Mannich Class 1
March 15, 2011
We are going to spend the next two classes talking in detail about the Mannich reaction. Unlike DielsAlder and olefin metathesis, I suspect there are a fair number of people here who have never heard of
the Mannich reaction. The general reaction is shown below:
The first step in the mechanism is formation of an iminium ion from the amine (primary or secondary)
and the formaldehyde:
In the next step, the carbonyl group forms an enolate (nucleophile) that attacks the iminium
(electrophile):
The net result is that you have added an amino group in the beta position of a carbonyl compound. The
reaction takes place usually under acidic conditions, which helps to generate the iminium intermediate.
The Mannich reaction has been used to generate unnatural peptide derivatives:
Example 1: Synthesis of phosphinopeptides
Researchers used the Mannich reaction to attach two peptides to each other. Here is the actual
reaction:
Here the water in the second step hydrolyzes the P-Cl bonds to P-O bonds. The key here is that the
amide group forms an imine with benzaldehyde that then gets attacked by the nucleophilic
phosphorous atom.
Once you form that, the only thing left to do is to displace the chlorides with water molecules. Ther e are
a bunch of arrow-pushing mechanisms that you can draw to get both chlorides off and replaced with
two oxygen atoms. I have shown one way of thinking about this above.
Example 2: The same research group synthesized sulfonophosphinopeptides:
The proposed mechanism here is basically the same as the first example, just now you have an SO2
group next to the primary amine rather than a carbonyl. An eample of a final product is shown below:
This can be disconnected retrosynthetically into four different components. To do this, first recognize
that the phosphorous always comes from an R-PCl2 type species. The second thing to recognize is that
the R-PCl2 had to have attacked an imine carbon, so you should reconstruct that imine:
The final step of deconstruction is to break the imine. Imines can always be disconnected
retrosynthetically across the double bond, to generate an aldehyde and amine.
We can also do this reaction in the forward direction (with the mechanism also shown below):
Example 3: The Petasis reaction can be thought of as a boronic acid-version of the Mannich reaction.
Two basic types of Petasis reactions are shown below:
The mechanism in both cases involves a pre-formation of an imine:
The next step is the nucleophilic addition of the organic ligand from the boronate to the imine. This step
can either be intermolecular or intramolecular:
One advantage here is that this step is irreversible, and in a standard Mannich reaction all steps are
reversible.
We can also do the mechanism for the first Petasis reaction shown above:
Here also you have formed an imine that acts as the electrophile. The R1-boron species becomes
negatively charged, and that allows the R1 to function as a nucleophile and attack the iminium cation.
People have used the Petasis reaction to synthesize interesting peptide mimetics using the general
scheme shown below:
For example, how would you synthesize the compound shown below via a Petasis reaction?
You really have two options, depending on where you choose to generate the imine:
Either way, you first generate an imine and kick off the boron nucleophile, and then the imine can be
disconnected retrosynthetically to an aldehyde + amine.
Example 4: People have also cyclized peptides on solid-phase supports using the Mannich reaction:
Key here is that formaldehyde acts as a source of one carbon in the Mannich reaction. Why does this
reaction attach to the phenol precisely in the place that it does?
That’s because the phenol acts like an enol/enolate, so the nucleophilic site is right next to the oxygen.
We are going to talk about this example next time and also about the Mannich reaction in the context of
total synthesis.