The first example of a crystallization-induced asymmetric transformation (CIAT) in the Mannich reaction

Article abstract of DOI:10.1016/j.tetasy.2009.12.014

The novel synthesis of highly enantioenriched N-substituted α-amino-γ-alkyl(aryl)-γ-oxobutanoic acids is described. The process involves the combination of a crystallization-induced asymmetric transformation (CIAT) and the Mannich reaction. The role of retro-Mannich and retro-Michael reactions in the mechanism of the highly stereoselective transformation is also discussed.

Full text of DOI:10.1016/j.tetasy.2009.12.014

Tetrahedron: Asymmetry 21 (2010) 69–74
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The first example of a crystallization-induced asymmetric transformation
(CIAT) in the Mannich reaction
*
*
ˇ
Pavol Jakubec , Pavel Petráš, Andrej Duriš, Dušan Berkeš
Department of Organic Chemistry, Institute of Organic Chemistry, Catalysis and Petrochemistry, Slovak University of Technology, Radlinského Street 9, SK-812 37 Bratislava, Slovakia
a r t i c l e i n f o
a b s t r a c t
Article history:
The novel synthesis of highly enantioenriched N-substituted a-amino-c-alkyl(aryl)-c-oxobutanoic acids
Received 16 November 2009
Accepted 21 December 2009
Available online 11 January 2010
is described. The process involves the combination of a crystallization-induced asymmetric transforma-
tion (CIAT) and the Mannich reaction. The role of retro-Mannich and retro-Michael reactions in the mech-
anism of the highly stereoselective transformation is also discussed.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
myces diastaticus (a subunit of longicatenamycin) and Claviceps
purpurea. Starting from the suitable Michael acceptor 2, our reaction
Despite the rapid improvement of classic protocols and the dis-
covery of new methods in asymmetric synthesis, crystallization-in-
duced asymmetric transformation (CIAT) remains one of the most
interesting methods for the stereoselective formation of enantiome-
rically pure organic compounds. There are numbers of intriguing
applications, where CIAT has been used to obtain enantiomerically
and diastereoisomerically pure compounds simply by preferential
crystallization of one of the equilibrating isomers. Notable advanta-
ges of CIAT over other tools of an asymmetric synthesis include mild
reaction conditions, the use of inexpensive reagent grade solvents,
no need for an inert atmosphere and simple work-up proce-
dures.1–3
sequence provides a straightforward approach to
a-amino-c-alky-
l(aryl)- -oxobutanoic acids 1. The synthesis of unsaturated Michael
c
acceptor 2 is very well documented by the Friedel–Crafts acylation
of arenes,13 elimination of bromoketones14 and other methods.15
Arguably, the most general methods for the synthesis of aroylacrylic
acid 2 is the condensation of ketones 4 with glyoxylic acid 5.7–9,16
Thus, aminoacids 1 are available in two steps starting from commer-
cially available compounds (ketone 4, ent-(1-phenylethyl)amine 3
and glyoxylic acid 5) utilising CIAT in the reversible Michael addition
of nucleophiles (Scheme 1, path A). An alternative retrosynthetic
analysis of 1 revealed a possibility to prepare enantiomerically pure
substituted aminobutanoic acids 1 directly from commercial ke-
tones 4 by employing one of the most powerful synthetic tools for
C–C bond formation, the Mannich reaction (Scheme 1, path B).17
Such a transformation might shorten the reaction pathway and
avoid the sometimes complicated synthesis of Michael acceptor 2.
The Mannich reaction, in its original or more sophisticated form,
has been known for almost a century and many excellent asymmet-
ric variants have been developed including metal-catalysed, organo-
catalysed and versions employing stoichiometric chiral reagents.18
However, to the best of our knowledge, there are no reported exam-
ples of the application of CIAT in Mannich reactions. Recently, an
example of asymmetric amplification in a heterogeneous mixture
was described, where an enantioenriched crystalline product was
obtained in a reversible Mannich reaction with the use of racemic
or achiral catalyst.19 The critical point of CIAT is the compatibility
of the epimerization in solution with preferential crystallization of
one stereoisomer.1 Knowing the physical-chemical properties and
behaviour of aminoacids 1 from our previous research,4–9 we be-
lieved that 1 could undergo simultaneous epimerization (either
via retro-aza-Michael addition or retro-Mannich reaction) with the
preferential crystallization of one stereoisomer.
