Solvent dependency though not solvate formation in the derivative-derivative resolution of N-formylphenylalanine

Article abstract of DOI:10.1016/j.tetasy.2007.10.021

The efficiency of the resolution of N-formylphenylalanine was remarkably improved using (S)-(+)-2-benzylaminobutanol resolving agent in acetone. The efficiency of the resolution strongly depended on the quality of the solvent. Nevertheless, solvate formation did not occur during the process. The nature of the solvent-dependence was studied. The solid-melt binary phase diagram of the diastereomeric salts formed during the resolution by (S)-(+)-2-benzylaminobutanol was measured and discussed. It was recognized that the (S)-(+)-benzylaminobutanol (S)-(+)-N-formylphenylalanine salt exists in two polymorphic modifications. The effect of structurally related chiral and achiral auxiliary reagents in the above resolution was also studied. Thus, (S)-(+)-2-benzylaminobutanol was applied together with an (R)-(+)-1-phenylethylamine auxiliary resolving agent and benzylamine was used as a half-equivalent achiral basic reagent in a Pope-Peachey type resolution of N-formylphenylalanine by (S)-(+)-2-benzylaminobutanol. The results are compared to those obtained by the structurally related (R)-(+)-1-phenylethylamine chiral auxiliary.

Full text of DOI:10.1016/j.tetasy.2007.10.021

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2531–2536
Solvent dependency though not solvate formation in the
derivative–derivative resolution of N-formylphenylalanine
a
b
c
b
´
Emese Palovics, Laura Bereczki, Katalin Marthi, Gyorgy Pokol,
¨
Ferenc Faigla,d and Elemer Fogassy
d,
*
´
aResearch Group for Organic Chemical Technology, Hungarian Academy of Sciences, Budapest University of Technology and Economics,
H-1521 Budapest, PO Box 91, Hungary
bDepartment of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, H-1521 Budapest,
PO Box 91, Hungary
cResearch Group of Technical Analytical Chemistry, Hungarian Academy of Sciences, Budapest University of Technology and Economics,
H-1521 Budapest, PO Box 91, Hungary
dDepartment of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1521 Budapest,
PO Box 91, Hungary
Received 5 August 2007; accepted 15 October 2007
Abstract—The efficiency of the resolution of N-formylphenylalanine was remarkably improved using (S)-(+)-2-benzylaminobutanol
resolving agent in acetone. The efficiency of the resolution strongly depended on the quality of the solvent. Nevertheless, solvate forma-
tion did not occur during the process. The nature of the solvent-dependence was studied. The solid-melt binary phase diagram of the
diastereomeric salts formed during the resolution by (S)-(+)-2-benzylaminobutanol was measured and discussed. It was recognized that
the (S)-(+)-benzylaminobutanol (S)-(+)-N-formylphenylalanine salt exists in two polymorphic modifications.
The effect of structurally related chiral and achiral auxiliary reagents in the above resolution was also studied. Thus, (S)-(+)-2-benzyl-
aminobutanol was applied together with an (R)-(+)-1-phenylethylamine auxiliary resolving agent and benzylamine was used as a half-
equivalent achiral basic reagent in a Pope–Peachey type resolution of N-formylphenylalanine by (S)-(+)-2-benzylaminobutanol. The
results are compared to those obtained by the structurally related (R)-(+)-1-phenylethylamine chiral auxiliary.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
simultaneous use of several structurally related resolving
agents has2,3 been studied in Dutch resolution experi-
ments.3 This phenomenon is found to be the result of
crystal nucleation inhibition effects between the members
of a family of resolving agents.4,5 The interaction of
structurally similar molecules is expressed as a kinetic
factor during the crystallization of the diastereomeric salts,
which can potentially be utilized to improve the results of
the resolution.
Molecular structural similarities between a racemate and a
resolving agent enhance chiral recognition by promoting
the formation of multi-point interactions. During chiral
recognition, homochiral and heterochiral associations
(e.g., diastereoisomeric complexes, salts, etc.) are formed,
which have different stabilities. Beyond the interactions
between two molecules, the effect of structurally related
compounds is also manifested on a higher supramolecular
level, during the formation of crystal nuclei and the crystal
growth. The structural similarity between the members of a
family of resolving agents makes the solid solution forma-
tion common within a family.1 The beneficial effect of the
In our attempt to study more extensively the interactions
between structurally related molecules in resolutions, race-
mic N-formylphenylalanine (FPhA) was chosen as a model
compound (Fig. 1). In several previous communications,6
we dealt with the applicability of structurally related
resolving agents and auxiliary reagents in the resolution
of FPhA. Separation methods of FPhA enantiomers were
worked out for several benzylamine-derivative resolving
*
Corresponding author. Tel.: +36 1 463 18 83; fax: +36 1 463 38 48;
e-mail: efogassy@mail.bme.hu
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.021

