Marissa C.

Rosen
Thursday, March 13, 2003

Asymmetric Synthesis of -Amino Acids: New Twists on Old Ideas

Chiral amino acids are important biological molecules. They are the building blocks
of proteins, and the twenty proteogenic L-amino acids are ubiquitous to all living
organisms on earth. Because of their biological importance, they were some of the first
chiral synthetic targets.
Amino acids can exist in either the D or L form. The majority of
naturally occurring amino acids are L-amino acids; however, some Damino acids occur naturally. For example, the peptidoglycan that
makes up the cell wall of the bacterium Staphylococcus aureus
contains D-isoglutamate and D-alanine. The twenty proteogenic
amino acids are L-amino acids and all except cysteine have the S
absolute configuration at the carbon.

H R
H2N
CO2H
(S)-L-amino acid
H2N

CO2H

H R
(R)-D-amino acid
Figure 1: Designations
of amino acids

Natural and non-natural amino acids have found many uses in

organic chemistry. They can be used as chiral starting materials for natural product total
synthesis, or as chiral auxiliaries, catalysts or catalyst ligands. In the field of protein
engineering, non-natural amino acids can be incorporated into proteins in order to study
protein structure and function They have also been used in order to create drugs or other
bioactive molecules that will not be degraded as quickly as natural amino acids by
protease enzymes.
Although enzymatic syntheses and resolutions are viable methods for the production of
naturally occurring chiral amino acids, they are often not useful for synthesizing nonnatural D-amino acids or amino acids with non-natural side chains. An alternate method
is the formation of diastereomeric salts of optically impure amino acid mixtures, followed
by chiral resolution. However, this method is time consuming and therefore expensive,
and not all mixtures are amenable to this approach. In general, L-amino acids can often
be obtained by biological methods; however non-natural D-amino acids and D- or Lamino acids with unusual side chains cannot. For that reason, synthetic routes to these
molecules are necessary.
There are 4 general methods of chiral amino acid synthesis.1 The first is selective
addition of a carboxylic acid equivalent to the pro-chiral carbon of an imine, as in the
asymmetric Strecker reaction. Also, hydrogen can be added asymmetrically to a
prochiral carbon of a di-dehydro amino acid, as in the Knowles Monsanto synthesis.
The Corey-Link reaction involves asymmetric addition of hydride to a ketone amino acid
precursor. Various asymmetric derivitizations of glycine involve creating a nucleophile
or electrophile at the carbon of a glycine equivalent and subsequent asymmetric
addition of an R group to that center. There are, of course, many other routes to chiral amino acids, such as use of Evans chiral auxiliary2, electrophilic amination of enolates,

nucleophilic amination of substituted acids, and enzymatic syntheses, including

enzymatic resolution3 or enzyme-catalyzed bond-forming reactions
The Strecker Synthesis
The Strecker reaction was developed by Adolph Strecker in 1850.4 It is a threecomponent reaction between an aldehyde, an amine and hydrogen cyanide to form an
amino nitrile. The nitrile can then be hydrolyzed to the free acid, resulting in a racemic
amino acid (Figure
NH2
O
NH2
2).
The Strecker
+ NH3 + HCN
R
CO2H synthesis is one of the
R
H
CN
R
(+/-)
most
convenient
Figure 2: The Strecker synthesis of amino acids
methods
for
synthesizing amino acids and much research has focused on the development of
asymmetric versions of this reaction.
The first asymmetric Strecker reaction was reported over one hundred years after the
introduction of the racemic version.5 In this reaction, a chiral -methylbenzylamine was
condensed with an aldehyde to form a chiral imine. The chiral center was able to direct
the addition to the imine with enantiomeric excesses from 9-58%, depending on the side
chain. After hydrolysis of the nitrile group, the chiral auxiliary is then destructively
removed to yield the free amino acid. While this method is not useful today, it represents
the initial attempts in an important field of asymmetric Strecker reactions.
The first non-metal catalyzed asymmetric Strecker synthesis, reported by Lipton and coworkers, used a cyclic dipeptide catalyst to achieve high yields and enantiomeric excess.6
In particular, phenylglycine and p-methoxyphenylglycine were synthesized in >99% and
96% ee, respectively. However, electron-poor aromatic side chains and aliphatic side
chains give essentially racemic products with this catalyst, making it useful only in the
synthesis of certain types of amino acids. This work was soon followed by Jacobsen and
co-workers report of on another chiral, non-metal
tBu O
H
catalyst for the asymmetric Strecker synthesis.7,8
Ph
N
N
N
Jacobsens catalyst was based on a tridentate Schiff
H
H
O
N
base scaffold that would be amenable to solid phase
synthesis. The catalyst was synthesized on solid
HO
O
support and optimized through a series of parallel
t-Bu
O
OtBu libraries. The final catalyst was superior to that
previously described by Lipton et. al. because it was
Figure 3: Jacobsen's Schiff base catalyst
capable of catalyzing the formation of aliphatic
amino nitriles with significant enantiomeric excesses (80-90%). The conversion of
ketimines to ,-disubstituted amino acids was also achieved with this catalyst.9 Because
it can be synthesized in 5 steps with 80% overall yield and no chromatographic
separation and the resin-bound catalyst has been shown to be recyclable at least 10 times
with no loss of yield or enantiomeric excess, Jacobsens Schiff base catalyst should find
use in other labs, and possibly in industry.10

