistry, so I have one question that I'd especially like your input on:

In Hendrickson-Wang (2004) the 3-chloro-pyridine-2,5-dicarboxylic acid dimethyl ester is made using thionyl chloride in DCM with a catalytic amount of DMF and subsequent quenching with methanol ... any ideas on alternatives to SOCl2?

StTimothy

PS. Of course, the indole-4-boronic acid can be bought from a few suppliers, but not for cheap!

grind - 1-1-2009 at 06:57

SOCl2 can be replaced by PCl5 or oxalyl chloride or phosgene. Another possibility is to avoid the way with the acid chloride and to esterify the acid directly (MeOH and H2SO4 or TsOH or HCl). There are a lot of other ways to esterify an acid, like Mitsunobu, activated acids (chloroformates) an so on.

Sauron - 1-1-2009 at 07:12

Always nice to chat with a saint.

The odd and only sketchily explained mechanism of the SOCl2 reaction with ICA does rather leap out of the page, doesn't it?

In the last two years I have spent a lot of time writing about chlorinating reagents here and that is because in the last 8 years I have spent a lot of time thinking about them. I am rather notorious on the forum for being an advocate of cyanuric chloride (TCT) (not to be confused with TCCA). My thought when I first read the W-H paper was, why not use TCT? It will certainly get to the acid chloride, it forms an adduct with DMF (Gold's reagent) and so it makes sense that it could be a candidate alternative reagent to SOCl2.

On the other hand, what is wrong with SOCl2? If your objection is based on difficulty of purchase, well, len1 has demonstrated that its Brauer prep from sulfur chloride and SO3 or oleum is something that can be done in an amateur setting. (Where I am, I cannot purchase SOCl2 at all, without a special permit from the MOD.) As I can buy 65% oleum, this is not a hassle.

Most people who have difficulty buying SOCl2 also have difficulty getting CC/TCT. While it is possible to make your own TCT, by either of two ways, it would be aggravating. One of the two ways involves CNCl, nasty, and the other is chlorination of MeSCN, not quite so nasty, as the cyanogen chloride is made in situ and stays in solution while trimerizing. MeSCN is not very cheap, and it can be made but ultimately it starts from CS2, also not cheap. I am lucky as I can buy TCT. And it is cheap.

The entire question of how to prepare isocinchomeronic acid is sort of up for grabs. The obvious method is to oxidize 5-ethyl-2-picoline per the lit., the procedure is in Bull. Chem. Soc. Japan, volume 34 if I recall, author Sato, cited in Merck Index. (The other Merck citations are dead ends. Possible exception is Monatsch one I have not dug out yet.)

But as I hate to have only one method, I am poised to re-enter the Hantzsch dihydroindole synthesis, which I have previously studied, but I need a refresher. I expect to start a thread on this (or append it to the 2,5-Pydicarboxylic acid thread) shortly.

I would not contemplate buying the 4-indoleboronic acid, the prep of 4-bromoindole looks to be fun and getting from there to the boronic acid is easy as long as you are competent with lithiation. I would advise doing a few lithiations on less precious substrates just as five finger exercises first.

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.

Those who only care about getting to LA in order to make the diethylamide will find little joy in either, since the LA produced is racemic. Doing a resolution is no fun. So those folks I guess are still married to ergotamine etc. till someone comes up with an assymetric variation of the final steps of the W-H.

@grind

The SOCl2 was used to introduce the Cl at the 3-position, by the mechanism proposed. I agree that the reagents you mention would be usual suspects for acyl chloride formation. However, there is no reason to assume in absence of literature or experimental results that they can be substituted for SOCl2

Another really good way to get to SOCl2 (besides the oleum route) is to use benzotrichloride or hexachloro-m-xylene to prepare it, see HCMX in the search engine for thread I did on this.

[Edited on 1-1-2009 by Sauron]

grind - 1-1-2009 at 08:23

Quote:
Originally posted by Sauron
The SOCl2 was used to introduce the Cl at the 3-position

I have overlooked that. You are right, in this case it is not self-evident to substitute the SOCl2.