Over the last decade, as a part of our ongoing research devoted
to the synthesis of
a-amino-c-alkyl(aryl)-c-oxobutanoic acids 1,
we have described the application of crystallization-induced asym-
metric transformation (CIAT) in the Michael addition of N-nucleo-
philes to acylacrylic acids 2 (Scheme 1, path a).4–10
The enantiomerically pure aminoacids 1 were further trans-
formed to
c-amino-c-hydroxy-c-aryl(alkyl)-butanoic acids, their
cyclic lactams or homophenylalanines.11,12 The synthetic utility of
our methodology has been well documented in several syntheses
of small target molecules represented by: furoylalanin7 isolated
from Fagopyrum esculentum, Rumex obtusifolius, Fagus silvatica;
substituted b-methyl-
ids of the nikkomycins and an aminoacid of depsipeptide kuloke-
kahilide-1) and aliphatic
-aminoacids8 isolated from Strepto-
a
-homophenylalanines9 (terminal aminoac-
a
* Corresponding authors. Present address: Department of Chemistry, Chemistry
Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
(P.J.). Tel./fax: +421 2 52968560 (D.B.).
E-mail addresses: pavol.jakubec@zoznam.sk (P. Jakubec), dusan.berkes@stuba.sk
(D. Berkeš).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.014

70
P. Jakubec et al. / Tetrahedron: Asymmetry 21 (2010) 69–74
Mannich
reaction
aza-Michael
addition
∗
∗
COOH
O
∗
H2N
O
Ph
H2N
Ph
5
O
HN
Ph
3
3
5
+
∗
O
O
O
R1
COOH
R1
1 step
R1
4
R1
COOH
2
up to >98% de,
3 component
R2
COOH
up to 92% yield 4-9
R2
R2
R2
4
1
path A: 3 components, 2 steps
path B
CIAT
Scheme 1. CIAT for the construction of aminobutanoic acids.
Without the need for an expensive catalyst, strictly anhydrous
nones 4a–d, products 1a–d were isolated in moderate to good
yields (29–66%), but excellent diastereoselectivities were observed
in all cases (dr 98:2 to >99:1).
conditions or other limiting factors, compound 1 could be filtered
off as a single stereoisomer directly from the reaction mixture in
a three component, one pot Mannich reaction.
The introduction of a substituent to the a-position of the ketone
Attracted by the simplicity and elegance of our idea, we started
our investigation.
(ketones 4e,f) did not decrease the high level of stereoselectivity;
from propiophenone the aminoacid 1e was isolated with impres-
sive dr (dr 98:1:0:1, 48% isolated yield). Tetralone 4f was found
to be an excellent substrate for the transformation and a derivative
of constrained homophenylalanine 1f with two newly created ste-
reogenic centres was obtained as a single diastereoisomer in good
yield (53% yield, dr >99:<1:0:0). With the Mannich reaction opti-
mized on arylalkyl ketones 4a–f, we turned our attention to
alkylmethyl ketones. From a range of possible aliphatic ketones,
we tested pinacolone 4g and cyclohexylmethylketon 4h as sub-
strates for the CIAT process in the Mannich reaction. The treatment
of ketones 4g,h with glyoxylic acid 5 and (R)-PEA 3a afforded 1g,h
in good yields and with excellent diastereoisomeric purity (66%, dr
99:1 for 1g and 58% yield, dr 98:2 for 1h, Scheme 4).
2. Results and discussion
Initially, feasibility studies were performed on a representative
ketone, acetophenone 4a, and the in situ formed enantiomerically
pure imine derived from glyoxylic acid 5 and (R)-phenylethyl-
amine (PEA) 3a (Scheme 2). The starting materials were reacted
in solvents ranging from aprotic to protic polar and completion
of the reaction was judged by HPLC analysis. The results are pre-
sented in Table 1. The desired product 1a crystallized out from a
range of solvents at room temperature (at 40 °C in EtOH, entry
10) and was isolated by simple filtration in good yields as a single
diastereoisomer. The attempts to carry out the reaction at a higher
temperature (>40 °C, entries 11 and 12) led to faster decomposi-
tion of the starting materials and resulted in lower yields.