Recently, the laboratory of Kobayashi reported a novel zirconium catalyst that could
effect the enantioselective synthesis of -aminonitriles.11 While Kobayashis catalyst
gave high yields and enantiomeric excesses for aromatic imines and improved yields and
enantiomeric excesses for aliphatic imines over the previously discussed catalysts, its
large molecular weight (1671.95 amu) endows this catalyst with very poor atom
economy. In a related work the authors report the first efficient, asymmetric three
component Strecker reaction that is amenable to industrial use, using the same zirconium
catalyst.12
Knowles-Monsanto Synthesis
William S. Knowles won the Nobel prize in 2001, along with Noyori and Sharpless, for
his pioneering work in the development of asymmetric hydrogenation of didehydroamino acids. Knowles and co-workers began this project while trying to develop
an efficient industrial process to synthesize L-DOPA that did not involve time-consuming
resolutions and recycling. This led to the development of DiPAMP, a chiral phosphine
ligand for asymmetric hydrogenations with rhodium metal (Figure 4).13 This new chiral
phosphine rhodium catalyst
R
R
was used in Monsantos
H2, Rh(L)(cod)
synthesis of L-DOPA (a
HO2C
NH2
P
HO2C
NH2
ligand =
OCH3
phenylalanine
derivative
H3 CO
OH
P
that is used in the treatment
L-DOPA: R=
OH
of Parkinsons disease) and
has since had widespread
(R,R)-DiPAMP
Figure 4: Knowles-Monsanto Synthesis
use
outside
of
the
laboratory in which it was developed. This catalyst gives high yields and enantiomeric
excesses, and the availability of both enantiomers of DiPAMP (R,R and S,S) affords
either enantiomer of amino acid.
Asymmetric Derivitizations of Glycine and Glycine Equivalents
The two general approaches for derivatizing glycine are nucleophilic and electrophilic.
Both involve the use of a chiral auxiliary to direct the formation of the new stereogenic
Nucleophilic
center (Figure 5).14
O
derivatizations are much more common in
Nucleophilic

+
R
the literature and will therefore be the focus
NR2
H
(enolate)
CO2H of this abstract. Some of the first efficient
R
examples of a nucleophilic derivatization
O
NH2
came from the labs of Schllkopf.15 In these
Electrophilic

+
R
examples, a chiral amino acid is cyclized
NR2
with glycine to form a bis-lactam.
(cation equivalent)
Treatment of the bis-lactam with
Figure 5: Types of Derivatizations of Glycine
Meerweins salt forms a bis-lactim ether,
which can be deprotonated at the -carbon to form an enolate. The chiral center on the
essentially planar bis-lactim anion directs the enolate to attack from the opposite side.
Chiral auxiliaries derived from L-t-leucine16, L- alanine15, L-valine17 and L-O,O-dimethyl-

