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Sauron
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The Wang-Hendrickson Synthesis
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 1589 times
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StTimothy
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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!
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grind
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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.
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Sauron
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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]
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grind
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| 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.
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Ebao-lu
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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  ).
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Sauron
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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]
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StTimothy
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| 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] |
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Sauron
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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!
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StTimothy
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| 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]
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Sauron
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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.
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StTimothy
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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]
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Sauron
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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.
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StTimothy
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| 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.
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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]
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Sauron
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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.
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vivi
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| 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!
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Here you go. Hope rapidshare is acceptable.
http://rapidshare.com/files/186886921/wang_total.synth.lyser...
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StTimothy
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Thank you so much! I didn't think I'd find this again. One thousand times... thank you. :-)
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Sauron
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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]
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StTimothy
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| 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?
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Sauron
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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.
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StTimothy
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| 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.
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Sauron
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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.
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StTimothy
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| 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. :-(
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vivi
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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.
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Sauron
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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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