Catalytic Stereoinversion of L -Alanine to Deuterated D -Alanine

Article abstract of DOI:10.1002/anie.201503616

A combination of an achiral pyridoxal analogue and a chiral base has been developed for catalytic deuteration of L-alanine with inversion of stereochemistry to give deuterated D-alanine under mild conditions (neutral pD and 25°C) without the use of any pr

Full text of DOI:10.1002/anie.201503616

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201503616
German Edition: DOI: 10.1002/ange.201503616
Stereoselective Deuteration
Catalytic Stereoinversion of l-Alanine to Deuterated d-Alanine**
Kimia Moozeh, Soon Mog So, and Jik Chin*
Abstract: A combination of an achiral pyridoxal analogue and
a chiral base has been developed for catalytic deuteration of l-
alanine with inversion of stereochemistry to give deuterated d-
alanine under mild conditions (neutral pD and 258C) without
the use of any protecting groups. This system can also be used
for catalytic deuteration of d-alanine with retention of
stereochemistry to give deuterated d-alanine. Thus a racemic
mixture of alanine can be catalytically deuterated to give an
enantiomeric excess of deuterated d-alanine. While catalytic
deracemization of alanine is forbidden by the second law of
thermodynamics, this system can be used for catalytic dera-
cemization of alanine with deuteration. Such green and
biomimetic approach to catalytic stereocontrol provides
insights into efficient amino acid transformations.
Scheme 1. Catalytic stereoselective deuteration of l-alanine to deuter-
ated d-alanine using a pyridoxal analogue (1) and a chiral base (2).
C
atalytic conversion of l-amino acids to d-amino acids is
ambient temperature. Deuteration of l-alanine is about five
times slower with a half-life of about 75 min.
a topic of considerable interest in biology and chemistry.[1]
Although l-amino acids dominate nature, d-alanine, d-
serine, d-proline, d-aspartic acid, and d-glutamic acid all
have biological functions and are produced from their
corresponding l-amino acids enzymatically.[2] Chemists have
been interested in making d-amino acids as they are building
blocks for making small-molecule pharmaceuticals.[3] There is
much interest in developing green and efficient methods for
modifying amino acids without the use of activating or
protecting groups.[4] Furthermore, stereoselective deuteration
of amino acids and drugs is a topic of considerable current
interest.[5] Preliminary studies in stereoselective recognition
of amino acids[6] and l to d conversion of amino acids[7] led us
to investigate their catalytic transformations with deuteration.
Here we show a proof-of-principle of how alanine can be
catalytically deuterated stereoselectively under mild condi-
tions without the use of any protecting groups (Scheme 1).
In a typical experiment, 1 (0.1m) and (S,S)-2 (0.2m) were
dissolved in CDCl3 (0.2 mL) and vigorously stirred with 1 mL
of a 1m solution of l-alanine or d-alanine in D2O (Scheme 1).
1H NMR of the D2O layer shows that the a-proton quartet of
alanine disappears and the methyl signal of alanine collapses
from a doublet to a singlet. With the above catalyst loading of
2% for 1 and 4% for (S,S)-2, the half-life for deuteration of d-
alanine in the D2O layer at neutral pD is about 15 min at
Remarkably, both l-alanine and d-alanine give predom-
inantly deuterated d-alanine at 90% deuteration. For exam-
ple, when l-alanine is reacted for 4 h under the present
condition, deuteration is about 87% complete (Figure 1,
Table 1) and the d/l ratio of the deuterated alanine is about
5:1 (67% ee). To determine the d to l ratio of this solution,
the water layer was first separated from the chloroform layer
Figure 1. Signals in the 1H NMR spectrum for the alanine salt methyl
group after extracting the D2O layer with CDCl3 as described in the
text. a) Deuterated d-alanine salt. b) Deuterated l-alanine salt. b’) Dou-
blet signal of the initial non-deuterated l-alanine salt partially hidden
under (b). a’) Doublet signal of non-deuterated d-alanine salt partially
hidden under (a).
[*] K. Moozeh, Dr. S. M. So, Prof. J. Chin
Department of Chemistry, University of Toronto
80 St George Street, Toronto, ON, M5S 3H6 (Canada)
E-mail: jchin@chem.utoronto.ca
Table 1: Catalytic deuteration of l-ala as described in the text.
