Sugar-assisted kinetic resolution of amino acids and amplification of enantiomeric excess of organic molecules

Article abstract of DOI:10.1002/chem.200600526

The origins of biological homochirality have intrigued researchers since Pasteur's discovery of the optical activity of biomolecules. Herein, we propose and demonstrate a novel alternative for the evolution of homochirality that is not based on autocataly

Full text of DOI:10.1002/chem.200600526

DOI: 10.1002/chem.200600526
Sugar-Assisted Kinetic Resolution ofAmino Acids and Ampliifcation of
Enantiomeric Excess ofOrganic Molecules
Armando Córdova,* Henrik SundØn, Yongmei Xu, Ismail Ibrahem, Weibiao Zou, and
Magnus Engqvist[a]
Abstract: The origins of biological homochirality have intrigued researchers since
Pasteurꢀs discovery of the optical activity of biomolecules. Herein, we propose and
demonstrate a novel alternative for the evolution of homochirality that is not
based on autocatalysis and forges a direct relationship between the chirality of
sugars and amino acids. This process provides a mechanism in which a racemic
mixture of an amino acid can catalyze the formation of an optically active organic
molecule in the presence of a sugar product of low enantiomeric excess.
Keywords: amino acids · asymmet-
ric amplification · homochirality ·
kinetic resolution · sugars
Introduction
our earlier studies on the amino acid catalyzed formation of
carbohydrates such as 2a and 3,[10] we found a remarkably
high asymmetric amplification in the formation of the
hexose product 3 (Reaction (1)).[11] In addition, a positive
nonlinear effect that is dependent on the reaction conditions
has been observed in the amino acid catalyzed a-aminoxyla-
tion of propionaldehyde.[7]
The origins of biological homochirality have intrigued re-
searchers since Pasteurꢀs discovery of the optical activity of
biomolecules.[1] In 1953, Frank proposed that evolution of
high asymmetry from a small imbalance of enantiomers
could be achieved by a combination of autocatalytic and in-
hibition processes.[2] This was
first experimentally accomplish-
ed by Soai and co-workers.[3]
Their original zinc addition ex-
periment has been widely used
to explain the origins of homo-
chirality.
The circular polarization in
star formation regions may
have led to the initial asymmetry of organic molecules such
as sugars and amino acids.[4] In fact, extraterrestrial amino
acids have been found on the Murchison meteorite with
enantiomeric excesses (ees) of up to 9%.[5] The finding has
led to speculation on the origins of homochirality by a proc-
ess mediated by amino acids.[6–8] Furthermore, extraterrestri-
al sugars are also present on the Murchison meteorite.[9] In
Hence, amino acids may have been the seed for the evolu-
tion of homochirality of carbohydrates. However, Frankꢀs
scheme is not applicable to Reaction (1) since the catalyst is
not catalyzing its own formation. In fact, the amino acid is
catalyzing the asymmetric formation of a sugar in a fashion
similar to the way in which enzymes have asymmetrically as-
sembled carbohydrates for millions of years.[12–13] Thus, there
is a need to find an alternative mechanism for the origins of
homochirality that is not based on autocatalysis. Bearing
this in mind, and given the intense interest in the origins of
homochirality, we became interested in finding a reaction
model that could provide new insights on the origin of
asymmetric amplification in amino acid catalyzed reactions.
Here, we propose and demonstrate a novel alternative for
the evolution of homochirality that forges a direct relation-
[a] Prof. Dr. A. Córdova, H. SundØn, Dr. Y. Xu, I. Ibrahem, Dr. W. Zou,
Dr. M. Engqvist
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University, 106 91 Stockholm (Sweden)
Fax : +(46)8-154-908
E-mail: acordova@organ.su.se
acordova1a@netscape.net
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Chem. Eur. J. 2006, 12, 5446 – 5451

FULL PAPER
ship between the chirality of sugars and amino acids. This
process provides a mechanism by which a racemic mixture
of an amino acid can catalyze the formation of an organic
molecule with an enantiomeric excess.
Results and Discussion
We first investigated the (S)-proline-catalyzed asymmetric
formation of aldose precursor 2b (Reaction (2)).[13d]
Figure 1. Relation between the enantiomeric excess of (S)-proline and
&
that of the newly formed tetrose 2b ( ) in the catalytic asymmetric dime-
rization of propionaldehyde.