Having investigated the possibility of ketones 4a–h undergoing
a highly diastereoselective Mannich reaction, we next investigated
the origin of the diastereoselectivity.
The stereochemical development in the Mannich reaction of
tetralone 4f with the (R)-PEA 3a and glyoxylic acid 5 was moni-
tored by HPLC analysis (Fig. 1). As can be seen from Figure 1, at
an early stage of the reaction, poor diastereoselectivity was ob-
served, originating from low asymmetric induction in the Mannich
reaction (dr 18:28:26:28 after 4 h). However, as the reaction pro-
gressed, (2R,20R,100R)-diastereoisomer 1f became the major diaste-
reoisomer in the reaction with simultaneous decline of its other
three diastereoisomers. Simultaneously, a significant change in
the appearance of the reaction mixture took place. The solution be-
came saturated and 1f began to crystallize out, resulting in a dra-
matic change in the ratio of diastereoisomers. The simultaneous
epimerization of the other diastereoisomers in the solution shifted
the equilibrium to the side of the preferentially crystallizing
(2R,20R,100R)-diastereoisomer. After 79 h (dr in the heterogeneous
mixture 87:3:2:8), (2R,20R,100R)-1f was isolated by simple filtration
as a virtually single diastereoisomer (dr 99:1:0:0) in 53% yield.
A similar stereochemical course was observed in all the sub-
strates tested, thus providing strong support for our explanation
of the high stereoselectivities observed (Fig. 2 represents the ste-
reochemical development of the reaction with propiophenone 4e,
the (R)-PEA 3a and glyoxylic acid 5).
One of the critical points of CIAT process is the reversibility of
the chemical reaction involved.1 In the reaction of ketones with
imines the most likely transformations, which should be consid-
ered, are retro-Mannich and retro-Michael reactions. To investigate
the role of both reactions, we performed a cross experiment be-
tween enantiomerically pure Mannich adduct 1c, (R)-PEA 3a and
acetophenone 4a (Scheme 5, Fig. 3).
The starting materials were reacted under standard Mannich
conditions (EtOH, 40 °C, Scheme 5) and monitored by HPLC
(Fig. 3). After 1 h, significant amounts of unsaturated aroylacrylic
acid 2c were detected, providing evidence for a fast retro-Michael
O
HN
Ph
O
+
+
COOH
H2N
Ph
O
Ph
COOH
Ph
4a
3a
5
1a
Scheme 2. The feasibility study on the model substrate 4a.
Table 1
The feasibility study on the model substrate
Entry
Solvent
T
Time
Yielda (%)
Dra
1
2
3
4
5
6
7
8
9
10
11
12
13
—
rt
rt
rt
rt
rt
rt
rt
rt
20 h
44
52
50
59
66
47
44
49
53
50
27
99:1
98:2
98:2
99:1
99:1
98:2
99:1
96:4
98:2
98:2
98:2
CH2Cl2
CHCl3
THF
5 days
6 days
5 days
4 days
6 days
4 days
6 days
5 days
3 days
4 days
1 day
Et2O
Dioxane
BuOH
PrOH
EtOH
EtOH
EtOH
EtOH
H2O
rt
40 °C
50 °C
Reflux
rt
b
b
—
—
1 day
46
99:1
a
Isolated by filtration of a reaction mixture.
Complex mixture obtained.
b
With the preferred conditions identified (in Et2O at rt or in EtOH
at 40 °C), the reaction scope and limitation were investigated. A
range of aromatic ketones with electron-donating or halogen sub-
stituents on the aromatic ring were reacted with glyoxylic acid 5
and (R)-PEA 3a. The results are shown in Scheme 3. Employing
the optimal reaction conditions (reaction performed at elevated
temperature in EtOH for some ketones) for substituted acetophe-

P. Jakubec et al. / Tetrahedron: Asymmetry 21 (2010) 69–74
71
O
O
HN
Ph
R
COOH
+
Ph
COOH
O
H2N
4a-f
1a-f
HN
3a
HN
5
O
Ph
O
Ph
COOH
COOH
Br
1a
>
, Et2O, 4 days, 66%, dr 99:1
1b
, EtOH, 7 days, 34%, dr 98:2
O
HN
Ph
O
HN
Ph
O
O
COOH
COOH
O
1c
, EtOH, 5 days, 29%, dr 99:1
1d
, EtOH, 6 days, 51%, dr 99:1
O
HN
Ph
O
HN
Ph
COOH
COOH
1e
, EtOH, 6 days, 48%, dr 98:1:0:1
1f, EtOH, 5 days, 53%, dr >99:<1:0:0
Scheme 3. The scope and limitation of the Mannich reaction on aryl-alkylketones.