Homepage: http://www.diaminopharm.com
[**] We thank the Natural Sciences and Engineering Research Council of
Canada for funding of the research. K.M. thanks NSERC for
a Graduate Scholarship.
Reaction time % Deuteration of Ala in D2O d/l ratio of d/l ratio of
S,S-(d)-3
S,S-(l)-4
4 h
72 h
87%
99%
5/1
1/1
7.5/1
1.5/1
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503616.
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and extracted with a fresh solution of CDCl3 that contains
(S,S)-2 but not 1. The chiral guanidine by itself, (S,S)-2, does
not racemize alanine under our conditions and is useful for
extraction of alanine from the water to the chloroform layer
by formation of the diastereomeric amino acid salts (3,
Scheme 2). This extraction step is non-stereoselective. The
two diastereomeric salts give distinct 1H NMR signals for
determination of the d/l ratio of alanine. The signals of the
methyl groups of deuterated d-ala and l-ala salts appear at
1.03 (signal (a); Figure 1) and 1.08 ppm (b), respectively. We
also observe half of the doublet signal (b’) owing to the
starting alanine salt that has not been deuterated. The other
half of the doublet is hidden under peak (b) and was corrected
in calculating the d/l ratio of deuterated alanine. Half of the
doublet signal (a’) due to d-alanine that is not deuterated is
also visible although very small.
When l-alanine is reacted for three days instead of 4 h
under the present conditions, the d/l ratio of deuterated
alanine in the water layer is close to equilibrium at 1:1
(Table 1). The drop in the d/l ratio (5:1 to 1:1) is due to
catalytic racemization of deuterated d-alanine.
In case of catalytic deuteration of d-alanine with 1 and
(S,S)-2, deuteration is about 95% complete in 90 min under
the condition to give deuterated d-alanine preferentially with
a d/l ratio of about 5:1. Thus deuteration of l-alanine takes
place more slowly with inversion of stereochemistry while
deuteration of d-alanine takes place more rapidly with
retention of stereochemistry. This system can also be used
for deracemization of racemic mixtures of alanine to give
deuterated d-alanine.
Scheme 2 shows the proposed mechanism for catalytic
deuteration of l-alanine with 1 and (S,S)-2. At neutral pH l-
alanine is in the water layer as the zwitterionic form. The basic
and highly hydrophobic guanidine ((S,S)-2) effectively
extracts l-alanine from the D2O layer to the CDCl3 layer
where it forms the amino acid salt (3). The amino acid salt is in
equilibrium with the imino acid salt (4), which deprotonates
(5) and then deuterates to give the two diastereomeric imino
acid salts (d-(S,S)-(D)-4 and l-(S,S)-(D)-4). The imino acid
salts are in equilibrium with the two diastereomeric amino
acid salts (d-(S,S)-(D)-3 and l-(S,S)-(D)-3). In the final step,
deuterated alanine is released back to the water layer. The d/
l ratio of the two imino acid salts (d-(S,S)-(D)-4 and l-(S,S)-
(D)-4), and the two amino acid salts (d-(S,S)-(D)-3 and l-
(S,S)-(D)-3) can be monitored by 1H NMR spectroscopy
(Figure 1).
Apart from monitoring the d/l ratio of alanine in the D2O
layer by extraction (Figure 1), we also separated and moni-
tored the CDCl3 layer of the catalytic system after 20 min of
1
vigorous stirring. For example, a H NMR spectrum (Sup-
porting Information, Figure S26) shows the chloroform layer
of the catalytic system for deuteration of l-alanine immedi-
ately after (top) and 3 h after (bottom) separation from the
water layer. Deuteration of alanine trapped in the separated
chloroform layer (Supporting Information, Figure S26 top) is
almost complete within the time (15 min) it takes to prepare
and run the NMR sample. Since only about 4% of alanine is
trapped in the chloroform layer, the half-life for deuteration
of the trapped alanine in the separated CDCl3 layer should
roughly be about 3 min (4% of 75 min). The d/l ratio of the
deuterated amino acid salts (d-(S,S)-(D)-3 and l-(S,S)-(D)-3)
in Scheme 2 is about 4.2:1 (Supporting Information, Fig-
ure S26 top right), corresponding to 62% ee. Thus the
chloroform layer is rapidly generating enantiomeric excess
of deuterated d-alanine from l-alanine within minutes
(Supporting Information, Figure S26 top). When this chloro-
form layer is in contact with the water layer, amino acid
exchange takes place between the two layers resulting in an
increase in enantiomeric excess of deuterated d-alanine
within hours (Figure 1) in the water layer. Not surprisingly,
the ratios of methyl signals in Figure 1 closely resemble those
in the Supporting Information, Figure S26 top right.
