Chemistry Reference
In-Depth Information
With the clear evidence that a basic side arm attached to pyridoxamine could act not
only to remove a proton but also subsequently to add it to the
-carbon of the devel-
oping amino acid, it seemed attractive to learn how to perform this reaction with high
stereoselectivity. Attachment of a chiral side chain to pyridoxamine could induce some
stereoselectivity, but the enantiomeric excess (ee%) in these cases were usually low.
For instance, compound
10
with an N,N-dimethylcysteinol side chain produced
D
-nor-
valine from
a
-ketovaleric acid in 39% ee, while
11
, carrying an N-acetylcysteine side
chain, produces a nearly racemic mixture of amino acids [7]. For stereoselective synth-
esis of a product amino acid the catalytic side arm must operate on one face or the
other of this planar system. This could be achieved by fusing a ring to the pyridox-
amine unit, so that a side arm coming off this ring would necessarily be aimed either
forward or backward.
Thus we designed and synthesized a bicyclic pyridoxamine derivative carrying an
oriented catalytic side arm (
16
) [11]. Rates for conversion of the ketimine Schiff base
into the aldimine, formed with
26
(below) and
a
-ketovaleric acid, indolepyruvic acid, or
pyruvic acid, were enhanced 20-30 times relative to those carried out in the presence
of the corresponding pyridoxamine derivatives without the catalytic side arm. With
a
-
ketovaleric acid,
16
underwent transamination to afford
D-
norvaline with 90% ee. The
formation of tryptophan and alanine from indolepyruvic acid and pyruvic acid, respec-
tively, showed a similar preference. A control compound (
17
), with a propylthio group
at the same stereochemical position as the aminothiol side arm in
16
, produced a 1.5:1
excess of
L-
norvaline, in contrast to the large preference for
D-
amino acids with
16
.
Therefore, extremely preferential protonation seems to take place on the si face
when the catalytic side arm is present as in
16
.
Bernauer et al. [12] developed an alternative method to induce chirality in the pyr-
idoxamine-mediated transamination reactions. They synthesized some chiral terden-
tate ligands (
18
-
20
) having C
2
symmetry. Using these auxiliary ligands they studied
the isomerization of the Cu(
II
) Schiff-base complex of pyridoxamine and various keto
acids. In a weakly acidic solution, optically active
a
-amino acids with (R)-configuration
were formed preferentially, and the maximum ee%s were 80, 54, 48, and 29 for phe-
nylalanine, alanine, leucine, and valine, respectively (Scheme 2.3). The authors pro-
posed that the enantioselectivity comes from formation of an intermediate Cu(
II
)-ke-
timine complex with the auxiliary ligand. However, the relatively high ee%s were only
obtained at the initial reaction stage because an undesirable racemization reaction oc-
curred subsequently.
a