2532
E. Pa´lovics et al. / Tetrahedron: Asymmetry 18 (2007) 2531–2536
OH
COOH
NH2
NH2
N
H
HN
CHO
BA
rac-FPhA
(R)-(+)-PhEA
(S)-(+)-BAB
Figure 1. Molecular structures of the racemate and of the structurally related agents used in this study.
OH
OH
N
H2
COOH
N
+
COO
H
NHCHO
NHCHO
rac-FPhA
(S)-(+)-BAB
(S)-(+)-BAB.(R)-(-)-FPhA
crystalline precipitate
Figure 2. Resolution of racemic FPhA with (S)-(+)-BAB resolving agent.
agents. The results obtained with the different resolving
agents were compared as a function of the molecular
structures.
precipitated. Using half an equivalent of resolving agent,
the result could be slightly improved upon (ee: 53%,
F = 0.22) but these results were far behind those attained
with PhEA (F = 0.42). Furthermore, the efficiency could
not be improved upon in water solvent. Consequently, in
aqueous solution, the minor structural similarity of the
resolving agent causes a negative effect on the chiral
separation.
Herein we report on the structural similarity using the sec-
ondary amine type benzylamine-derivative: 2-benzylamino-
butanol (BAB) as a resolving agent.1 We intended to study
the effects of larger structural differences among the race-
mate and the chiral and achiral auxiliaries (BA, Fig. 1)
compared to the previously investigated agents. The sub-
stantial difference among the structures of the new resolv-
ing agent (BAB) and the previously used compounds is
that the stereogenic carbon atom is placed on the other side
of the nitrogen atom and not in the benzylamine moiety.
2.2. Binary phase diagram of the (S)-(+)-benzylaminobuta-
nol (R)-(ꢀ)-N-formylphenylalanine [(S)-(+)-BABÆ(R)-(ꢀ)-
FPhA] and (S)-(+)-benzylaminobutanol (S)-(+)-N-formyl-
phenylalanine [(S)-(+)-BABÆ(S)-(+)-FPhA] diastereomeric
salt mixture
For comparison, the joint effects of (R)-(+)-1-phenylethyl-
amine [(R)-(+)-PhEA] and benzylamine (BA, Fig. 1) have
also been investigated in different solvents.
In order to gain a deeper insight into the details of the chi-
ral recognition process, we determined the binary phase
diagram8,9 of the (S)-(+)-BABÆ(R)-(ꢀ)-FPhA and (S)-(+)-
BABÆ(S)-(+)-FPhA diastereoisomeric salts (Fig. 3). The
eutectic composition was found at 0.33 (S)-(+)-BABÆ(R)-
(ꢀ)-FPhA/(S)-(+)-BABÆ(S)-(+)-FPhA ratio, the eutectic
2. Results and discussion
temperature is 371 K. The calculated expected efficiency
ꢀ
2.1. Resolution of racemic N-formylphenylalanine (FPhA)
with (S)-(+)-2-benzylaminobutanol [(S)-(+)-BAB] in water
on the basis of the data of the phase diagram is Fcalc
=
0.51.9 As was mentioned before, the experimentally
determined F parameters of both resolutions in water
(using an equivalent and half equivalent of resolving agent)
have fallen far behind this value and could not be further
optimized.
At an early stage of the method development, we used
water as a solvent in a similar way to the previously studied
resolutions of racemic FPhA. In water, using (R)-(+)-
PhEA as resolving agent, high enantiomeric excess could
be achieved7 (racemate: resolving agent 1:1 ratio:
ee = 95%, yield = 44%, F = 0.42; half equivalent ratio:
ee = 74%, yield = 46%, F = 0.34).
2.3. Resolution of racemic N-formylphenylalanine (FPhA)
with (S)-(+)-2-benzylaminobutanol [(S)-(+)-BAB] in acetone
In order to improve the results and attain the efficiency that
was predicted by the phase diagram the solvent of the
Under similar conditions, in aqueous solution, the effi-
ciency of (S)-(+)-BAB was much smaller (ee: 27%,
F = 0.18). In this case the diastereomeric salt that con-
tained an excess of the (R)-(ꢀ)-FPhA enantiomer (Fig. 2)
ꢀ F calc
¼
1ꢀ2xeu
; xeu: eutectic composition (molar ratio).
1ꢀxeu