When the above chloroform layer is kept separated from
the water layer for 3 h, the d/l ratio of the deuterated amino
acid salts (d-(S,S)-(D)-3 and l-(S,S)-(D)-3) goes down from
4.2:1 and reaches equilibrium at 1:1 (Supporting Information,
Figure S26 bottom right). This is due to catalytic racemization
of deuterated d-alanine trapped in the NMR tube. The d/
l ratio of the imino acid salt (d-(S,S)-(D)-4 plus d-(S,S)-(H)-4
and l-(S,S)-(D)-4 plus l-(S,S)-(H)-4) reaches equilibrium at
about 1.5:1 (Supporting Information, Figure S26 bottom left)
as determined by the ratio of the imine hydrogen signals at
7.72 ppm (d-(S,S)-(D)-4 plus d-(S,S)-(H)-4) and 7.69 ppm
(l-(S,S)-(D)-4 plus l-(S,S)-(H)-4). Our NMR data (Support-
ing Information, Figure S26) indicates that the stablilities in
CDCl3 of the two diastereomeric amino acid salts (Table 1)
are about the same (1:1) while for the imino acid salts, d-
Scheme 2. Proposed mechanism for catalytic conversion of l-alanine
to deuterated d-alanine.
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(S,S)-(D)-4 is slightly more stable than l-(S,S)-(D)-4 (1.5:1).
There appears to be some stereoselective interaction between
the guanidyl and salicyl groups in the imino acid salt (4). It is
interesting that the kinetic stereoselectivity (5:1) is consid-
erably greater than the thermodynamic stereoselectivity
(1.5:1). Table 1 shows that even at 4 h as at 72 h, the
diastereomeric ratio of the imino acid salt (7.5:1) is greater
than that of the amino acid salt (5:1) by a factor of 1.5.
The results are quite different if we carry out the above
experiment with l-alanine in H2O (Supporting Information,
Figure S27) instead of D2O. Unlike in D2O, there is no
enantiomeric excess of d-alanine in H2O at any point in time.
Immediately after separating the two layers, the CD3Cl layer
shows that the amino acid salt ratio (d-(S,S)-(H)-3/l-(S,S)-
(H)-3) is about 0.87:1 (Supporting Information, Figure S27
top). After 3 h of separation of the chloroform layer, the
amino acid salt ratio is about 1:1 while the imino acid salt ratio
is about 1.5:1 favoring the d form (Supporting Information,
Figure S27 bottom). In comparing the experiments in D2O
and H2O, the results are very different initially (Supporting
Information, Figure S26 vs S27 top) but similar at 3 h
(Supporting Information, Figure S26 vs S27 bottom). Initially,
there is equilibrium overshoot (net l to d conversion) in the
D2O experiment but not in the H2O experiemnt. At 3 h, both
the H2O and the D2O experiments reach the same thermody-
namic equilibrium (same d/l ratios of the imino acid salts
(1.5:1) and the amino acid salts (1:1)).
It is interesting that we observe catalytic l to d conversion
of alanine in D2O (Figure 1; Supporting Information, Fig-
ure S26). This could not take place in H2O (Supporting
Information, Figure S27 top) since it would violate the
principle of microscopic reversibility to have net directional
catalysis (that is, more efficient l to d than d to l).
Furthermore, it would go against the second law of thermo-
dynamics to go beyond racemization to enantiomeric excess
of d-alanine in H2O with a catalyst since that would represent
decreasing entropy without change in enthalpy. In our case,
significant kinetic isotope effect allows catalytic l to d
conversion of alanine to take place in D2O.
