In the previous tutorial we discussed an important three-component reaction called the Passerini
reaction.
This involves the use of isonitriles as mild nucleophiles.
You may recall that isonitriles are the less stable structural isomers of nitriles.
Whereas in nitriles the CN group is bound to an R group via the carbon atom, in an isonitrile
it is bound via the nitrogen atom.
Again, isonitriles are often represented as carbenes in resonance with a zwitterion, where
there is a positive charge on the nitrogen and a negative charge on the carbon.
The latter is the way we prefer to represent them for these particular reactions.
We are now ready to examine a four-component reaction called the Ugi reaction.
It was invented by Estonian-born German chemist Ivar Karl Ugi in 1959.
If you recall the details of the Passerini reaction, this is a simple extension.
Three of the components are identical, those being the carbonyl compound, the carboxylic
acid and the isonitrile.
To these we add a primary amine.
When mixed in stoichiometric amounts at room temperature, the four components react to
form an alpha-acylamino amide.
The mechanism for the Ugi reaction is similar to the one for the Passerini reaction, but
differs in the first step, which involves the formation of an imine from the aldehyde
or ketone and the amine, with loss of water.
We should already be familiar with the chemistry of imine formation from a previous tutorial
so we do not need to illustrate this simple mechanism here.
This imine is then activated by protonation by the carboxylic acid, and is then subjected
to nucleophilic attack by the isonitrile.
Here we see that the carbanion attacks this carbon here, and this pi bond goes to neutralize
the nitrogen.
This leads to the very electrophilic nitrilium ion, and just as we saw with the Passerini
reaction, the carboxylate anion will attack this carbon, pushing this pi bond here to
neutralize this other nitrogen.
The intermediate formed then undergoes the familiar 1,3 intramolecular shift of the acyl
group.
So this nitrogen attacks this carbonyl, this carbon-oxygen bond goes to form this other
carbonyl, and this carbon-nitrogen pi bond will pick up a proton.
And this will yield the more stable alpha-acylamino amide.
Now, in the previous tutorial we discussed the preparation of chemical libraries for
random screening.
This reaction is even more popular in library synthesis than the Passerini reaction.
If one chooses ten readily available ketones, ten carboxylic acids, ten primary amines,
and then prepares ten isonitriles, all possible combinations will afford 10,000 different
compounds for the screen.
This is very useful in searching for compounds with desirable properties.
We will also again notice that the reaction leads to a chiral compound.
Just as with the Passerini reaction, if R1 does not equal R2, the carbonyl group is prochiral,
and the product will have a stereogenic center.
If the reaction is promoted by a chiral acid, in principle an enantioselective synthesis
is possible, as we have illustrated previously.
We will not review this research at this time, as it is rather specialized.
Suffice it to say that there are already a few examples of quite enantioselective Ugi
reactions, using a variety of chiral Brønsted acids, but the results are not yet satisfactory
and the field is still evolving.
As we have already stated for the Passerini reaction, obtaining racemates is not a problem
for library building.
Actually, if every compound in the 10,000-member library is racemic, that actually gives us
20,000 different compounds, which only gives us more diversity.
Nevertheless, this reaction still has utility in organic synthesis.
As an example of the application of this reaction to the synthesis of complex targets, we will
illustrate the work of Professor Ruijter’s group working at the University of Amsterdam.
The molecule to synthesize is the Hepatitis C drug Telaprevir, developed and marketed
by the companies Vertex and Johnson & Johnson.
As you can see this is a rather complex target, and the synthesis actually combines a Passerini
and an Ugi reaction in a very clever way.
The first step is a Passerini reaction, as shown here, with these three reagents.
The product is an alpha-acyloxy amide and it is a mixture of two diastereomers, because
the stereochemistry at the newly formed stereogenic center is not controlled.
As we will see in a moment, this is not important as this center will be oxidized at the end
of the synthesis.
Next, the formamide moiety on this side of the molecule is dehydrated by the usual methods
to afford another isonitrile, in this case using a mix of triphosgene and N-methyl morpholine
as reagents.
Then the Ugi reaction is applied.
Instead of using an aldehyde and an amine, which will form an imine in situ, a preformed
cyclic imine is used.
Thus, this particular Ugi reaction is only a three-component reaction.
The product is obtained in 80% yield in one pot.
Then simple hydrolysis of the acetate and oxidation of the resulting alcohol to give
the ketone yields the drug as the final product.
So what can we say about this drug?
First, note that it contains four stereocenters.
Three are derived from the building blocks we have used, and these are prepared by rather
straightforward syntheses.
A new stereocenter, marked with the asterisk, is created in the Ugi reaction.
This time, since we already have three stereocenters in complete optical purity, it is no longer
the issue of an enantiospecific reaction, because the existing stereocenters will influence
the stereochemistry at the newly formed carbon-carbon bond.
It is very hard to predict the stereochemical outcome of these reactions.
Although there are theoretical approaches one can use to estimate the relative stabilities
of the two competing transition states, another approach is to just try the reaction and see
whether one obtains the correct stereochemistry.
In this case, it fortuitously turns out that the desired stereochemistry, S, is favored
by a factor of 7:1 with respect to the undesired R. This then simply requires a separation
before the final two steps, but it still represents a highly effective and high-yielding approach
to the synthesis of this drug.
Applications to other complex targets demonstrate that the Ugi reaction is an important tool
in synthesis, and its utility is not limited to the preparation of libraries for biological
screening.
However, the hallmark of this reaction is its multi-component character, a rarity in
organic synthesis, and it is rather likely that the need for biological screening has
been the key to the current popularity the Ugi reaction is enjoying.