100
90
O
O
HN
Ph
80
70
60
50
40
30
20
10
0
+
COOH
O
H2N
Ph
3a
Alk
Alk
COOH
1g,h
4g,h
5
O
HN
Ph
COOH
O
HN
Ph
COOH
, EtOH, 5 days, 58%, dr 98:2
Scheme 4. The Mannich reaction with dialkylketones.
1
5
8
12
14
Time [h]
16
18
20
28
48
120
1g
1h
, EtOH, 6 days, 66%, dr 99:1
Figure 2. Stereochemical development of the Mannich reaction of 4e with 3a and
5; j (2R,3S,10R)-diastereoisomer 1e,
other 3 diastereoisomers of 1e.
90
80
70
60
50
40
30
20
10
0
product of the retro-Mannich reaction of 1c, ketone 4c, was de-
tected. The presence of a second degradative product of the retro-
Mannich reaction, imine 6 derived from glyoxylic acid and (R)-
PEA 3a, was confirmed indirectly. Imine 6 reacted in a competitive
Mannich reaction with the present ketone 4a providing aminoacid
1a. This underwent a subsequent retro-Michael reaction providing
the product of elimination, unsaturated acid 2a, which was identi-
fied in the reaction mixture as well. Although, the amount of the
acids 2a,c in the reaction mixture remained at constant concentra-
tion (a comparison of the trace after 24 h and 120 h), the amount of
acetophenones 1a,c varied until it become approximately equal
(after 120 h). This simplified model with fast retro-Michael reaction
and relatively slow retro-Mannich reaction (we did not consider the
further possible transformation of imine 6 or degradative reaction
of glyoxylic acid) provides a plausible explanation for epimerization
in such type of transformations and is supported by several related
examples in the literature.20 retro-Michael addition, as a competi-
tive undesired side-reaction, was described in aminomethylation
of aldehydes by Gellman.21 A subsequent example of retro-Michael
addition explains the syn–anti epimerization in a three component
phenolic Mannich reaction.22 Based on both, literature precedence
and our experimental findings, we believe that retro-Michael and
(2R,2'R,1''R)-diastereoisomer 1f
unidentified diastereoisomer 1f
unidentified diastereoisomer 1f
unidentified diastereoisomer 1f
0
10
20
30
40
time [h]
50
60
70
80
Figure 1. Stereochemical development of the Mannich reaction of 4f with 3a and 5.
addition. Only trace amounts of other new compounds were de-
tected at an early stage of the reaction (HPLC trace after 1 h and
6 h). However, after 24 h several products of retro-Mannich reac-
tion and consequent transformation were observed. The primary

72
P. Jakubec et al. / Tetrahedron: Asymmetry 21 (2010) 69–74
retro-Michael
H2N
retro-Michael
H2N
COO
COO
Ph
COOH
COOH
O
O
OHH2N
O
HN
O
O
2a
1a
2c
1c
Ph
3a
Ph
3a
Ph
The reagents introduced
for cross experiment
Mannich
retro-Mannich
COOH
Ph
N
+
+
O
O
O
4c
4a
6
Scheme 5. A plausible explanation of epimerization in the cross experiment.