In initial experiments, we performed the amino acid cata-
lyzed asymmetric synthesis of 2b using different levels of
enantioenriched (S)-proline as the catalyst (Figure 1). Nota-
catalysis, to react at different rates with the (S)- or (R)-
amino acid and consequently “auto” kinetically resolve the
catalyst without forming a new catalyst species (Scheme 1).
bly, we found
a significant
asymmetric amplification of the
enantiomeric excess in the
amino acid catalyzed asymmet-
ric formation of b-hydroxyalde-
hyde 2b, even though, a single
proline molecule takes part in
the formation of aldose precur-
sors 2 according to the pro-
posed mechanisms and transi-
tion states of previously report-
ed proline-catalyzed enantiose-
Scheme 1. Different reaction rates of (S)- and (R)-proline with sugars 2.
lective aldol reactions.[10,11,13,14]
The results indicated to us
that the asymmetric amplification in the amino acid cata-
lyzed reactions was plausibly caused by chiral product 2b.
We therefore decided to test an alternative and novel ex-
planation for the origins of homochirality that is consistent
with transition state theory. The model is based on the in-
trinsic ability of chiral organic molecules such as sugars and
b-hydroxyaldehydes 2,[15] which are formed by amino acid
This sugar-assisted kinetic resolution leads to asymmetric
amplification of the chiral organic product in the next cata-
lytic cycle because the free amino acid has a higher optical
activity (Figure 2).
The product-assisted auto-kinetic resolution scheme is
also applicable to sequential (Pn+1 =Sn+1) and two parallel
amino acid catalyzed reactions where the amino acid de-
Figure 2. Proposed model for the catalytic asymmetric amplification.
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5447

A. Córdova et al.
Table 1. Product-assisted in situ kinetic resolution of racemic proline.
rived products Pn+1 or Pn+2 synergistically contributes to the
asymmetric amplification of one of the products. The theory
can be tested with a racemic amino acid as the catalyst. In
this case, the presence of a chiral sugar P1 with enantiomeric
excess should be able to kinetically resolve the amino acid
catalyst, which subsequently catalyzes the formation of opti-
cally active product P2. This plausible scenario would sug-
gest that a chiral sugar could have set the seed for the evolu-
tion of homochirality of sugars and amino acids. To further
test our theory of a sugar-assisted kinetic resolution of an
amino acid catalyst, we chose the racemic proline-catalyzed
a-aminoxylation of cyclohexanone 4 that furnishes the cor-
responding racemic a-aminoxylated ketone 5 as the model
reaction (Reaction (3)).[16]
Entry Sugar
1
d.r.[a]
4:1
ee [%][b] Product Yield [%][c] ee [%][d]
98
98
5
5
57
27
2
3
2b
4:1
4:1
51[e]
66[e]
99
>99
>99
>99
>99
>98
5
5
5
5
5
5
26
5
10
27
À5
À2
7
4
5
6
7
8
4:1
>19:1
>19:1
>19:1
48
55
45[f]
24[f]
47
This proline-catalyzed reaction exhibits no asymmetric
amplification and only one proline molecule takes part in
the transition state.[16d,e] In an initial experiment, we added
aldose precursor 2b with 98% ee (1 mmol), which had been
obtained by (S)-proline catalysis (Reaction (2)),[13d] to a mix-
ture of racemic proline (10 mol%) in DMSO (1 mL)
(Table 1, entry 1). After the mixture had been stirred for 1h,
the reaction mixture became homogeneous and cyclohexa-
[a] The diastereomeric ratio (d.r.) (anti:syn) determined by NMR analy-
ses. [b] The ee determined by chiral-phase GC analyses. [c] Yield of pure
product isolated. [d] The ee determined by chiral-phase HPLC analyses.
[e] The mixture was premixed for 4 h. [f] The mixture was premixed in
water for 15 min.
none
4
(1 mmol) was added. Next, nitrosobenzene
curred, and optically active ketone 5 was furnished. To fur-
ther establish that the sugars 2 were responsible for the in
situ kinetic resolution and not just any chiral additive,[17] we
investigated the racemic proline-catalyzed a-aminoxylation
reaction in the presence of several natural chiral molecules
(Table 2).
