Thanks Rhodium and Lili. :)
I wonder why he went that route? I look at it now and see an alternate possibility that I'd like to bring up:
At the stage after the Wittig reaction with the bicyclic, but before the Mannich reaction, where one has a 3-unsubstituted indole still, why not chloromethylate the 3-position?
After chloromethylation, react with sodium cyanide, to give the indole-acetonitrile. Then use the Stephen Aldehyde Synthesis ( http://themerckindex.chemfinder.com/TheMerckIndex/NameReactions/onr376.htm (http://themerckindex.chemfinder.com/TheMerckIndex/NameReactions/onr376.htm)
) to change the nitrile to the aldehyde. Condense with methylamine and remove the water to have the imine.
Now you have the exact same compound they used for the retro-diels-alder, minus the oxygen between the nitrogen and methyl groups. :) Eliminate the cyclopentadiene, and Diels-Alder to the lysergo-skeleton cousin we are familiar with, but minus that oxygen. :)
I like this series better, because it involves simpler reagents than ones like TiCl3 and disubstituted formamides, etc. But of course a rebuttal to that statement could be, "If simple acquisition of chemicals is an issue at this point, you have no chance of succeeding in this anyway."
Well, I agree, but it doesn't change the fact that simpler is better. :)
You still need the bicyclic for these steps, to protect the double bond and prevent jumping the gun on the diels-alder, as it could occur as soon as the nitrile is formed, and the aldehyde as well.
Another idea, just do the diels'alder on the indole-acetonitrile? Why not? It would cyclize in the traditional manner, but giving the cyclic imine, with no function off the nitrogen. Could the imine be reduced without reducing the olefin as well? Arent imines a lot easier to reduce than C=C olefins?
The worst case scenario would be cyclization at the aldehyde stage, giving an inert ether.
If one chloromethylated either of the following compounds, would the chloromethyl function go into the "correct" 4-position of the indole ring (once the compound is turned into indole that is) ?
1.o-toluidine (or the N-protected toluidine) --> 1-chloromethyl-2-methyl-3-aminobenzene ??? (yes or not likely.)
2.o-nitrotoluene --> 1-chloromethyl-2-methyl-3-nitrobenzene. ?
3.2-amino-phenylethanol --> 1-chloromethyl-3-amino-phenyl-2-ethanol (bad IUPAC I know) ??
The first two compounds can of these compounds can of course be used to synthesize indole rings.
Also, (sorry for so many things in one post) imagine an indole ring, but as an imine. The double bond on the indole ring isnt between the 2 and 3 carbons, but at the 1-nitrogen and the 2-carbon. Would this automatically aromatize to indole? (Indole would be more stable, so I would think so.) I am just curious if 2-amino-phenylacetaldehyde --> indole + H2O.
Thanks for everything so far. :)
Lili, you actually have a "Lysergic Acid Total Synthesis" folder? That's funny. ;D :)
PrimoPyro