tions are given in g/100 mL. IR spectra were measured on Nicolet
5700 FTIR spectrometer in KBr disks. 1H NMR spectra were re-
corded on a Varian VXR-300 (299.94 MHz) spectrometer. Chemical
shift (d) is quoted in parts per million and is referenced to the tet-
ramethylsilane (TMS) as an internal standard (dMe = 0.00 for
299.94 MHz). Coupling constant (J) is recorded in Hertz. The follow-
ing abbreviations were used through to characterize signal multi-
plicities: s (singlet), d (doublet), t (triplet), m (multiplet) and br
(broad). Abbreviations with quotation marks mean that the appear-
ance of the signal is different from that theoretically predicted. 13C
NMR spectra were recorded on a Varian VRX-300 (75.43 MHz)
spectrometer. The multiplicities of the carbons were assigned from
a broadband decoupled analysis used in a conjunction with either
APT or DEPT. Chemical shifts are quoted in parts per million and
are referenced to the tetramethylsilane (TMS) as the internal stan-
dard (d = 0.00 for 75.43 MHz). HPLC experiments were performed
on PYE UNICAM chromatographic system (PU 4015 pump working
in isocratic mode). Multichannel detector PU 4021 was performed
in SUM ABS mode at wavelengths ranging from 210 to 310 nm.
The following columns and eluents were used for HPLC experi-
Figure 3. HPLC traces of reaction mixture of a cross experiment between 1c, amine
3a and ketone 4a. Retention times: tR 6.6 min 1a, tR 7.2 min 1c, tR 13.2 min 2a, tR
15.0 min 2c, tR 18.5 min 4a, tR 21.4 min 4c.; trace ordered according to reaction time
from 1 h to 120 h.
retro-Mannich reactions take place simultaneously in the Mannich
condensation between ketones 4 and imines 6. Both transforma-
tions ensure reversibility of the process, a necessary point for CIAT
process. On the other hand, we assume that the degradation of
some reactive intermediates causes lower chemical yields in sev-
eral examples (transformation of 4b,c to 1b,c).
The absolute stereochemistry of derivatives 1a, e, f and 1g was
assigned by comparison of those with authentic samples obtained
previously (NMR data and chirooptical properties).4–9 Assuming
the same stereochemical outcome of the CIAT process, stereochem-
istry of new compounds 1b–d, 1h was assigned by analogy.
ments: C18 5
250 ꢁ 4.6 mm or Phenomenex Luna Phenyl–Hexyl 250 ꢁ 4.6 mm
or Waters Symmetry 5
lm reverse phase column Phenomenex Luna C18
l
m C18 250 ꢁ 4.6 mm. Eluent was a mix-
ture of acetonitrile/water/Et3N 400:600:10 or 250:750:15, pH ad-
justed to 2.9–3.5 by H3PO4. The mobile phase was pumped
through the system at 0.5–1.5 mL/min at room temperature.
3. Conclusion
4.2. General procedure for the Mannich reaction
In conclusion, an efficient Mannich reaction of ketones with an
in situ formed imine derived from phenylethylamine and glyoxylic
acid has been developed. Using mild conditions, substituted amin-
obutanoic acids were isolated in excellent stereochemical purity.
Further development to this work and its application in the synthe-
sis of complex biologically active compounds is ongoing in our lab-
oratory, and the work will be disclosed in due course.
To a solution of (R)-phenylethylamine 3a (20.0 mmol, 2.424 g)
in EtOH (or Et2O) was added slowly glyoxylic acid 5 (10.0 mmol,
0.921 g). After being stirred for 10 min, ketone 4 (10.0 mmol)
was added and the resulting solution was stirred at 40 °C (at rt
where Et2O used) until HPLC analysis had shown complete con-
sumption of starting materials (typical 4–6 days). The suspension
was cooled to rt, at which point, the solid was filtered off, washed
(EtOH, Et2O) and dried to obtain aminoacid 1 as a white solid.
4. Experimental
4.1. General
4.2.1. (2R)-4-Oxo-4-phenyl-2-{[(1R)-1-phenylethyl]amino}buta-
noic acid 1a
Reagents were used as received without further purification, un-
less otherwise stated. (R)-Phenylethylamine (99+%, 99% ee) was ob-
tained from ACROS. Melting points were obtained using a Kofler hot
plate and are uncorrected. Optical rotations were measured with
According to the general procedure (for 10.0 mmol, 1.202 g of 4a
was used 20.0 mmol, 2.424 g of (R)-PEA 3a, 10.0 mmol, 0.920 g of
glyoxylic acid monohydrate 5 and 10 mL of Et2O; 4 days, RT, washed
with Et2O) 1a (1.952 g, 66%, dr >99:1) was obtained as a white solid.
