Total Synthesis Strychnine - Steps 18 & 19

Our next steps in this synthesis involve the de-functionalization of the double bond we had just created.  At this point, it may be well to compare where we are now, to where we want to be.

Figure 1. We can see that several double bonds must be removed to obtain the final structure

Our first step in removing the functional groups that will no longer serve us include removing the vinyl sulfide that we had just added, followed by removing the double bond it is attached to.  In order to do this, Woodward had utilized Raney nickel, followed by palladium on carbon to perform each step, respectively.  The following scheme illustrates the goal.

Figure 2. Following 2 reductions with deactivated Raney nickel, and palladium on carbon.

Overview:
Raney Nickel
The step with Raney nickel I found particularly interesting, as I was not aware that this finely divided nickel over aluminum can de-sulfurize compounds.  This lends it as an exceptionally useful organic reagent.  The summed up version of what Raney Nickel actually is is described here briefly. If you are really curious more about Raney Nickel, I recommend (of course) the wiki page which can be found here.  However, in short, Raney Nickel is a nickel aluminum alloy with a small amount of a third metal to enhance its activity.  It is ground into a small powder, and then activated with strong NaOH to etch away some of the aluminum to create hydrogen gas, which becomes absorbed onto the surface.  This creates a very strong reducing agent (recall that raney nickel and hydrogen can reduce benzene to cylohexane!).  It is for this reason, that deactivated Raney nickel is used, otherwise, we would also reduce our bezene ring, as well with our pyridone ring.  To avoid this, Woodward deactivates it by boiling in acetone, followed by ethyl acetate, each for 3 hours.  This significantly reduces the activity of the catalyst through reduction of both the acetone and ethyl acetate, depriving the catalyst of its rich hydrogen environment in turn for an environment with a lower concentration of hydrogen.  Raney nickel is usually supplied as a slurry in water to prevent its reduction of oxygen in air which will also deactivate it (as well a potentially cause it to ignite!).

Palladium on Carbon
Palladium on carbon seems to me to be the bread and butter for the reduction of simple double bonds as well a benzyl ethers and benzyl esters.  Palladium on carbon is palladium metal with a high surface area due to its dispersion onto porous carbon (same thing as activated carbon).  We can see from the Figure 2 that simple reductions take place very quickly to yield the desired product.  From my experience with using this chemical (only 1 reaction) the product can "stick" to the palladium in the small pores.  The necessitates the use of often excessive rinsing with hot solvent to remove as much of the material as possible.  This is the case in Woodwards case as well it seems as he washes the palladium with lots of solvent.

Mechanism:
The mechanism for the reductions is actually very complicated.  Unless you are getting your Ph.D. studying hydrogenation, it usually suffices to have the following general scheme in your head.  It's accuracy may not be valid, but the mechanism is actually quite complex, and may involve radicals, which I am by no means capable of tackling.  So instead, I leave you with the following scheme.

Figure 3. Generic scheme for reduction by palladium or other metal catalyst.

In this scheme we see that the palladium (or could be nickel) adsorbs hydrogen atoms to its surface.  Transfer of these atoms in a syn addition to the same side of the double bond which is catalyzed by the environment at the surface of the metal releases the product.  In this case, it is important to notice that due to sterics, we only see the cis isomer formed (with the methyl ester coming towards us in Figure 2) and a small fraction of the trans isomer.  This is due to sterics of the approach of the catalyst surface.  We can see from the following figure that approach from the bottom is more favorable than approach from the top due to the 3D structure of the 5 member ring which hinders approach from the top of the molecule.

Figure 4. Pink atoms represent the alkene which will be hydrogenated. A.) Hindered approach from the top of the molecule (see arrow). B.) Less hindered approach from the bottom.

Workup:

The workup for these reactions are often quite simple.  Since the catalyst is suspended in the reaction solvent (usually an alcohol, as it is not reduced by the catalyst) it is simple to just filter it off either through a little bit of celite or silica.  The alcohol will pull the compound through the silica fast if it is a nonpolar compound so usually one doesn't have to worry about the compound getting retained in the silica.  However, one hazard one has to be aware of is the possibility of ignition of the catalyst.  Since there is still often a lot of hydrogen adsorbed onto the catalyst surface, and oxygen in the air, this can create a reaction that, due to the high surface area of the catalyst, can oxidize much of the hydrogen quicky, and release enough heat to start a fire.  For this reason it is necessary to make sure that the catalyst does not become dry during filtering, always keeping solvent above the top of the filtered catalyst.  Also, when done filtering, make sure to cover the catalyst with water, and properly dispose of the catalyst (or reuse it!).

For the first reaction with deactivated Raney nickel, after deactivation (as described earlier in the post), refluxing for 3h with the catalyst was sufficient to complete the reaction.  Often hydrogenations are quick and efficient due to the large excess of hydrogen, so it is likely that this step is very very efficient.  However, we see that when filtering the catalyst, Woodward washed the 500mg scale reaction with over 250mL of hot ethanol.  This is because often the product can get caught on the catalyst.  The poor yield (I believe) is actually due to the incomplete removal of product from the catalyst.  Rinsing with more solvent will likely just be wasteful rather than improving the yield much.  After concentrating and precipitating from a concentrated solution of acetone by diluting with ether, the product was yielded (no description of crude product).

The next step was performed in a similar manner to the previous.  Hydrogen transfer occurred quickly under 2 minutes at room temperature.  Afterwards, filtration and recrystallization from acetone/ether afforded clusters of colorless needles.

Next time we will look at how we can change the stereochemistry of the methyl ester which will be necessary for proving the structure we have created so far through comparison with breakdown products of strychnine.