Total Synthesis Strychnine - Step 13 and 14

The next steps in the synthesis involve preparing the molecule for the desired Dieckman Condensation that was expected to occur previously.  Since we have now removed the offending N-tosyl group, this should be accomplishable.  What we have done in this process, however, was also hydrolyze the esters to their carboxylic acids.  Our next goal will be to re-obtain the esters as such a condensation cannot take place with the acids.  This is because under the basic conditions required deprotonate the carboxylic acids, we form a resonance stabilized carboxylate anion which makes deprotonation of the alpha hydrogen unlikely.  To accomplish this, diazomethane is the gold standard reagent for methylation of carboxylic acids.  Additionally, we will also need to re-protect the nitrogen that previously held the N-tosyl group so it does not interfere with future steps.  While accomplishing both of these tasks may seem like a lot of work, actually these modification are quite simple and both can be accomplished in one day.  Taking a look at Scheme 1 below, here are the steps we are going to accomplish.

Scheme 1. Acetylation of the secondary nitrogen followed by methylation with diazomethane.

Overview:
Acetylation of Nitrogen
The first step is the acetylation of the secondary nitrogen.  Why must we add this group?  Well, I suppose there are two possibilities, which we will see only one of which will be relevant.  The first possibility is that if we did these two steps in reverse (that is, diazomethane first, then acetic anhydride) that we may methylate the secondary nitrogen.  Actually, this is not the case.  While diazomethane is a strong methylating agent, it is really only very active in this role once it has been activated with some sort of acid, whether it be the typical bronsted acid, or a lewis acid.  Amines, amides, and alcohols in this compound are not able to attack the diazomethane because they lack a strongly acidic functionality, and so we are not worried about these side reactions.  While one may conceive that the carboxylic acids may make the solution more acidic which could lead to side reactions, once the diazomethane is activated, it becomes so reactive that it has no time to diffuse away before reacting with the carboxylate ion.  For this reason we do not see diffusion of the activated diazomethane to other regions of the molecule.  The second possibility then, is that this amine may react with future steps in the reaction.  For instance, two steps from now we will be using tosyl chloride again, which would react with the secondary nitrogen.  It is really for this precautionary reason that we are protecting the nitrogen with acetic anhydride.  This reaction has been covered before in Step 9.

Dangers of Diazomethane
For those of you who have never heard of diazomethane, this is not a step in the reaction many of us would be comfortable with.  Why is that?  Well, diazomethane is a toxic, carcinogenic, volatile, and spontaneously explosive gas.  Wow, sign me up right?  It makes sense that for these reasons, you can't go to Sigma and buy diazomethane, it's just too unstable.  So what chemists have to do is make it.  Diazomethane like I said before is a gas, but it is soluble in ether, ethanol, and dichloromethane.  Most typically is is prepared as a dilute solution in ether for safety precautions.  Dilute solutions are less likely to explode, and ether is used because its low boiling point.  Purification of diazomethane after synthesizing it involves distillation.  The closer the boiling point of the solvent is to the diazomethane, the less concentrated the vapors are with diazomethane, which leads to a safer isolation.  So how does one actually prepare diazomethane?  Diazomethane is prepared using specialized glassware that contains no sharp points (such as ground glass joints), as these sharp points can detonate diazomethane (scary).  For this same reason, whenever you want to pipette diazomethane, you must use flame dulled pipette tips to prevent detonation as well.  Two common chemicals used as a precursor to diazomethane are diazald and MNNG.  Under basic conditions, these compound decomposes to give off diazomethane and by products.  If you are still curious about the setup and mechanisms, there is a great resource here.  Typically, however, once the diazomethane is generated, it is co-distilled into the receiving flask with the ether and some small amounts of ethanol (which is the solvent of the decomposition reaction) to create a deep yellow clear solution as shown here.  One can either distill the diazomethane/ether solution right into the reaction to use it up right away, or one can store the solution for a while in a freezer (but this is not recommended).  It's best just to use what you need, but the temptation is to make a lot of it at once so you don't have to make it again.  Lastly, when one makes diazomethane, what safety equipment should be used?  Thick gloves, goggles, lab coat, and most importantly, fume hood as well as extra protection with the use of a blast shield.  There are a lot of stories about diazomethane which you can read about here, and it more than clear why all of this is needed.