Mp = 192–195 °C (EtOH–H2O, lit.11 194–196 °C (CH3CN–H2O);
POLAR L-lP polarimeter (IBZ Messtechnik) with a water-jacket
10,000 cm cell at a wavelength of sodium line D (k = 589 nm). Spe-
½
a 2D0
ꢂ
¼ ꢀ23:0 (c 0.6, THF/1 M HCl 4:1), lit.11
½
a 2D0
ꢂ
¼ ꢀ36:5 (c 0.5,
cific rotations are given in units of 10ꢀ1 deg cm2 gꢀ1 and concentra-
MeOH/1 M H2SO4 3:1); IR (KBr disk) 3047, 3008, 2987, 2862,

P. Jakubec et al. / Tetrahedron: Asymmetry 21 (2010) 69–74
73
1697, 1628, 1607, 1568, 1458, 1449, 1385, 1355, 1301, 1277, 1244,
1076, 1054, 1001, 986, 772, 750, 703, 689. NMR data and elemental
analysis are in agreement with those published.11
808, 784, 764, 755, 698; NMR data and elemental analysis are in
agreement with those published.9
4.2.6. (2R)-[(2R)-1-Oxo-1,2,3,4-tetrahydronaphthalen-2-yl]-
{[(1R)-1-phenylethyl]amino}ethanoic acid 1f
4.2.2. (2R)-4-(4-Bromophenyl)-4-oxo-2-{[(1R)-1-phenylethyl]-
amino}butanoic acid 1b
According to the general procedure (for 6.8 mmol, 1.000 g of 4f
was used 13.7 mmol, 1.658 g of (R)-PEA 3a, 6.8 mmol, 0.630 g of gly-
oxylic acid 5, 8.0 mL of EtOH; 5 days, washed with Et2O) 1f (1.170 g,
53%, dr >99:<1:0:0) was obtained as a white solid. Mp = 161–164 °C
According to the general procedure (for 2.5 mmol, 0.498 g of 4b
was used 5.0 mmol, 0.606 g of (S)-PEA 3a, 2.5 mmol, 0.230 g of gly-
oxylic acid 5, 0.5 mL of EtOH; 7 days, washed with Et2O) 1b
(0.320 g, 34%, dr 98:2) was obtained as a white solid. Mp = 187–
(EtOH–H2O). lit.6 mp = 163–164 °C; ½a 2D0
¼ ꢀ88:0 (c 0.8, THF/1 M
ꢂ
189 °C (EtOH–H2O); ½a D20
ꢂ
¼ ꢀ43:0 (c 0.9, MeOH/1 M HCl 3:1); IR
HCl 4:1); lit.6
½
a 2D0
ꢂ
¼ ꢀ88:0 (c 0.8, THF/1 M HCl 4:1); IR (KBr disk)
(KBr disk) 3027, 2983, 2851, 1697, 1631, 1606, 1587, 1566, 1478,
1458, 1383, 1354, 1275, 1248, 1207, 1072, 1053, 1012, 988, 810,
771, 760, 700; 1H NMR (300 MHz, acetone-d6/DCl): 1.80 (d, 3H,
J = 6.9), 3.89 (ddd, 2H, J = 18.8, 5.5, 5.0), 4.10 (‘t’, 1H, J = 5.5, 5.1),
4.83 (q, 1H, J = 6.9), 7.35–7.48 (m, 3H), 7.61–7.70 (m, 4H), 7.82–
7.89 (m, 2H); 13C NMR (acetone-d6/DCl): 21.5, 40.3, 54.4, 60.4,
129.8, 129.9, 130.9, 131.1, 131.7, 133.4, 136.0, 137.1, 170.3, 196.3.
3075, 3029, 2979, 2938, 2881, 2842, 1693, 1618, 1591, 1581, 1470,
1456, 1438, 1430, 1377, 1346, 1324, 1284, 1236, 1223, 1082, 1066,
1001, 926, 770, 748, 700; NMR data are in agreement with those
published.6
4.2.7. (2R)-5,5-Dimethyl-4-oxo-2-{[(1R)-1-phenylethyl]amino}-
hexanoic acid 1g
According to the general procedure (for 25.0 mmol, 2.500 g of
4g was used 50.0 mmol, 6.06 g of (R)-PEA 3a, 25.0 mmol, 2.300 g
of glyoxylic acid 5, 4.0 mL of EtOH; 6 days, washed with EtOH,
Et2O) 1g (0.320 g, 66%, dr 99:1) was obtained as a white solid.