Ebao-lu - 1-1-2009 at 09:18

Sauron, your pdf is not opening because of some reason.. i've tried it from 2 different PC's, with same result.. Could you reupload it, or maybe you could give another link (for me :D).

Sauron - 1-1-2009 at 09:37

Which pdf?

I just downloaded the last one I posted in this thread and it is working fine.

If it shows up as a php file rename it to a pdf.

If you are right clicking try left clicking.

You must appreciate that the forum software interacts with the Net and the Net with your browser, and I can'be responsible for fuckups at your end.

[Edited on 2-1-2009 by Sauron]

StTimothy - 1-1-2009 at 15:56

Quote:
Originally posted by Sauron
> Always nice to chat with a saint.

Indeed. :-)

> The odd and only sketchily explained mechanism of the SOCl2 reaction with ICA does rather leap out of the page, doesn't it?

Yes, I do find it slightly peculiar, but I have to trust them unless I try experimentally.

*snip* I've enjoyed your posts on chlorinating agents, definately. I'll have to review them while thinking about this.

> On the other hand, what is wrong with SOCl2? If your objection is based on difficulty of purchase, well, len1 has demonstrated that its Brauer prep from sulfur chloride and SO3 or oleum is something that can be done in an amateur setting. (Where I am, I cannot purchase SOCl2 at all, without a special permit from the MOD.) As I can buy 65% oleum, this is not a hassle.

I'm a hobbyist, so I can't buy it. I'm also relatively new to organic lab work, so my confidence in making it properly when I've never done bulb to bulb distillation and whatnot, is shall we say, low. But I am tempted to try. What I'm not tempted to do is break the law. :-)

> Most people who have difficulty buying SOCl2 also have difficulty getting CC/TCT. While it is possible to make your own TCT, by either of two ways, it would be aggravating. One of the two ways involves CNCl, nasty, and the other is chlorination of MeSCN, not quite so nasty, as the cyanogen chloride is made in situ and stays in solution while trimerizing. MeSCN is not very cheap, and it can be made but ultimately it starts from CS2, also not cheap. I am lucky as I can buy TCT. And it is cheap.

I'd have to look into it, but I think it may be difficult to buy CC/TCT.

> The entire question of how to prepare isocinchomeronic acid is sort of up for grabs. The obvious method is to oxidize 5-ethyl-2-picoline per the lit., the procedure is in Bull. Chem. Soc. Japan, volume 34 if I recall, author Sato, cited in Merck Index. (The other Merck citations are dead ends. Possible exception is Monatsch one I have not dug out yet.)

This I wouldn't bother with, as I see you suggest buying from suppliers often when the chemical is cheap and available. 2,5-Pyridinedicarboxylic acid certainly is.

*snip*

> I would not contemplate buying the 4-indoleboronic acid, the prep of 4-bromoindole looks to be fun and getting from there to the boronic acid is easy as long as you are competent with lithiation. I would advise doing a few lithiations on less precious substrates just as five finger exercises first.

Definately. I personally would need to learn schlenk techniques, first of all.

> 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.

I agree, this synthesis of LA compared to all others seems like a walk in the park. The only negative I see is the reduction with BH3-THF complex near the end with a 41% yield.

> Those who only care about getting to LA in order to make the diethylamide will find little joy in either, since the LA produced is racemic. Doing a resolution is no fun. So those folks I guess are still married to ergotamine etc. till someone comes up with an assymetric variation of the final steps of the W-H.

I think those who were really determined to make the diethylamide would accept half of their "product" being inactive.

*snip*

> Another really good way to get to SOCl2 (besides the oleum route) is to use benzotrichloride or hexachloro-m-xylene to prepare it, see HCMX in the search engine for thread I did on this.

I'll look into this.

