Asymmetric amplification in the amino acid-catalyzed synthesis of amino acid derivatives

Article abstract of DOI:10.1002/adsc.200700110

The origins of biological homochirality have intrigued researchers since Pasteur's discovery of the optical activity of biomolecules. Herein, we present the first example of asymmetric amplification in the amino acid-catalyzed enantioselective synthesis o

Full text of DOI:10.1002/adsc.200700110

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DOI: 10.1002/adsc.200700110
Asymmetric Amplification in the Amino Acid-Catalyzed
Synthesis of Amino Acid Derivatives
a
a
a
a
Ismail Ibrahem, Henrik SundØn, Pawel Dziedzic, Ramon Rios,
a,
and Armando Córdova *
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
a
Fax : (+46)-8-154-908; e-mail: acordova@organ.su.se
Received: February 27, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The origins of biological homochirality
have intrigued researchers since Pasteurꢀs discovery
of the optical activity of biomolecules. Herein, we
present the first example of asymmetric amplifica-
tion in the amino acid-catalyzed enantioselective
synthesis of amino acid derivatives that provides
support for a synergistic model for the evolution of
homochirality by amino acid catalysis.
Mannich-type reaction is a very useful transformation
for the asymmetric synthesis of functional amino acid
[
7f,8]
derivatives with high stereoselectivity.
these reactions is the amino acid-catalyzed asymmet-
One of
[8d]
ric synthesis of amino acid derivatives [Eq. (1)].
Keywords: amino acids; asymmetric amplification;
homochirality; kinetic resolution
Herein, we show the first example of asymmetric
amplification in the amino acid-catalyzed enantiose-
The origins of biological homochirality have fascinat- lective synthesis of amino acid derivatives giving prec-
ed researchers since Pasteurꢀs discovery of the optical edence for amino acid catalysis as a route for the ori-
[
1]
activity of biomolecules. Frank proposed that evolu- gins of homochirality.
tion of high asymmetry from a small imbalance of en-
During our studies of the amino acid-catalyzed re-
antiomers could be achieved by a combination of au- action between propionaldehyde 1a and N-p-methoxy-
[
2]
tocatalytic and inhibition processes. In this context, phenyl (PMP) protected a-imino glyoxylate 2 using
Soai and co-workers were first able to demonstrate differentlevels of enan it oenriched ( S)-proline as the
experimentally that a product of certain chirality is catalyst, we found a significant asymmetric amplifica-
generated faster because of a non-linear forward reac- tion of the enantiomeric excess in the formation of
[
3]
tion step in zinc-promoted additions. Recently, sig- the corresponding amino acid derivative 3a [Eq. (2),
nificantnon-linear effe cs t have been observed in
purely organocatalytic reactions involving amino
Figure 1].
[
4,5]
acids or peptides as catalysts. The works of Hayashi
[6a]
[6b,c]
[6e]
etal.,
Blackmond etal.
and Breslow
imply
the disproportionation of enantiomers between solu-
tion phase and solid phase without overall amplifica-
[6]
tion of ee. These phase transition effects are not re-
lated to chemical reactions, but rather to solubility
equilibria. Moreover, asymmetric amplification is
present in the amino acid-catalyzed formation of
[
5d,e]
sugars under homogeneous reaction conditions.
These results have led to speculations of amino acid
catalysis as a route to the origins of homochirality.
To the best of our knowledge this is the first report
of a positive non-linear effect in an amino acid-cata-
The Mannich reaction is an important reaction in lyzed Mannich-type reaction. We have now investiga-
[7]
[5e]
organic synthesis. In this context, the direct catalytic ted whether the enantioenriched amino acid prod-
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Adv. Synth. Catal. 2007, 349, 1868 – 1872