Mp = 213–216 °C (EtOH–H2O), lit.8 ent-1g mp = 213–214 °C;
4.2.3. (2R)-4-(3-Methoxyphenyl)-4-oxo-2-{[(1R)-1-phenylethyl]-
amino}butanoic acid 1c
According to the general procedure (for 2.5 mmol, 0.375 g of 4c
was used 5.0 mmol, 0.606 g of (R)-PEA 3a, 2.5 mmol, 0.230 g of gly-
oxylic acid 5, 1.0 mL of EtOH; 5 days, washed with Et2O) 1c
(0.240 g, 29%, dr 99:1) was obtained as a white solid. Mp = 165–
½
a 2D0
ꢂ
¼ þ14:4 (c 0.1, MeOH/1 M HCl 3:1), lit.8 ent-1g ½a D25
¼ ꢀ14:7
ꢂ
(c 1.0, MeOH/1 M HCl 3:1); IR (KBr disk) 2976, 2960, 2870, 1720,
1705, 1637, 1608, 1571, 1515, 1478, 1382, 1366, 1319, 1302,
1279, 1205, 1089, 1076, 1061, 1000, 860, 770, 759, 701; NMR data
and elemental analysis are in agreement with those published.8
170 °C (EtOH–H2O); ½a D20
¼ ꢀ46:4 (c 1.0, MeOH/1 M HCl 3:1); IR
ꢂ
(KBr disk) 3028, 2982, 2939, 2841, 1696, 1631, 1608, 1583, 1566,
1483, 1458, 1451, 1432, 1382, 1354, 1319, 1302, 1288, 1276,
1262, 1229, 1193, 1076, 1041, 993, 856, 788, 769, 701, 685; 1H
NMR (300 MHz, acetone-d6/DCl): 1.81 (d, 3H, J = 6.9), 3.80 (s, 3H),
3.89 (ddd, 2H, J = 18.7, 5.3, 5.2), 4.09 (‘t’, 1H, J = 5.5, 5.2), 4.82 (q,
1H, J = 6.9), 7.12–7.19 (m, 1H, J = 8.2, 2.6), 7.35–7.60 (m, 6H),
7.67 (m, 2H); 13C NMR (acetone-d6/DCl): 21.5, 40.5, 54.7, 60.4,
56.7, 114.0, 121.7, 122.5, 130.0, 131.0, 131.2, 131.6, 137.3, 138.5,
161.4, 170.6, 197.1; Calcd for C19H21NO4: C, 69.71; H, 6.47; N,
4.28. Found: C, 68.05; H, 6.23; N, 4.20.
4.2.8. (2R)-4-Cyclohexyl-4-oxo-2-{[(1R)-1-phenylethyl]amino}-
butanoic acid 1h
According to the general procedure (for 24.0 mmol, 3.029 g of
4h was used 48 mmol, 5.792 g of (R)-PEA 3a, 24.0 mmol, 2.2 g of
glyoxylic acid 5, 10.0 mL of EtOH; 5 days, washed with Et2O) 1h
(3.928 g, 58%, dr 98:2) was obtained as a white solid. Mp = 169–
172 °C (EtOH–H2O), ½a D20
¼ þ0:5 (c 0.8, MeOH/1 M HCl 3:1); IR
ꢂ
(KBr disk) 3030, 2984, 2934, 2850, 1725, 1639, 1609, 1558, 1499,
1481, 1455, 1382, 1355, 1318, 1275, 1211, 1145, 1084, 1073,
1012, 993, 893, 841, 769, 700; 1H NMR (300 MHz, acetone-d6/
DCl): 1.80 (d, 3H, J = 6.9), 3.89 (ddd, 2H, J = 18.8, 5.5, 5.0), 4.10 (t,
1H, J = 5.1), 4.83 (q, 1H, J = 6.9), 7.40–7.95 (m, 9H); 13C NMR (ace-
tone-d6/DCl): 20.8, 26.0, 26.4, 28.6, 40.9, 50.3, 53.3, 59.5, 129.2,
129.9, 130.1, 138.6, 169.7, 209.6.