OMe

OMe
18

-methyldopa have all shown good

N
N 1. n-BuLi
2. RCH2X
N
yields
and
good
to
excellent
N
H
enantiomeric excesses, depending on the
OMe
OMe
nucleophilic substrate. Bis-lactim ethers
can also be used to synthesize ,
OMe
L-Val-OMe
disubstituted amino acids, by cyclizing
+
N
0.25 N HCl
the chiral auxiliary amino acid with
H
N
CO2Me
2
N
CH2R
racemic alanine instead of gylcine.
CH2R
OMe
Again, the chiral auxiliary directs the
Figure 6: Bis-Lactim Ether Glycine Enolates
enolate to attack from the opposite face
to yield the disubstituted amino acid in good yields and enantiomeric excesses in most
cases.19
Williams and co-workers developed a similar system in which a cyclic lactone consisting
of a glycine equivalent and a chiral auxiliary was deprotonated to form the enolate. The
chiral auxiliary acts to direct the enolate to attack from the opposite side to form the
amino acid precursor. The real strength of this methodology is that different cleavage
methods can be used to obtain either the N-protected amino acid or the zwiterionic free
amino acid.20 , Disubstituted amino acids could also be synthesized by this method.21
Lu et. al. recently published another example of a chiral glycine enolate in which a chiral
auxiliary derived from (+)-R-camphor was coupled with glycine to give the chiral
template (Figure 7).22 This could then be deptrotonated at the -carbon to form the
enolate. The chiral auxiliary directs the formation of the endo product in high
diastereomeric excesses. Both enantiomers of amino acids are accessible through two
different chiral auxiliaries, both derived from the inexpensive (+)-R-camphor.23
R
N
O

O
OH
H

H
O
(+)-(R)-Camphor

OH
H
O

H2N

OH

O
OH

D -amino acid

H R

O
N

H2N

OH

L -amino acid

H
+

OH
H
O

Figure 7: Chiral Tricyclic Iminolactone Derived from (1R)-(+)-Camphor

Corey-Link Reaction
The Corey-Link reaction involves the application of the CBS reduction, originally
applied to the reduction of carbonyls, to chiral -amino acid synthesis.24,25 This sequence
involves first the stereoselective reduction of a substituted trichloromethyl ketone to the
corresponding (R)-secondary alcohol with the (S)-oxazaborolidine CBS reduction
catalyst, with > 97:3 enantioselectivity in most cases. The alpha-trichloromethyl alcohols
can be converted to (S)-amino acids in four steps high overall yields. This methodology
is useful for preparing -amino acids with a wide range of side chains, from aryl and
napthyl to cyclic and acyclic aliphatic groups.

Seebachs Self-Reproduction of Chirality

A very interesting example of
amino acid synthesis comes from
O
OLi
N
N
LDA
the laboratory of Seebach, in which
CO2H
O
O
N
THF
92%
H
a chiral amino acid starting
-78 C
material such as L-proline is used.
Although the chirality of the
E
15-48%
O
+
E
original stereogenic center of the
N
E
HBr
CO2H
O
N
amino acid is lost in enolate
E+ = R X
H
formation, that stereocenter is
or O
directed back to its original
R
conformation (Figure 8).27 In an
Figure 9: Self-Reproduction of Chirality
example of this methodology, Lproline is condensed with pivalaldehyde to yield a single diastereomer of the bicyclic
aminal. The stereogenic -carbon of proline directs the formation of the (S)
conformation at the newly formed stereogenic center. The aminal is then deprotonated to
form the enolate, thereby erasing the stereochemistry at prolines -carbon. However,
upon nucleophilic attack by the enolate to an electrophlie (such as an alkyl halide or
aldehyde), the (S) stereocenter directs the reproduction of the original (S) conformation at
the prolines -carbon. This methodology can be used to synthesize other, non-cyclic
amino acid derivatives besides proline.28
O

Conclusions
There are many methods available for the synthesis of chiral -amino acids, and the large
amounts of time and effort that has gone into the development of these methods attests to
the importance of chiral -amino acids as synthetic targets today. The different
approaches presented herein have various strengths and weaknesses, but together they
present an arsenal that is capable of synthesizing a wide range of natural and non-natural
chiral -amino acids.
References
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Chiralittszentrums