@Ebao-lu: here is a direct link to an html version from rhodium: http://www.erowid.org/archive/rhodium/chemistry/lysergic.hen...
[Edited on 1-1-2009 by Sauron]

Sauron - 2-1-2009 at 08:35

Again, my advice is, do not buy the 2,5-pyridinedicarboxylic acid, for simple reason that LA is a Schedule 1 compound carrying same penalties as LSD. Instead, use nicotonic acid, and chlorinate the 2-position, or picolinic acid and chlorinate the 3-position. Your end product will be same skeleton as LA but will lack that pesky carboxylic moiety up top.

AFAIK this may bend the law but not break it. You would have 100% of the satisfaction of a job well done and (arguendo) none f the legal downside. My guess is that the diacid is watched. DEA reads the journals too! That article has been out 5 years and appears on all the usual suspect websites like erowid. It would be naive IMO and reckless to think they don't watch immediate precursors. Cover thine ass!

StTimothy - 2-1-2009 at 18:58

Quote:
Originally posted by Sauron
Again, my advice is, do not buy the 2,5-pyridinedicarboxylic acid, for simple reason that LA is a Schedule 1 compound carrying same penalties as LSD. Instead, use nicotonic acid, and chlorinate the 2-position, or picolinic acid and chlorinate the 3-position. Your end product will be same skeleton as LA but will lack that pesky carboxylic moiety up top.


Hmm. Interesting idea. It would be fun to invent a novel ergot alkaloid. I notice this is sometimes done in attempts at new approaches to syntheses of LA that get close but fail in some way. :-)
Quote:
Originally posted by Sauron
AFAIK this may bend the law but not break it. You would have 100% of the satisfaction of a job well done and (arguendo) none f the legal downside. My guess is that the diacid is watched. DEA reads the journals too! That article has been out 5 years and appears on all the usual suspect websites like erowid. It would be naive IMO and reckless to think they don't watch immediate precursors. Cover thine ass!


Maybe... I'd like to think that they only monitor what they tell us is monitored, but I know that isn't quite true.

Another point of interest: Mr. Wang's dissertation (I think) was once online, unfortunately I've lost it! It was wonderful, with pages and pages (at least 15) about the failed attempts with bondset A, then failures in the bondset B approach, etc. One thing I remember explicitly is that they tried making the 3-chloro-derivative into its alcohol and then aldehyde before the suzuki coupling with the indole-4-boronic acid, but they found the overall yield was reduced, so it was decided it would be done afterwards. If anybody has this paper stashed somewhere, please, contact me!

Sauron: you did you read the supporting notes, just for fun, right? :-)
http://pubs.acs.org/doi/suppl/10.1021/ol0354369/suppl_file/o...

I just realized looking over the paper again that it would be nice to find an alternative to MeI. I read here on SM that trimethyl phosphate isn't very good for N-methylation, tho? :-(

PS. On an unrelated (to H-W) note, a recent novel tot syn of LA using some more complicated chemistry: http://style.pendulus.net/~fb/chemistry/ol8022648.pdf

PPS. For those very interested in the tot syn of LA, here is a paper with a good review: https://repositories.lib.utexas.edu/bitstream/handle/2152/30...

[Edited on 2-1-2009 by StTimothy]

Sauron - 2-1-2009 at 20:33

Yes I did read the experimental section as it is in erowid and that's where I made my pdf from.

Nice to have the original though.

As to alternatives to MeI, if one is not going for LA there is no need for N-methylation. Is there?

But FYI trimethyl phosphate is not much of a methylating agent, I think that poster meant trimethyl phosphite. And I believe that is quite hard to acquire as it is a OP CW precursor controlled under CWC.

The main alternative to MeI is dimethyl sulfate, a nastier brain carcinogen than MeI.

A distant possibility: see the current thread on methyl tosylate.

But as I said, I intend to skip the N-alkylation entirely.