4.2.4. (2R)-4-(3,4-Dimethoxyphenyl)-4-oxo-2-{[(1R)-1-phenyl-
ethyl]amino}butanoic acid 1d
According to the general procedure (for 25.0 mmol, 4.500 g of 4d
was used 50.0 mmol, 6.060 g of (R)-PEA 3a, 25.0 mmol, 2.300 g of
glyoxylic acid 5, 4.0 mL of EtOH; 6 days, washed with EtOH, Et2O)
1d (4.600 g, 51%, dr 99:1) was obtained as a white solid. Mp = 173–
176 °C (EtOH–H2O); ½a D20
¼ ꢀ65:9 (c 1.0, MeOH/1 M HCl 3:1); IR
ꢂ
(KBr disk) 3132, 2980, 2960, 2934, 2837, 1690, 1623, 1595, 1587,
1581, 1517, 1468, 1458, 1449, 1439, 1413, 1381, 1355, 1332, 1268,
1230, 1214, 1196, 1169, 1125, 1021, 997, 903, 842, 824, 767, 703;
1H NMR (300 MHz, acetone-d6/DCl): 1.82 (d, 3H, J = 6.9), 3.84 (s,
3H), 3.88 (s, 3H), 3.84–3.96 (dd, 2H, J = 18.5, J = 5.4), 4.06 (‘t’, 1H,
J = 5.5, 5.2), 4.82 (q, 1H, J = 6.8), 7.03 (d, 1H, J = 8.5), 7.36–7.51 (m,
4H); 7.61–7.72 (m, 3H); 13C NMR (acetone-d6/DCl): 21.6, 40.0,
54.0, 60.4, 57.0, 57.2, 111.9, 112.4, 125.1, 130.0, 130.1, 131.0,
131.2, 137.4, 150.6, 155.7, 170.8, 195.8; Calcd for C20H23NO5: C,
67.21; H, 6.49; N, 3.92. Found: C, 63.65; H, 6.50; N, 3.73.
4.3. The cross experiment
A mixture of (R)-phenylethylamine 3a (20.0 mmol, 2.440 g), ke-
tone 4a and amino acid 1c in EtOH (1.5 mL) was stirred at 40 °C.
From a heterogenous mixture an analytical sample was taken after
1 h, 6 h, 24 h, 33 h, 56 h and 120 h and analyzed by HLPC on the
Phenomenex Luna Phenyl–Hexyl column 250 ꢁ 4.6 mm with a
mixture of acetonitrile/water/Et3N 400:600:10 pH adjusted to 3.3
by H3PO4, flow 0.5 mL/min, inject 20 lL. Retention times: tR
6.6 min 1a, tR 7.2 min 1c, tR 13.2 min 2a, tR 15.0 min 2c, tR
18.5 min 4a, tR 21.4 min 4c.
4.2.5. (2R,3S)-3-Methyl-4-oxo-4-phenyl-2-{[(1R)-1-phenyleth-
yl]amino}butanoic acid 1e
According to the general procedure (for 5.0 mmol, 0.670 g of 4e
was used 10.0 mmol, 1.212 g of (R)-PEA 3a, 5.0 mmol, 0.460 g of
glyoxylic acid 5, 1.0 mL of EtOH; 6 days, washed with Et2O) 1b
Acknowledgements
Financial support by the Slovak Grant Agency No. 1/0629/08
and NMR measurements provided by the Slovak State Programme
Project No. 2003SP200280203 are gratefully acknowledged.
(0.750 g, 48%, dr 98:1:0:1) was obtained as
a white solid.
Mp = 197–198 °C (EtOH–H2O), lit.9 ent-1e mp = 197–198 °C
(H2O);
½
a 2D0
ꢂ
¼ ꢀ17:4 (c 1.0, MeOH/1 M HCl 3:1), lit.9 ent-1e
References and notes
½
a 2D5
ꢂ
¼ þ17:4 (c 1.0, MeOH/1 M HCl 3:1); IR (KBr film) 3041,
2998, 2879, 1694, 1644, 1631, 1576, 1465, 1447, 1426, 1388,
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