Total Synthesis Strychnine - Step 7

It's a late night at lab and I'm getting bored, so it's time to finish up the V ring of Strychnine (a.k.a. the first step with some actual complexity).  What we will try to accomplish today will be the formation of a 5 membered ring with concomitant formation of a stereocenter.  While doing this we will also be breaking the aromaticity on the indole ring which will actually cost us quite a bit of energy to do so.  Below is what we are trying to accomplish.

General:

It is easy to observe that this transformation could be made to happen with acid (well, maybe not easy, but at least it can be understood).  This occurs through protonation of the imine which allows the nucleophilic beta-carbon of the indole to arrange for good trajectory for attack, and formation of the ring.  The trouble is, while Woodward attempted these conditions, actually he was unable to attain a useful result (so it seems is the case with most experiments).  Other papers at the time had shown actually the reverse reaction of the above to occur under acidic conditions due to the aromaticity gained and higher stability in the reverse direction.  Actually for them to get the reaction to go forward, they had to somehow lower the energy of the product molecule to stabilize it.  The very crude energy diagram may help to show what is happening in this step.  The question is, well, how do the pyridine and tosyl amide stabilize the product.  First of all, deprotonation of the indole hydrogen by pyridine is not a likely thing to happen.  The pKa of the indole hydrogen is nearly 20 (in DMSO) and requires very strong bases.  So why then is such a weak base like pyridine used?  Well, in this case, only a weak base is needed, due to the activation of the electrophile by the work of tosyl chloride on the imine nitrogen.  This creates a potent and reactive electrophile which should react with the already nuclephilic indole beta carbon.  The pyridine is simply here to remove the proton once this attack happens so as to push the reaction forward.

The purpose of the tosyl chloride also serves in this case to stop the reverse reaction from happening.  once the amide forms (with the tosyl group) the electron pair of the nitrogen is no longer a good donating group, and so the reverse reaction is essentially hindered, driving the reaction forward.

During this process the one thing still yet untouched has been the stereochemistry.  Woodward was able to determine (I am not sure how) that only one diastereomer (because 2 chiral centers were formed) was obtained.  In this case we created a stereocenter on the indole ring, as well as on the carbon alpha to the ethyl ester.  As is in most cases, this is driven by almost solely sterics.  When Woodward carried out this reaction he had predicted that this product was likely to be formed, but actually he also stated that it was very possible that the other diastereomer of the carbon alpha to the ethyl ether could have been formed.  We can now rationalize that the ester has steric clashes with the veratryl (the fancy name for the di-methoxy benzene ring) group.  As for the stereochemistry of the indole ring, I had tried to find a convincing argument as to why only one stereocenter was formed, but I came up short.  Seems that this may be the most favorable conformation of the ring, but to me it seems that the opposite stereochemistry would be equally likely.  I'll have to think on this a bit more.

Workup:

The solvent in this reaction is actually the pyridine (as is the case in most reactions where pyridine is the base.  Usually seen in acetylations with acetyl chloride).  Letting the reaction stir essentially overnight (18h) completed the reaction.  Now, how can we isolate the product.  Precipitating in water seems to be something Woodward enjoys doing, and se he employs this here.  Upon adding an equivalent amount of water as solvent, a precipitate formed, while at the same time, excess p-toluenesulfonyl chloride was destroyed.  Collecting these crystals and then washing with methanol and water yielded a fairly pure product.  Further recrystallization from hot methanol was able to give an even more pure product.

Again we see that precipitation of the product and filtering is the easiest way to not only get all of the material out of the reaction, but also to wash away that pesky pyridine which can often be so tricky to remove.  What I am surprised about is how the starting material did not precipitate in this reaction.  I am curious to know if it is soluble in methanol which would lead to the purification of the material from the starting compound.

Last thing to note.  It is interesting to note how only the intramolecular product was formed, and how one indole ring did not attack the activated imine on another molecule.  The reason for this suppression is due to the close proximity of the imine on the same molecule.  The term "effective concentration" is often used, where most of the time, the imine on the same molecule is in higher concentration because of its close proximity.  For this reason, 5 and 6 membered rings are often favored as products rather than dimers or other oligomers.