Total Synthesis Strychnine - Step 1

To start off, I love total synthesis.  Even though I don't myself perform it, I appreciate the complexity and ingenuity that goes into figuring out synthetic schemes of these complex molecules.  So every so often I like to take some time to read "Classics in Total Synthesis", of which the first entry is the total synthesis of Strychnine by B.R. Woodward.  I will try to go over each step every day or two, and really break down the importance of every chemical involved, possible side reactions, and planning.

Here is the structure of Strychnine.  While not as complex as some other molecules, there is still quite a bit of somewhat hidden complexities, most notably the number of chiral centers, and the odd ring structure.  I'm still always amazed that what may look like a straightforward molecule, in practice, can be extremely difficult to synthesize.

If you are interested in the synthesis, it's reported synthesis by Woodward was published in Tetrahedron in 1963.  It can also be found on the SynArchive website.


To start off, the first step of the synthesis will involved the least labile groups of the molecule.  In this case, this would involve the indole ring on the left side of the molecule.  The benzene is quite unreactive and should maintain its integrity throughout the remainder of the synthesis.  So here is the first step of the synthesis.

Overview:

In this first step, the reaction that takes place is the Fischer Indole Synthesis.  It is one of the oldest ways of making an indole ring.  First, the hydrazine moiety is condensed with the ketone of the di-methoxy substituted benzene to form a hydrazone (the hydrazine equivalent of a ketone) with a concomittant loss of water.  The use of polyphosphoric acid in the reaction is twofold.  First of all, polyphosphoric acid is simply a very very concentrated phosphoric acid solution.  So concentrated that it forms essentially a polymer of phosphates.  Its first use is that water will hydrolyze these bonds to form regular concentrated phosphoric acid.  Well wouldn't you know that water is evolved from this reaction in the first step of the condensation of the hydrazine to form the hydrazone.  Secondly, the fischer indole synthesis is catalyzed by acid throughout the duration of the reaction.

Workup: I find it interesting how quickly this reaction proceeds, finishing in nearly 10-15 minutes.  It is to note that this reaction is highly exothermic due to the additional stabilization attained by the aromatic indole product.  For the same reason, this is the driving force of the reaction bringing it forward, creating a sink to bring products toward reactants.  It is to note that the entire molecule is conjugated and relatively hydrophobic.  The amine in the indole is not very basic (it takes a pH of 3.6 to protonate half of these sites) as the electron pair is involved in the aromatic system, again, making this molecule relatively non-polar.  Isolation of this compound involved precipitating the reaction melt into water, then extracting the compound into chloroform (a good solvent for most compounds, non-polar compound such as this should be soluble).  Using a chloroform/methanol mixture the compound was recrystallized in a 54.4% yield.  It is to note that the more polar phenylhydrazine is likely to be soluble in the methanol and as the desired compound precipitates out as the more polar solvent is added, the phenylhydrazine should remain in the liquid layer, effectively purifying the compound.

Looking Ahead: One note about indoles is that they are quite nucleophilic at the alpha and beta nitrogen carbons, leaving them reactive with electrophiles (see figure below).  The introduction of the di-methoxy benzene moiety on the alpha carbon effectively blocks this carbon and helps to activate the other for attack in the next step via the indole modified Mannich Reaction.

Important resonance forms of Indole