Asymmetric Amplification in the Amino Acid-Catalyzed Synthesis of Amino Acid Derivatives
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Figure 1. Relation between the enantiomeric excess of (S)-proline and that of the newly formed amino acid derivative 3a ( )
&
and 3b (^) in the catalytic asymmetric amino acid synthesis using propionaldehyde 1a and cyclohexanone 1b as donors, re-
spectively. The standard deviation for the ee values is Æ0.5% and based on three separate experiments.
Figure 2. Oxazolidinone formation between 3a and (S)-proline (a) and (R)-proline (b), respectively.
uct 3a was involved in the mechanism of the asym- the difference in reactivity due to diastereoselective
metric amplification.
interactions between the (S)- and (R)-amino acid with
According to this scenario, the amino acid deriva- the chiral (S)-amino acid product 3a in the formation
tive 3a derived by amino acid catalysis would react at of covalent chiral product intermediates such as oxa-
different rates with the (S)- or (R)-amino acid and zolidinones gives rise to amplification of the enantio-
consequently “auto”-kinetically resolve the amino meric excess. In order to support our hypothesis, we
acid catalyst by forming covalent intermediates such performed a series of experiments. High-resolution
as oxazolidinones giving rise to amplification of the mass spectroscopic analyses of the proline-catalyzed
enantiomeric excess in the next catalytic cycle reactions between 1a and 2 established the formation
(
Figure 2). This would also be in line with the suppo- of an oxazolidinone intermediate I between the
sition that a single proline molecule takes part in the amino acid product 3a and the proline catalysts (Eq.
[
11]
formation of the amino acid derivative 3a according [2]).
to the proposed mechanisms and transition states of
previously reported proline-catalyzed enantioselective
[
9]
Mannich reactions. Moreover, Seebach and Eschen-
moser recently proposed in an elegant study that the
oxazolidinones formed in proline-catalyzed reactions
may also have a pivotal role during the catalytic cycle
[
10]
and notonly be “dead ends”.
This novel mechanis-
tic suggestion additionally supports our theory that
Adv. Synth. Catal. 2007, 349, 1868 – 1872
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1869