(0.5 mmol) in DMSO (1 mL) was slowly added by syringe
pump to the reaction mixture. The reaction was quenched
by directly purifying the reaction mixture by silica-gel
column chromatography. Remarkably, product 5 was isolat-
ed in 57% yield with 27% ee (Table 1, entry 1). Thus, a
product-assisted kinetic resolution of the amino acid catalyst
by the aldehyde 2b had occurred. The added aldose precur-
sor 2b was recovered with 97% ee as determined by chiral-
phase GC analyses. Notably, increasing the pre-mixing time
of 2b with racemic proline to 4 h increased the ee of 5 to
66% ee (Table 1, entry 2). In addition, no product 5 was fur-
nished without a catalytic amount of racemic proline. The
addition of different aldose precursors 2a–d, which had
been furnished by (S)-proline catalysis, to the racemic pro-
line-catalyzed model reaction (vide infra) furnished the opti-
cally active ketone product 5 in all cases (Table 1). Of the
investigated aldose precursors, 2b and 2d reacted fastest
with (R)-proline and created the highest concentration of
free (S)-proline, which led to the highest asymmetric induc-
tion of ketone 5. We also performed the premixing of the
simplest sugars glyceraldehyde and tetroses 2 with proline
under prebiotic conditions, which was followed by removal
of the water and a-aminoxylation of 4. In all cases, a sugar-
assisted kinetic resolution of the amino acid catalyst had oc-
We found that the enzyme-like kinetic resolution of the
amino acid exclusively occurred in the presence of natural
C-3and C-4 sugars or aldose precursor 2, which can be
formed by proline catalysis. None, of the other chiral natural
products 7–10 were able to resolve the amino acid catalyst.
Hence, a free aldehyde moiety is essential for the kinetic
resolution of the amino acid. Moreover, the C-6 sugar glu-
cose 8, which is preferentially in its pyranose form, was
unable to kinetically resolve the amino acid catalyst. This is
in accordance with the fact that the tetroses 2 f and 2g have
a faster equilibrium between the furananose form and the
open form, which have a free reactive aldehyde moiety, than
the pyranose ring of glucose 8. Next, we performed the ex-
periment with different levels of enantiomeric purity of te-
trose 2b (Table 3).
Notably, even though 2b with low optical activity was
added, the racemic proline catalyzed the formation of opti-
cally active ketone 5. Thus, the optical purity of the tetrose
2 does not have to be high to create an imbalance between
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Amplification of Enantiomeric Excess of Organic Molecules
FULL PAPER
Table 2. Influence of chiral aldose precursors, sugars, amino acids, a-hy-
droxy acids and nucleotides on the racemic proline catalyzed reaction.
Entry Additive
d.r.[a]
4:1
>19:1
>19:1
ee Product Yield
ee
[%][b]
[%][c]
[%][d]
1
2
3
4
2b
98
>99
>99
>98
5
5
5
5
51[e]
45[f]
24[f]
47
66
À5
À2
7
ent-2e
ent-2 f
2g
5.16 ppm (d, J=3.9 Hz) and the higher field shift of the
methyl groups of the acetonide at d=1.35 and 1,27 ppm, re-
spectively, established the formation of I. Notably, perform-
ing the same experiment with (R)-proline furnished the cor-
responding diasteromeric oxazolidinone II with a clear shift
of the C-2 ring-proton at d=5.12 ppm (d, J=5.0 Hz) and
the higher field shift of the methyl groups of the acetonide
at d=1.31 and 1.26 ppm, respectively.
We next mixed racemic proline together with aldehyde 2g
and found that the ratio between oxazolidinones I and II
was 1:1.5 (Figure 3). Thus, (R)-proline forms the oxazolidi-
none at a faster rate than (S)-proline.
5
6
>98
5
6
17
>99
5
64
0
7
8
9
10
d-glucose 8
d-glucose 8
(S)-alanine 9
d-2-deoxy-thymi-
dine 10
>99
>99
>99
>99
5
5
5
5
47[f]
49[g]
59
<1
<1
0
64
0
[a] The d.r. (anti:syn) determined by NMR analyses. [b] The ee deter-
mined by chiral-phase GC analyses. [c] Yield of pure product isolated.
[d] The ee determined by chiral-phase HPLC analyses. [e] The mixture
was premixed for 4 h. [f] The mixture was premixed in water for 15 min.
[g] The mixture was premixed in water for 48 h at 1208C.
