Total Synthesis Strychnine - Steps 16 & 17

Now, after just completing the synthesis of another ring of srychnine through the Dieckmann Condensation, it is now time to perform a series of steps which remove the vinyl alcohol group.  This is necessary because there are quiet a few steps to accomplish this, and if we performed it at the end, we must worry about the reactivity of the enol group throughout the synthesis.  The rule in synthesis is, keep the number of reactive groups to a minimum and this eases the chemistry a lot.  So here I will take us through the next two steps which will aid in the removal of the double bond, as well as the vinyl alcohol group.

Scheme 1. Steps 16 and 17 involving the addition of tosyl chloride, followed by hetero michael addition of the alkene.

Overview:
The first step is rather straightforward.  Tosyl chloride is a very common reagent for installing a tosyl protecting group, which is more common than tosylic acid for this transformation.  The reason being that the acid chloride is more activated, thus less vigorous conditions are required.  THe only nucleophile available is the alcohol, as we have previously acetylated the secondary (now tertiary) nitrogen to prevent such side reactions from occurring.  The mechanism is similar to any addition to a carbonyl compound with expulsion of chloride ion.  Note that out favorite base for scavenging chloride ions from forming HCl, pyridine, is again used as the solvent.
The next step involves addition of sodium benzylthiolate to the α,β unsaturated methyl ester.  This is a type of michael addition known generally as a hetero Michael Addition, and more specifically as a sulfa Michael Addition.  One thing I would like to point out is that many people incorrectly use the term "Michael Addition" to refer to any atom attacking the alkene of the α,β unsaturated carbonyl compound.  This is incorrect!!  A Michael Addition or Michael Reaction only refers to a enolate (or a carbon nucleophile) which adds to this position.  The addition of other atoms to this position are related somewhat, but the terminology is different.  Any atom other than carbon which is added to the α,β unsaturated carbonyl compound is known as a hetero Michael Addition.  These can be categorized into the sulfa, aza, and oxa Michael Reactions for sulfur, nitrogen, and oxygen acting as the nuclephile, respectively.

The Chemistry:
One thing I would like to point out about the addition of tosyl chloride is the typical lack of propensity for enols to be reacted with electrophiles.  This is because typically the keto tautomer is preferred, thus the utility of treating the ketone with TsCl and forming the enol is perhaps limited (however silyl chlorides are good reagents for trapping the activated enol, See Mukaiyama Aldol).  The reason for the proclivity of this enol to react with TsCl is because of the electron withdrawing pyridone ring which greatly stabilizes the enol form, leading to great yields.

The next step I will focus on will be the sulfa Michael Addition.  The mechanism is the same as for any type of michael addition, however, the catch is that we have a tosylate group (a very stable leaving group due to lots of conjugation) which will be come displaced.  In some senses, this is kind of like a conjugated version of a transesterification, with the double bond acting as a mediator between the tosyl ester for the substitution by the sulfur group.  The mechanism is below.

Scheme 2. Mechanism for sulfa Michael Addition

One thing I find so astonishing is the preference for leaving of the tosylate ion over the methoxide ion. With a yield of 77%, it is possible that some methoxide may leave, however, the preference is obvious for the tosylate group.  The reason is the higher stability of the tosylate ion with its higher conjugation.  Elimination of an akoxide is always a higher energy process unless there is some thermodynamic sink that traps the product in a very stable state upon elimination of such a group.  In this reaction.  If the methoxide ion were to leave, there is no additional conjugation or other interaction that will stabilize it, and so we find that the tosylate is the preferred ion to leave.  One last thing to mention is the solvent for this addition, methanol!  Isn't methanol a nucleophile that could add to the double bond as well?  Well, yes, it is, and it would be labeled as an oxa Michael Addition, however, comparing the nuclephilicities between the thiolate anion and the alcohol, there is a very big gap in nucleophilicity.  According to the Linear Free Energy Relationships (LFER, a huge topic in chemistry if you haven't heard of it, take a peek in Physical Organic Chemistry text here) the thiolate has a Swain-Scott parameter of 9.92 vs methanol, which is 0.0.  This means that the thiolate is a better nucleophile by nearly 10 billion times!  This explains why methanol as the solvent does not affect the reaction.

Workup:
For the tosyl chloride step, reaction took place with pyridine as the solvent.  After standing for 10 hours, water was added and allowed to stir longer.  I believe this extra time stirring helps to get rid of any pyridine complexes that may have formed.  It greatly helps in its removal as I have tried this.  Then addition of 6M HCl helps to protonate the remaining free pyridine to its HCl salt.  Subsequent extraction of the mixture with chloroform.  Washing the combined organic layers with aq. potassium carbonate, followed by water and brine helps to remove any other salts from the reaction mixture, as well as any unreacted enol, as the potassium carbonate may deprotonate it and allow it to transfer to the aqueous layer.  Evaporation and recrystallization from acetone yielded the product as yellow crystals.

The second reaction used an excess of the thiolate to press the reaction forward.  Allowing these reactants to stir at room temperature under nitrogen (this is to protect the thiolate from moisture in the air, and possibly oxidation to disulfide?) for 3 hours resulted in a precipitate forming from the reaction mixture.  Collection of this precipitate yielded the pure product as yellow needle-like crystals.

Next we will explore the final steps remaining in the removal the vinyl sulfide we just added, as well as the removal of the alkene.