The deuteration of l-alanine takes place more rapidly if
1 is used with (R,R)-2 instead of (S,S)-2. The half-life for
deuteration of l-alanine when (R,R)-2 is used with 1 is about
15 min in contrast to about 75 min when (S,S)-2 is used with
1 under our experimental conditions. However we do not
observe net l to d conversion of alanine if we use (R,R)-2
instead of (S,S)-2. We observe deuteration of l-alanine with
retention of configuration when (R,R)-2 is used with 1.
Similarly, we observe deuteration of d-alanine with retention
of configuration when (S,S)-2 is used with 1. This can be
explained by using an energy diagram (Scheme 3) for
catalytic deuteration of l-alanine (l-alaH, Scheme 3) to give
deuterated d-alanine (d-alaD) and deuterated l-alanine (l-
alaD). The starting material and products in Scheme 3 may be
regarded to be in the chloroform layer or the D2O layer.
The energy diagram is consistent with all our experimen-
tal results but is not drawn to scale. The intermediate ((S,S)-5,
Scheme 2) deuterates stereoselectively to give d-alaD over l-
alaD as depicted by the energy difference h in Scheme 3. The
selectivity can be seen experimentally as amino acid salt ratios
Scheme 3. Energy diagram for deuteration of l-alaH.
in CDCl3 (Supporting Information, Figure S26 top right). The
two products equilibrate slowly due to kinetic isotope effect
and eventually reach equilibrium ratio of 1:1 as depicted by
equal energies of the two products (Scheme 3). This can also
be seen experimentally to be about 1:1 amino acid salt ratio in
1
CDCl3 as determined by integration of the H NMR peaks
(Supporting Information, Figure S26 bottom right). Note that
the imino acid salt ratio is not 1:1 at equilibrium (Supporting
Information, Figure S26 bottom left) as there is some
stereoselectivity for formation of the diastereomeric imino
acid salts. Conversion of the starting material to products is
downhill since there is much more D2O than H2O in the
experiment. d-alaD should dedeuterate more rapidly than l-
alaD (f > g) as shown in Scheme 3. It follows that d-alaH
should deprotonate more rapidly than l-alaH. In agreement,
we observe that (S,S)-2 is more reactive for deprotonating d-
alanine than l-alanine. Indeed, the relative rate of deproto-
nation of d-alaH and l-alaH with (S,S)-2 should be essentially
equal to the relative rate of deuteration of (S,S)-5 to give d-
alaD and l-alaD (given by h in Scheme 3). When the experi-
ment is carried out with H2O instead of D2O (Supporting
Information, Figure S27), there cannot be enantiomeric
excess of the product (d-alaH) since it would be equal in
energy as the starting material (l-alaH) unlike in Scheme 3.
If (R,R)-2 is used instead of (S,S)-2 as catalyst, intermedi-
ate (R,R)-5 would form and preferentially give l-alaD over d-
alaD in symmetry with Scheme 3, and therefore not result in
net l to d conversion of alanine. Thus, deuteration of l-
alanine with (R,R)-2 and 1 should take place with retention of
configuration in agreement with the experiment.
The only previous examples for obtaining catalytic
stereoselective deuteration of amino acids is with enzymes.
Alanine[8] and proline[9] racemases have been shown to
deuterate amino acids streoselectivity. It is remarkable that
our simple system provides greater stereoselectivity (67% ee)
than the enzymic systems (< 20% ee) for deuteration of
alanine or proline. In the enzymic studies, CD spectroscopy
was used to determine the enantiomeric excess of d-amino
acids. While detailed NMR studies are readily accessible with
both enantiomers of the catalyst in our system ((S,S)-2 and
(R,R)-2), it would be technically difficult to do similar studies
with enzymes. Highly efficient chemoenzymatic catalytic l to
d conversion of amino acids under non-equilibrium condi-
tions using oxidation and reducing agents have been
reported.[10]
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1 or (S,S)-2 by itself does not catalyze deuteration or
racemization of alanine under our experimental condition but
together they represent the most efficient non-enzymic
system for catalytic racemization of alanine and other
amino acids. We do not observe deuteration of alanine if we
replace (S,S)-2 in our experiment with DBU. Less hydro-
phobic bases like DBU does not work in our system because it
cannot extract alanine to the chloroform layer. Indeed alanine
extracts DBU to the water layer instead. Similarly, we do not
observe deuteration of alanine when (S,S)-2 is replaced with
triethylamine or tetrabutylammonium hydroxide. Triethyl-
amine is a weaker base than (S,S)-2 and tetrabutylammonium
hydroxide is quenched by neutral alanine. In contrast, (S,S)-2
is not fully quenched by neutral alanine. Some (S,S)-2 in the
chloroform layer exists as the amino acid salt and some as the
neutral form.