Mechanism:
Since I had covered the acetylation previously, I will discuss only the methylation reaction.  The reaction of diazomethane with a carboxylic acid is shown below.  You will see why alcohols and amines are not acidic enough to form the activated species, so these functional groups do not react unless a lewis acid is added.  This is why the reaction is allowed to proceed in methanol as the solvent.

Figure 1. Mechanism of diazomethane with a carboxylic acid.

We can see that with the resonance structures there could be two competing sites of protonation from the carboxylic acid, the carbon or the nitrogen, both of which carry a partial negative charge.  If the terminal nitrogen is protonated, it leads to no stable product and so is likely reversible.  What drives the reaction forward is protonation at the carbon.  This creates a strongly electrophilic carbon which reacts with the poor to moderate carboxylate nucleophile.  This displaces nitrogen gas which bubbles out of the solution and drives the reaction forward.  That is what makes this reaction so efficient is that product leaves immediately after the desired reaction takes place effectively forming a sink into which more and more reactant falls into.  It also makes it easy to determine when the reaction is complete.  Just drop in diazomethane until no more gas is evolved.  At that point one knows that they have added either just enough, or a little too much.  The excess diazomethane in the solution is then destroyed using acetic acid, which undergoes the exact same methylation reaction to form methyl acetate which can be easily evaporated away.

Workup:
Acetylation
The first acetylation step involved mixing the starting material into a solution of pyridine, and slowly adding acetyl chloride.  This is slightly exothermic and so the solution is usually cooled, however, in this case it appears that it was not.  After 1h reaction, water was added, and after half an hour, then the solution was evaporated.  As to why Woodward waited the 30 minutes before evaporating is odd.  I have used pyridine once, and in my attempts to remove it, I did notice that upon letting it stir with water for a while did aid in the removal of the pyridine.  Perhaps the water helps to break up some of the pyridine salts and dissolve them establishing an equilibrium between the protonated and deprotonated pyridine.  Water also forms an azeotrope with pyridine, boiling at 92˚C which may also aid its removal.  The dried material was rinsed with ether to get rid of any oily material, possibly extra acetyl chloride or acetic acid, both of which are soluble in ether.  After this, dissolving the remaining material in hot water (remember, we have a dicarboxylic acid at this point, but the rest of the molecule is hydrophobic, thus it may take hot water to dissolve the compound) and acidifying with acid precipitated the protonated di acid as yellow crystals.

Methylation
The material from the acetylation was dissolved in methanol (which to me is surprising, as I would not expect it to be very soluble in methanol, but anyways) to which a fresh, cooled solution of diazomethane was added dropwise until no nitrogen was seen to be evolved (even Woodward practiced the use of fresh diazomethane and not storing it in the freezer).  He let the solution sit in the cold for an hour to allow complete reaction, and then added acetic acid to quench any remaining diazomethane in the solution.  One thing I would like to point out as well, is that we likely now have excess acetic acid in solution as well if we are sure to destroy any remaining diazomethane.  We use acetic acid for two reasons, one, it reacts with diazomethane to form volatile by-products, and two, it is also slightly volatile, and can be pumped off under high vacuum.  Thus, after quenching with acetic acid, the solvent was vacuumed to dryness.  Then, Woodward dissolved the residue in a small amount of ethyl acetate (a small amount because it is likely very very soluble in acetic acid).  The next steps involve adding diethyl ether, followed by cyclohexane.  Why did Woodward do this?  These are poor solvents for our compound as they are both non-polar, with cyclohexane being the most non-polar of the two.  Essentially Woodward is doing somewhat of a crude recrystallization by adding poor solvent.  This doesn't mean he adds both of that very very fast, but in fact, he likely added these slowly, likely drop-wise.  How does he know when to switch over from ether to cyclohexane?  Once no more crystals appear while adding ether, he probably switched to cyclohexane to get any last remaining product out.  So the real recrystallization mixture is really ethyl acetate/ether.  This is in fact the solvent system that Woodward used afterwards to attempt to gain a more pure product, but in fact, it was identical to the crude precipitation/recrystallization.

Next Steps:
Now our molecule is set up to perform the Dieckmann Condensation that was desired this entire time.  As we will see, this is accomplished by adding base, and allowing the condensation to take place.