Table 3. Influence of the ee of 2b in the product-assisted in situ kinetic
resolution of racemic proline.
Entry
Sugar
d.r.[a]
ee [%][b]
Product
Yield [%][c]
ee [%][d]
1
2
3
4
5
2b
2b
2b
2b
2b
4:1
4:1
4:1
3:1
3:1
98
86
70
48
15
5
5
5
5
5
57
55
41
67
72
27
24
20
10
3.5
[a] The d.r. (anti:syn) determined by NMR analyses. [b] The ee deter-
mined by chiral-phase GC analyses. [c] Yield of pure product isolated.
[d] The ee determined by chiral-phase HPLC analyses.
the two enantiomers of the amino acid. In fact, this small
imbalance of enantiomeric excess of the amino acid catalyst
is enough to give rise to asymmetric amplification
(Figure 1). The kinetic resolution of the amino acids is plau-
sible due to a combination of inhibition and reaction be-
tween sugars 2 and the proline catalyst.[18] For example, stir-
ring racemic proline in the presence of glyceraldehyde 2h or
tetrose 2e for 1 h followed by the a-aminoxylation reaction
1
Figure 3. The H NMR spectra of the C-2 protons of the oxazolidinones I
and II, respectively, formed by mixing racemic proline with glyceralde-
hydes 2h in [D6]DMSO. The ratio between I and II is 1:1.5.
Moreover, kinetic experiments revealed that the (S)-pro-
line-catalyzed a-aminoxylation reaction in the presence of
the (S)-proline-derived tetrose 2b was faster than the corre-
sponding (R)-proline-catalyzed reaction (Figure 4). Conse-
quently, optically active ketone (2R)-6 is formed in the race-
mic proline-catalyzed reaction in Tables 1–3.
1
(vide infra) did not give ketone 5. HNMR analysis of the
reaction between glyceraldehyde 2h and (S)-proline in
[D6]DMSO showed that complete conversion to the corre-
sponding oxazolidinone I had occurred within this time. The
clear shift of the oxazolidinone C-2 ring-proton at d=
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A. Córdova et al.
temperature, TMS served as internal standard (d=0 ppm) for 1H NMR
spectra, and CDCl3 was used as internal standard (d=77.0 ppm) for
13C NMR spectra. GC was carried out using a Varian 3800 GC instru-
ment. Chiral GC-column used: CP-Chirasil-Dex CB 25 m”0.32 mm. Op-
tical rotations were recorded on a Perkin Elemer 241 Polarimeter (l=
589 nm, 1 dm cell). Optical rotations were recorded on a Perkin Elemer
241 Polarimeter (l=589 nm, 1 dm cell). High-resolution mass spectra
were recorded on an IonSpec FTMS mass spectrometer with a DHB-
matrix.
(S)-Proline-catalyzed asymmetric synthesis of(2 S, 3S)-3-hydroxy-2-meth-
ylpentanal (2b): Propionaldehyde (1 mL, 13.7 mmol) was added to a vial
containing (S)-proline (30 mg, 0.26 mmol) and DMSO (2 mL). The reac-
tion was left to stir at 48C for 16 h. The reaction mixture was readily pu-
rified by silica-gel chromatography (pentane/EtOAc 3:1) to furnish pure
2b in 68% yield with 98% ee. Analytical data of this compound are iden-
tical in every aspect to previously reported values.[13d] The ee was deter-
mined by GC analysis of the acetal derived from 2,2-dimethylpropane-
1,3-diol according to the method of Yamamoto et al.[19] GC: Tdet =2758C,
flow=1.8 mLminÀ1, ti =1008C, hold 35 min, tf =2008C rate=808CminÀ1
,
Figure 4. Relationship between the time and the asymmetric formation of
6 for the (S)-proline-catalyzed reaction (*, black), (S)-proline-catalyzed
hold 10 min, major isomer: tr =35.514 min, minor isomer tr =35.778 min.
The cross-aldol adducts 2c and 2d were synthesized according to Mac-
Millanꢀs[13d] and our[10] procedures by utilizing (S)-proline (10 mol%) as
the catalyst.
~
reaction in the presence of tetrose 2b ( , blue) and (R)-proline-catalyzed
&
reaction in the presence of tetrose 2b ( , red).
