Amino acids are the monomers that comprise proteins, and thus they are fundamental
components of every known living organism, just as we have discussed in the biochemistry series.
But while nature has considerable expertise in their production, chemists have also developed
a wide variety of techniques for amino acid synthesis. The first lab synthesis of these
compounds was published in 1850 by German chemist Adolph Strecker, and is now known as the Strecker
amino acid synthesis. Although 170 years old, this synthesis still plays an important role in
the repertoire of the synthetic organic chemist. Strecker discovered that heating a mixture of an
aldehyde, such as formaldehyde, with hydrogen cyanide and ammonia, led to an amino nitrile,
which could then be hydrolyzed at the nitrile to produce an amino acid, in this case glycine. It is
widely believed that this reaction may have led to the formation of amino acids on this planet,
since aldehydes, hydrogen cyanide, and ammonia were likely abundant on prebiotic earth.
However in the lab, the reaction is carried out by heating an aldehyde with potassium cyanide
and an ammonium salt, in order to avoid the dangers associated with ammonia and especially
hydrogen cyanide gas, which is extremely toxic. When the synthesis is applied to higher aldehydes
such as acetaldehyde, a chiral amino acid is formed, in this case alanine. Of course with
this reaction the product is racemic, meaning an equal mixture of the R and the S enantiomers,
because the reaction is not supported or catalyzed by a chiral template or catalyst.
The mechanism of the reaction is believed to be as follows,
proceeding at first just like imine formation, which we learned about in a previous tutorial.
But then the cyanide ion attacks here, to give the amino nitrile.
Then hydrolysis of the nitrile occurs over several steps under acid catalysis, again via chemistry we
have already learned, and there is our amino acid. The reaction applies to ketones as well, producing
alpha-alkyl amino acids, and can also work with primary amines, to give N-alkyl amino acids.
While amino acids are produced industrially by enzymatic methods because it’s so cheap,
the Strecker synthesis can be extremely useful for producing unnatural amino acids. However, in
order for it to be really useful, a procedure must be developed to produce only a single enantiomer
of the desired target, because separation by resolution is often tedious and inefficient.
Over the last 60 years or so, chemists have been able to turn the Strecker amino acid synthesis
into a tool to prepare enantiomerically pure amino acids. To illustrate the concept,
we will focus on a reaction recently discovered by German chemist Magnus Rueping, which is an
especially efficient method. In this approach, a chiral acid catalyst is used in small amounts.
Although this doesn’t immediately resemble what we think of as a chiral compound, given that it lacks
any actual chiral centers, notice the bonds that are more heavily shaded, and how they differ from
one ring system to the other. These are like wedge bonds, protruding towards the viewer, and this
configuration makes the molecule geometrically different from its mirror image, and therefore
chiral, just like some other examples of chiral molecules with no chiral centers that we examined
in another tutorial. Now the first step is to pre-form the imine, such as the one shown here.
Then, when the imine is treated with this chiral acid, a chiral salt forms in situ, and now the two
faces of the imine are no longer equivalent, as one becomes more hindered than the other.
The two faces are called diastereotopic, because the transition states leading to the S and the R
enantiomer of the product are diastereomeric, and one is kinetically preferred over the other.
After the synthesis, the small amount of chiral acid is available to perform another cycle,
because it is not consumed. As you can see, in the case of this unnatural amino nitrile, the
enantioselectivity of the process is excellent, with a preference for the S isomer of 200 to 1,
which propagates through to the product. With the many enantioselective versions of this
original chemistry and their applications in producing a variety of unnatural amino acids,
this ancient Strecker chemistry remains alive and well today.