amino esters. Chiral-phase transfer catalysts were used to
obtain impressive stereoselective alkylation of the activated
amino esters under highly basic conditions. In contrast,
alanine racemase or our system consisting of 1 and 2 can
efficiently catalyze stereoselective deuteration of unprotected
and unactivated amino acids under mild conditions by
reversible formation of imine intermediates. It is interesting
that our simple system (1 and 2) provides greater stereose-
lectivity (67% ee) than alanine racemase (< 20% ee) for
deuteration of alanine. Lessons learned from the catalytic
deuteration may be applicable to catalytic alkylation of amino
acids in the future. The stereoselectivity is expected to
become higher as the size of the reactant is increased from
deuterium to carbon-based electrophiles for alkylation reac-
tions.
3,5-dichlorosalicylaldehyde (1) was chosen as a pyridoxal
mimic. Both aldehydes are electron deficient and both Experimental Section
General procedures for amino acid racemization: Mesitylguanidine
aldehydes have intramolecular resonance assisted hydrogen
bonds. The rate of deuteration of alanine decreases about 50
fold if 1 is replaced with salicylaldehyde in our experiment.
The deuteration reaction slows even further if 1 is replaced
with benzaldehyde or 2-pyridinealdehyde. Combination of
two weak forces (electronic and H-bonding) for the aldehyde
together with a strongly basic and hydrophobic guanidine
provides enormous rate-acceleration for the racemization
reaction at neutral pH and ambient temperature.
((R,R) or (S,S),40 mmol), and 3,5-dichlorosalicylaldehyde (20 mmol)
in CDCl3 (0.2 mL) was vigorously mixed with a D2O (or H2O)
solution (1 mL) of alanine (l- or d-, 1000 mmol). The reaction mixture
was stirred vigorously at room temperature for times specified herein.
To determine the d to l ratio of alanine, the D2O/H2O layer of
the above reaction mixtures were separated after 4 h. The water layer
was extracted with mesitylguanidine (40 mmol) in CDCl3 (0.7 mL).
The 1H NMR of the solution was taken to determine the ratio of
amino acid salts.
K.M. and S.S. contributed equally to experiments.
To study the scope of our racemization reaction, we
investigated 18 natural amino acids. The concentration of the
amino acids was lowered to 0.2m, 0.1m or 0.05m in D2O
(1 mL) to accommodate the solubility of all amino acids. 12 of
the amino acids (ala, thr, trp, phe, met, glu, gly, gln, asn, ser,
lys, leu) were fully deuterated at the a-position within a few
hours. Valine and isoleucine did not deuterate appreciably
under our conditions presumably due to steric effects. Proline
did not deuterate because the secondary amine does not form
the imine with 1. Cysteine can form the imine with 1 but the
side chain thiol group adds to the imine and prevents
deuteration. Arginine and histidine did not extract well and
did not deuterate appreciably. The solubility of tyrosine in
water is too low for our studies.
Keywords: amino acids · catalysis · deuteration ·
stereoinversion · stereoselectivity
How to cite: Angew. Chem. Int. Ed. 2015, 54, 9381–9385
Angew. Chem. 2015, 127, 9513–9517
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Above amino acids that can be catalytically racemized
may be considered for catalytic deracemization. For example,
phenylalanine can be catalytically deracemized (Supporting
Information, Figures S27–S29) with comparable extent and
same sense of stereoselectivity as for alanine deracemization.
Our mixture of 1 and 2 is the most efficient non-enzymic
catalytic system for racemization of alanine reported to date.
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Received: April 21, 2015
Revised: May 30, 2015
Published online: June 26, 2015
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