Typical experimental procedure for the proline-catalyzed asymmetric
synthesis of(2 S, 3S)-3-hydroxy-2-methylpentanal (2b): Propionaldehyde
(1 mL, 13.7 mmol) was added to
a vial containing proline (30 mg,
Conclusion
0.26 mmol, the ee of the proline was varied according to Figure 1) and
DMSO (2 mL). The reaction was left to stir at 48C for 16 h. The reaction
mixture was readily purified by silica-gel chromatography (pentane/
EtOAc 3:1) to furnish pure 2b. The ee was determined as described
above.
In summary, we have shown that sugar product 2-assisted ki-
netic resolution as well as inhibition of an amino acid cata-
lyst is the origin of the significant amplification of enantio-
meric excess in the amino acid catalyzed formation of carbo-
hydrates. The reaction scheme is complementary to the
model of autocatalysis and provides a mechanism in which
an optically inactive amino acid can mediate the formation
of organic molecules with enantiomeric excesses in the pres-
ence of a sugar product with low enantiomeric excess. Thus,
we have found that the optical enrichment of products de-
rived by amino acid catalysis may be influenced by the
action of simple sugars and amino acids. The symbiotic be-
havior of these additives, in combination with the likely
presence of each in the prebiotic milieu, suggests that their
cooperative action could have contributed to the early ach-
ievement of highly enantioenriched products under prebiotic
conditions and may be an explanation for the origin of ho-
mochirality where the initial asymmetry may have been set
by an amino acid or sugar.
Typical experimental procedure for the racemic proline-catalyzed synthe-
sis of5 in the presence ofaldose precursors 2 : A solution of aldose pre-
cursors 2 (1 mmol, with an ee according to Tables 1 and 2) or glyceralde-
hyde 2g (0.75 mmol) and racemic (R),(S)-proline (6 mg, 10 mol%) in
DMSO (1 mL) was left to stir for 1–2 h. Next, cyclohexanone 4 (1 mmol)
was added to the homogeneous reaction mixture followed by slow addi-
tion with a syringe pump over 1 h of a solution of nitrosobenzene (54 mg,
0.5 mmol) in DMSO (1 mL). Next the reaction mixture was let to stir for
an additional 0.5 h (3h when tetrose 2a was used). The reaction was
quenched by putting the reaction mixture directly on a silica-gel column
(pentane/EtOAc 10:1), which furnished the pure 5 and 2 after chroma-
tography. Analytical data of 5 are identical to previously reported value-
s.[16a,d] The ee was determined by chiral-phase HPLC analysis (Diacel
Chiralpak AD, n-Hex/iPrOH 90:10, flow rate 0.5 mLminÀ1, l=254 nm):
minor isomer: tr =27.208 min, major isomer: tr =31.791 min.
Typical experimental procedure for the racemic proline-catalyzed synthe-
sis of5 in the presence ofsugars 2 or glucose : A solution of erythrose,
threose 2 (0.25 mmol, with an ee according to Table 1 and Table 2), or
glucose (2 mmol) and racemic (R),(S)-proline (6 mg, 10 mol%) in H2O
(1 mL) was left to stir for 15 min. The water was removed under reduced
pressure and DMSO was added (1 mL). Next, cyclohexanone 4 (1 mmol)
was added to the homogeneous reaction mixture followed by slow addi-
tion with syringe pump over 1 h of a solution of nitrosobenzene (54 mg,
0.5 mmol) in DMSO (1 mL). The reaction mixture was then left to stir
for an additional 0.5 h (3h when tetrose 2a was used). The reaction was
quenched by putting the reaction mixture directly on a silica-gel column
(pentane/EtOAc 10:1), which furnished pure 5 and 2 after chromatogra-
phy. Analytical data of 5 are identical to previously reported values.[16a,d]
The ee was determined by chiral-phase HPLC analysis (Diacel Chiralpak
AD, n-Hex/iPrOH 90:10, flow rate 0.5 mLminÀ1, l=254 nm): minor
isomer: tr =27.208 min, major isomer: tr =31.791 min.