StTimothy - 2-1-2009 at 22:21

trimethyl phosphate does in fact find some use in methylating phenols, ie http://www.erowid.org/archive/rhodium/chemistry/me3po4.html

Klute has a thread or two where he methylates things using it.
It seems easier to handle than MeI or dimethyl sulfate.

From other things I've read it seems its especially useful for O-methylation.

See also EXAMPLE 4: http://v3.espacenet.com/textdes?DB=EPODOC&IDX=US4453004&...

[Edited on 2-1-2009 by StTimothy]

Sauron - 2-1-2009 at 23:52

None of that is N-methylation.

MeI and DMS are the two best, (MeO)3P a dark horse, and the phosphate does not show up on my radar.

StTimothy - 3-1-2009 at 23:31

Quote:
Originally posted by Sauron
... or picolinic acid and chlorinate the 3-position. Your end product will be same skeleton as LA but will lack that pesky carboxylic moiety up top.


Thinking about this I find it very interesting! Do you know of any ergot alkaloids having a moiety at position 7? I can't think of any, off the top of my head, but I'll begin reviewing Ergot: the Genus Claviceps again.

Edit: Hmm, the closest I can find is a hydroxymethyl group at position 7 in isochanoclavine-i, which is one of the clavines with an open D ring.

I found a couple more in "Chemistry of indoles carrying a basic function. Part 8: A new approach to the ergoline skeleton" (Tet 2003 4281)

If you attempt this synthesis, how far will you go? The tetracycle? N-methylation, reduction...?

We know these things will definately not be psychedelic, but perhaps medications could be made from them.

[Edited on 4-1-2009 by StTimothy]

Sauron - 4-1-2009 at 00:01

I agree that the tetracycle with a benzene ring for ring D rather than pyridine is unlikely to be pharmacologically active and AFAIK a pyridine at ring D, either unreduced, or reduced, with or without the N-methylation, is unlikely to be hallucinogenic if it has no carboxylic acid moiety in the usual place for La. Look at the effect of simple epimerization (iso-LA) has on that, or the effect of the enantiomers (-)-LA and (-)-isoLA also.

The broad physiological effects are something else, and only a structure-activity survey of the hydrolyzates of the ergot alkaloids can tell the tale.

It is known that a bromo at the -2 position of the indole ring B totally destroys the hallucinatory effects of LSD itself. See Merck Index entry on 2-bromo-lysergide.

I am not 100% of the legal implications. But as I am not in USA I am not very concerned.

vivi - 20-1-2009 at 18:03

Quote:
Originally posted by StTimothy


Another point of interest: Mr. Wang's dissertation (I think) was once online, unfortunately I've lost it! It was wonderful, with pages and pages (at least 15) about the failed attempts with bondset A, then failures in the bondset B approach, etc. One thing I remember explicitly is that they tried making the 3-chloro-derivative into its alcohol and then aldehyde before the suzuki coupling with the indole-4-boronic acid, but they found the overall yield was reduced, so it was decided it would be done afterwards. If anybody has this paper stashed somewhere, please, contact me!



Here you go. Hope rapidshare is acceptable.
http://rapidshare.com/files/186886921/wang_total.synth.lyser...

StTimothy - 20-1-2009 at 20:25

Quote:
Originally posted by vivi
Here you go. Hope rapidshare is acceptable.
http://rapidshare.com/files/186886921/wang_total.synth.lyser...


Thank you so much! I didn't think I'd find this again. One thousand times... thank you. :-)

Sauron - 21-1-2009 at 03:57

vivi's document is missing the bibliography and the entire section on the D-A synthesis of pyridines.

So much, I suppose, for scholarship.

The bibliography and footnotes are there for very good reasons.

[Edited on 21-1-2009 by Sauron]

StTimothy - 21-1-2009 at 14:59

Quote:
Originally posted by Sauron
vivi's document is missing the bibliography and the entire section on the D-A synthesis of pyridines.

So much, I suppose, for scholarship.

The bibliography and footnotes are there for very good reasons.

[Edited on 21-1-2009 by Sauron]


If you have the entire document, provide it?

