Total Synthesis Strychnine - Step 12a

This next step in the total synthesis of Strychnine is a complex yet interesting one indeed.  I was not so familiar with the reaction myself until coming across it, so I took some time to learn as much as I could about it to make this post worth the read.  Below is where we are at in the synthetic scheme (Scheme 1).

Scheme 1. Reaction we will cover today involving reduction of the tosylate group, as well as the esters.

The whole point of this reaction is to remove the tosylate group, but why?  Well, even the great mind of Woodward can't predict everything that can happen during a synthesis.  Actually, this step was not part of the original synthetic scheme, but rather, needed to be included because the tosylate group was interfering with their original synthetic plan.  So let's take a moment to look at what Woodward was really trying to do in Scheme 2 below.

Scheme 2. Original reaction Woodward hoped would happen, but in actuality, this reaction does not occur.  Rather, Scheme 3 occurs.

Woodward desired to perform a Dieckman Condensation, which is essentially just an aldol condensation modified for the enolate of an ester, condensing with another ester.  A strong base such as sodium methoxide is used to deprotonate the enolate (actually, both alpha carbons of the esters can be deprotonated since they are both acidic, however, the less hindered carbon is more likely to be the attacking nucleophile which is shown in Scheme 2).  However elegant this reaction appears to be, actually it does not happen.  The reaction that does occur under the reflux with sodium ethoxide is quite unexpected, but understandable.  Let's take a look at the reaction that actually occurred in Scheme 3.

Scheme 3. One possible mechanism explaining the final confirmed molecule.  Other mechanisms exist, this is one of two proposed originally in the paper.

Wow! What a crazy mechanism, no wonder Woodward didn't predict this.  To verbally explain this mechanism, the key thing is to note we are under very very strong basic conditions (sodium methoxide under reflux, 65˚C).  The pKa of methanol is 15.5, which is over 100X stronger than sodium hydroxide (pKa = 13).  Under these conditions, lots of things can go wrong if you are not careful (obviously).  The first step is deprotonation of the acidic alpha hydrogens, followed by leaving of the stable tosylate anion.  Once this step occurs, it is likely irreversible as the tosyl anion is very stable (lots of resonance structures).  After this, a base induced rearrangement of the alpha-beta unsaturated ester to the beta-gamma isomer (yes there is such a thing!  I had no idea until I saw this however.)  Another deprotonation of the now moderately acidic aldimine leads to cleavage of the C-C bond.  Normally aldimines are not very acidic at the alpha hydrogen, however, because deprotonation here leads to a structure with a high amount of resonance (conjugation through the double bond into the ethyl ester), this can actually have a pKa on the order of 22 (source).  Now I know that a jump between pKa of 15.5 and 22 seems like a large jump, but higher temperatures may help bridge this gap.  Also, aldol condensations typically work with large differences between base strength and pKa.  This is an example of thermodynamic control, where once deprotonated, the enolate reacts quickly to form a stable product, pushing the reaction forward.  This is realized during the last step where formation of the enolate of the methyl ester attacks the newly formed aldimine (which reacts in a similar fashion to a ketone).  Proton transfers catalyzed by the basic conditions pushes the product toward the aromatic product which is the final product.  The large stability gained by this product is what pushes the reaction forward through the last step, elimination of the nitrogen anion which is rather unfavorable.

All of this is what we didn't want to happen.  So to get back to the main point of the post, why do we want to remove this tosylate group with the hydroiodic acid and red phosphorus?  Well, its the leaving of this group that started the whole cascade of reactions that led to the undesired product.  Conditions for removing the tosylate group however, without also hydrolyzing the esters are not realizable, and so hydrolysis of these esters are collateral damage.  We will see in ensuing steps that these esters are reformed to prevent undesired reactions from occurring.

Well despite the whole point of the post, I've been writing this for almost 2 hours now, and I have other things that require my attention.  I hope to cover the more interesting part of the reaction this weekend, which is the actual reduction of the tosylate group.  Stay tuned.