Experimental Section
General: Chemicals and solvents were either purchased puriss p.A. from
commercial suppliers or purified by standard techniques. For thin-layer
chromatography (TLC), Merck 60 F254 silica gel plates were used, and
compounds were visualized by irradiation with UV light and/or by treat-
ment with a solution of phosphomolybdic acid (25 g), Ce(SO4)2·H2O
G
(10 g), concentrated H2SO4 (60 mL), and H2O (940 mL) followed by
heating or by treatment with a solution of p-anisaldehyde (23mL), con-
centrated H2SO4 (35 mL), acetic acid (10 mL), and ethanol (900 mL) fol-
lowed by heating. Flash chromatography was performed by using Merck
60 silica gel (particle size 0.040–0.063mm), 1H NMR and 13C NMR spec-
tra were recorded on a Varian AS 400 instrument. Chemical shifts are
given in d relative to tetramethylsilane (TMS), the coupling constants J
are given in Hz. The spectra were recorded in CDCl3 as solvent at room
Typical experimental procedure for the racemic proline-catalyzed synthe-
sis of5 in the presence ofa chiral derivative : A solution of chiral natural
product (1 mmol, with an ee according to Table 2) and racemic (R),(S)-
proline (6 mg, 10 mol%) in DMSO (1 mL) was left to stir for 1–2 h.
Next, cyclohexanone 4 (1 mmol) was added to the homogeneous reaction
mixture followed by slow addition with syringe pump over 1 h of a solu-
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Chem. Eur. J. 2006, 12, 5446 – 5451

Amplification of Enantiomeric Excess of Organic Molecules
FULL PAPER
tion of nitrosobenzene (54 mg, 0.5 mmol) in DMSO (1 mL). The reaction
mixture was then left to stir for an additional 0.5 h (3h when tetrose 2a
was used). The reaction was quenched by putting the reaction mixture di-
rectly on a silica-gel column (pentane/EtOAc 10:1), which furnished pure
5 and 2 after chromatography. Analytical data of 5 are identical to previ-
ously reported values.[4] The ee was determined by chiral-phase HPLC
analysis (Diacel Chiralpak AD, n-Hex/iPrOH 90:10, flow rate
0.5 mLminÀ1, l=254 nm): minor isomer: tr =27.208 min, major isomer:
tr =31.791 min.
Acknowledgements
We gratefully acknowledge the Swedish National Research Council,
Wenner-Gren Foundation, Carl-Trygger Foundation and Lars-Hierta
Foundation for financial support.
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Typical experimental procedure for the kinetic study of the (S)-proline-
catalyzed formation of ketone 5 (Figure 4, *, black): A solution of nitro-
sobenzene (54 mg, 0.5 mmol) in DMSO (1 mL) was slowly added with sy-
ringe pump to a homogeneous mixture containing (S)-proline (6 mg,
10 mol%), cyclohexanone (1 mmol), and DMF (0.155 mmol, 12 ml, inter-
nal standard) in DMSO (1 mL). Aliquots (25 mL) were taken out from
the homogeneous reaction mixture and diluted with CDCl3 and the prog-
1
ress of the reaction was monitored by H NMR analyses. The ratio of the
area of the quintet at d=4.35 ppm corresponding to the CHONHAr
proton of 5 and the area of the broad singlet at d=7.93ppm correspond-
ing to a formamide proton of DMF (A5/Ainternal standard) was directly corre-
lated to the known calibration curve and gave the product formation as a
function of time.
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Chem. Int. Ed. 2004, 43, 5138.
Typical experimental procedure for the kinetic study of the (S)-proline-
and (R)-proline-catalyzed formation of ketone 5 in the presence of te-
~
&
[13] a) Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615, and ref-
erences therein. b) B. List, C. F. Barbas III, R. A. Lerner, J. Am.
Chem. Soc. 2000, 122, 2395; c) A. B. Northrup, I. K. Mangion, F.
Hettche, D. W. C. MacMillan, Angew. Chem. 2004, 116, 2204;
Angew. Chem. Int. Ed. 2004, 43, 2152; d) A. B. Northrup, D. W. C.