Sauron - 22-1-2009 at 00:47

The paper uploaded by vivi is missing everything after page 101

That is Chapter 4, the experimental section, and Bibliography.

Perhaps Chapter 4 is of little interest to acid cooks, but surelt the Experimental section is vital and ought to be seen as such.

The same is true of the Bibliography. Dr Wang did not put in all those references just to impress her doctoral committee.

Yes of course the whole document.

StTimothy - 22-1-2009 at 03:26

Quote:
Originally posted by Sauron
The paper uploaded by vivi is missing everything after page 101

That is Chapter 4, the experimental section, and Bibliography.

Perhaps Chapter 4 is of little interest to acid cooks, but surelt the Experimental section is vital and ought to be seen as such.

The same is true of the Bibliography. Dr Wang did not put in all those references just to impress her doctoral committee.

Yes of course the whole document.


And I'm asking you to provide it. Will you? I'm disappointed, honestly, since I asked in a posting quite a while ago if anybody had this paper, and you didn't speak up. I'd like to have all the references, myself.

Sauron - 22-1-2009 at 05:58

Whaddya mean mean "you"? What makes you think I have it? I am disappointed just as you are. I went looking for Bibliography, not there, Experimental section, not there. The library at Brandeis may have it, and if so it could be interlibrary loaned, then scanned to PDF. But I am in Thailand, rather a far piece from Ivy League sorority houses.

StTimothy - 22-1-2009 at 14:56

Quote:
Originally posted by Sauron
Whaddya mean mean "you"? What makes you think I have it? I am disappointed just as you are. I went looking for Bibliography, not there, Experimental section, not there. The library at Brandeis may have it, and if so it could be interlibrary loaned, then scanned to PDF. But I am in Thailand, rather a far piece from Ivy League sorority houses.


I thought you meant you had the entire document, and that you were disappointed somebody had posted only a portion of it. My apologies. I can't remember whether my original copy had the chapters on pyridines, etc. I don't think it did. :-(

vivi - 22-1-2009 at 17:36

Thoughtless on my part, I guess.

Full copy here:
http://rapidshare.com/files/187960556/Wang_Total_Synthesis_o...

I would've just edited it into my previous post, but am unable to do so.

Sauron - 22-1-2009 at 22:08

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.

StTimothy - 22-1-2009 at 22:57

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.


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...

Sauron - 23-1-2009 at 01:07

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.

chemrox - 23-1-2009 at 20:12

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]

Sauron - 23-1-2009 at 21:31

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 1721 times

Sauron - 24-1-2009 at 00:01

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 1505 times

Sauron - 24-1-2009 at 01:03

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 2011 times

Sandmeyer - 19-2-2009 at 13:32

Sauron, thank you very much for posting Wang's dissertation.

Sauron - 19-2-2009 at 16:47

You're welcome.

StTimothy - 22-2-2009 at 10:56

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

Sauron - 22-2-2009 at 22:20

Phosgene, oh joy oh joy!

Makes SOCl2 look like after shave lotion.

Pryta - 1-1-2012 at 10:36

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 1578 times

[Edited on 1-1-2012 by Pryta]

CuReUS - 15-6-2015 at 04:57

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.

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.)

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.


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]

clearly_not_atara - 15-6-2015 at 08:28

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.

CuReUS - 16-6-2015 at 07:18

Quote: Originally posted by clearly_not_atara  
I unfortunately must report a drawback of the Wang-Hendrickson method: it doesn't work.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265357/

the same article was posted just above my post.
Quote:
Ho hum. I did come up with this though:
http://imgur.com/LubChBn

did you really come up with that:o.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

zed - 16-6-2015 at 14:11

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]

clearly_not_atara - 16-6-2015 at 14:38

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:o.Its so beautiful.You have my respect.

._. 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
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]

CuReUS - 17-6-2015 at 05:16

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

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):o
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]

CuReUS - 18-6-2015 at 23:15

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 ?