Ismail Ibrahem etal.
Hence, we added
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[
5e]
We also investigated the relation between the enan- chosen as the model reaction.
tiomeric excess of (S)-proline and that of the newly amino acid derivative 3a with 99% ee (0.7 mmol) that
formed amino acid derivative 3b in the catalytic had been obtained by (S)-proline catalysis, to a mix-
asymmetric Mannich-type reaction between cyclohex- ture of racemic proline (11 mol%) in DMSO
anone 1b and 2 [Eq. (3), Figure 1].
(0.4 mL) [Eq. (4)].
After 24 hour of stirring, cyclohexanone 1b
(
0.7 mmol) was added to the homogeneous solution.
Next, nitrosobenzene (0.3 mmol) in DMSO (0.4 mL)
was slowly added by a syringe pump to the reaction
mixture. Notably, product (2R)-4 was isolated in 33%
yield with 19% ee after 2 h. Moreover, product 4 was
not formed without the addition of a catalytic amount
of racemic proline under our reaction conditions. The
presence of oxazolidinone I, formed by the reaction
The reaction showed a linear relationship between between amino acid 3a and the proline catalysts, in
the ee of (S)-proline and the ee of the amino acid de- this reaction was established by high-resolution mass
rivative 3b. Moreover, high-resolution mass spectro- spectroscopic analysis. Consequently, amino acid de-
scopic analyses of the reaction between 1a and 2 did rivative 3a can be used for the in situ kinetic resolu-
not detect the formation of an oxazolidinone inter- tion of racemic proline catalyst according to Figure 2.
mediate II.
The possibility of an autocatalytic asymmetric am-
plification in the catalytic enantioselective synthesis
of amino acid derivatives 3 was also investigated [Eq.
[
13,14]
(
5), Supporting Information].
This suggests that the amino acid derivative 3b with
a keto group did not react with the catalyst to form
the corresponding bicyclic oxazolidinone II due to
possible steric constraints. In comparison, amino acid
derivative 3a with a more reactive aldehyde moiety
For instance, propionaldehyde 1a was reacted with
will form the corresponding oxazolidinone I with less imine 2 in the presence of a catalytic amount (30
steric interactions under the set reaction conditions. mol%, 20 mg) of amino acid derivative 3a with 52%
Moreover, we also investigated the ee of (S)-proline ee in wetDMSO (1.02 mL). The rea icot n was
(
6 mg) in wet DMSO (1.09 mL) as function of the ee quenched after 4 days and 3a was isolated in <1%
of the initially added solid (S)-proline after 16–18 h of yield after subtracting the initially added 30 mol% 3a
stirring and observed a negative non-linear effect and with an ee of 40% (the measured ee is for the total
lower enantiomeric excess of the (S)-proline in solu- isolated product). The control reaction without an ini-
[
12]
tion (see Supporting Information). Thus, no phase tial addition of a catalytic amount of chiral amino
behaviour of the amino acid catalysts was responsible acid derivative 3a gave racemic product 3a in 6%
for the positive non-linear effects observed in the yield. This productwas possibly ca at lyzed by p-anisi-
amino acid-catalyzed synthesis of amino acid deriva- dine formed from minor hydrolysis of imine 2. More-
[
6c,12]
tives under our reaction conditions.
We also in- over, product 3a (20 mg) did notracemize in wet
vestigated whether the chiral amino acid product 3a DMSO (1.02 mL) under 4 days of stirring and was re-
could be used to kinetically resolve proline in a paral- covered in 83% yield with 99% ee. Thus, no signifi-
lel transformation. The racemic proline-catalyzed a- cant asymmetric amplification or autocatalysis had oc-
aminoxylation of cyclohexanone 1b that furnishes the curred in the reaction shown in Eq. (5).
corresponding racemic a-aminoxylated ketone 4 was
Based on our experiments, we propose a synergistic
mechanism between the amino acid-derived products
and their amino acid catalyst to be due to the asym-
metric amplification in the amino acid-catalyzed syn-
thesis of amino acid derivatives (Scheme 1).
Thus, the enantioenriched (S)-amino acid product
3a reacted faster with (R)-proline as compared to (S)-
proline due to plausible different diastereoselective
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Adv. Synth. Catal. 2007, 349, 1868 – 1872

Asymmetric Amplification in the Amino Acid-Catalyzed Synthesis of Amino Acid Derivatives
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Scheme 1. The synergistic model for the asymmetric amplification in the amino acid catalyzed asymmetric formation of
amino acid derivative 3a.
propionaldehyde (0.75 mmol), H O (1.25 mmol) and imine 2
2
interactions between the b-amino group of 3a and the
amino acid, which increased the concentration of free
(
0.25 mmol, 1.0 equiv) sequentially. The reaction was vigo-
rously stirred at room temperature for 18 h. Next, the crude
(
S)-proline in the solution and gave rise to amplifica- was purified by silica gel column chromatography (tolu-
tion of the enantiomeric excess of 3a in the next cata- ene:AcOEt, 6:1) to afford the final compound 3a.
lytic cycle. This is also in accordance with the origins
of asymmetric amplification in the amino acid-cata-
lyzed enantioselective sugar formation where kinetic Acknowledgements
data clearly show that the (S)-proline-derived b-hy-
droxy aldehyde product reacts faster with (R)-proline We gratefully acknowledge the Swedish National Research
[
5e]
Council, Wenner-Gren Foundation, Carl-Trygger Foundation
and Lars-Hierta Foundation for financial support. We thank
Prof. Jan-E. Bäckvall for valuable discussions.
as compared to (S)-proline.
Hence, the intrinsic
ability of amino acid-derived products to kinetically
resolve their amino acid catalyst, which leads to am-
plification of the enantiomeric excess in their own for-
mation, provides additional support for our original
synergistic model for the evolution of asymmetry of
biomolecules by organic catalysis.
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