MacMillan, J. Am. Chem. Soc. 2002, 124, 6798.
trose 2b (Figure 4, , blue and , red, respectively): A solution of tetrose
2b (1 mmol, 98% ee) and (S)- or (R)-proline (6 mg, 10 mol%) in DMSO
(1 mL) was left to stir for 1 h. The reaction mixture became homogene-
ous after it had been stirred for 2 min. Next, cyclohexanone 5 (1 mmol)
and DMF (0.155 mmol, 12 mL, internal standard) was added, followed by
slow addition with a syringe pump over 1 h of a solution of nitrosoben-
zene (54 mg, 0.5 mmol) in DMSO (1 mL). Aliquots (25 mL) were taken
out from the homogeneous reaction mixture and diluted with CDCl3, and
the progress of the reaction was monitored by 1H NMR analyses. The
ratio of the area of the quintet at d=4.35 ppm corresponding to the
CHONHAr proton of 5 and the area of the broad singlet at d=7.93ppm
corresponding to formamide proton of DMF (A5/Ainternal standard) was di-
rectly correlated to the known calibration curve and gave the product
formation as a function of time.
[14] a) L. Hoang, S. Bahmanyar, K. N. Houk, B. List, J. Am. Chem. Soc.
2003, 125, 16; b) for original work on nonlinear effect in proline-cat-
alyzed reactions see: C. Puchot, O. Samuel, E. DuÇach, S. Zhao, C.
Agami, H. B. Kagan, J. Am. Chem. Soc. 1986, 108, 2353.
[15] a) A. Córdova, I. Ibrahem, J. Casas, H. SundØn, M. Engqvist, E.
Reyes, Chem. Eur. J. 2005, 11, 4772; b) E. Reyes, A. Córdova, Tetra-
hedron Lett. 2005, 46, 6605. Proline can also react with glucose ac-
cording to the Maillard reaction see: c) I. Blank, S. Devaud, W. Mat-
they-Doret, F. Robert, J. Agric. Food Chem. 2003, 51, 3643–3650.
[16] a) A. Bøgevig, H. SundØn, A. Córdova, Angew. Chem. 2004, 116,
1129; Angew. Chem. Int. Ed. 2004, 43, 1109; b) Y. Hayashi, J. Yama-
guchi, K. Hibino, M. Shoji, Angew. Chem. 2004, 116, 1132; Angew.
Chem. Int. Ed. 2004, 43, 1112; c) P. Merino, T. Tejero, Angew. Chem.
2004, 116, 3055; Angew. Chem. Int. Ed. 2004, 43, 2995; d) A. Córdo-
va, H. SundØn, A. Bøgevig, M. Johansson, F. Himo, Chem. Eur. J.
2004, 10, 3673; e) P. H.-Y. Cheong, K. N. Houk, J. Am. Chem. Soc.
2004, 126, 13912.
[17] E. M. Vogel, H. Grçger, M. Shibasaki, Angew. Chem. 1999, 111,
1672; Angew. Chem. Int. Ed. 1999, 38, 1570; see also: J. E. Imbriglio,
M. M. Vasbinder, S. J. Miller, Org. Lett. 2003, 5, 3741.
[18] B. List, L. Hoang, H. J. Martin, Proc. Natl. Acad. Sci. USA 2004,
101. 5839.; H. Iwamura, D. H. Wells, J. S. P. Mathew, M. Klussmann,
A. Armstrong, D. G. Blackmond, J. Am. Chem. Soc. 2004, 126,
16312; A. Hartikka, P. I. Arvidsson, Eur. J. Org. Chem. 2005, 4287.
[19] K. Furuta, S. Shimizu, S. Miwa, H. Yamamoto, J. Org. Chem. 1989,
54, 1481.
Typical experimental procedure for the NMR experiments between glyc-
eraldehyde 2g and proline:
(0.347 mmol, >98% ee) and (S)- or (R)-proline (0.087 mmol) in DMSO
(1 mL) was left to stir for 1 h in [D6]DMSO (1 mL). Next, H NMR anal-
ysis was performed, which showed that all (S)- or (R)-proline had reacted
with aldehyde 2g and formed the corresponding oxazolidinones I or II,
respectively.
A
solution of glyceraldehyde 2h
1
Typical experimental procedure for the NMR experiments between glyc-
eraldehydes 2g and racemic proline: A solution of glyceraldehyde 2h
(0.043mmol, >98% ee) and (S),(R)-proline (0.087 mmol) in DMSO
(1 mL) was left to stir for 15 min in [D6]DMSO (1 mL). Next, 1H NMR
analysis was performed, which showed that the ratio between the corre-
sponding oxazolidinones I and II was 1.53.
Received: April 13, 2006
Published online: June 13, 2006
Chem. Eur. J. 2006, 12, 5446 – 5451
ꢁ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5451