E. Pa´lovics et al. / Tetrahedron: Asymmetry 18 (2007) 2531–2536
2533
considerably high efficiency (F = 0.73); this was much bet-
ter than the results achieved with the previously used struc-
turally related resolving agents.
Since the efficiency of the resolution in acetone was signif-
icantly higher (Table 1, 0.73, line 3) than the calculated va-
lue on the basis of the thermodynamic data (0.51), we were
able to establish that acetone has an additional effect,
which improves the results in an extent to exceed the ther-
modynamically determined state of the binary system
investigated. Presumably, acetone, an achiral solvent, selec-
tively interacts with the diastereomeric molecule-associates
during the crystal formation. As a result of this interaction
the chiral recognition processes are influenced and im-
proved upon.
Rationalization of the observed phenomena can be done if
the possible hemiaminal forming reaction of acetone with
the resolving agent is taken into consideration (Fig. 4).
Even this equilibrium reaction is slightly shifted into the
(S)-BABHA direction, the latter compound exists in solu-
tion as a structurally similar resolving agent related to
(S)-BAB. In other words, a special type of ‘Dutch-resolu-
tion’3 was accomplished by in situ formation of the relative
of the original resolving agent. Presumably, (S)-BABÆ(R)-
FPhA is the less soluble salt within the equilibrium system
while the other enantiomer stays in the solution mainly as
an (S)-BABHAÆ(S)-FPhA salt or at least a strong acetone
solvate of the (S)-BABÆ(S)-FPhA salt exists in the solution
while the crystalline diastereoisomeric salt does not contain
any solvate. Thus, we have a different system in the
thermodynamic equilibrium of the reaction mixture, than
we have measured during the determination of the binary
phase diagram mixing the separately prepared, solid,
unsolvated diastereoisomeric salts in different ratios.
Figure 3. Binary phase diagram of the diastereomeric salt mixture.
diastereoisomeric salt formation was changed. By working
in acetone with a 1:1 molar ratio, a remarkable enantiomer
separation was achieved (Table 1). The (S)-(+)-BABÆ(R)-
(ꢀ)-FPhA diastereomeric salt precipitated, from which
(R)-(ꢀ)-FPhA could be recovered with 83% ee and with
Table 1. Comparison of the resolution results of FPhA with (S)-(+)-BAB
in water and acetone
Solvent Molar ratio
racemate:
eea (%) Yb (%) Fc
Time of
crystallization
resolving agent
Water
Water
Acetone 1:1
Acetone 1:1
Acetone 1:0.5:0.5 Et3N
1:1
1:0.5
27
53
83
49
51
66
42
88
93
42
0.18 12 days
0.22 2 days
0.73 15 h
Using this theory we can explain the increase of the charac-
teristic parameters of the (S)-BABÆ(R)-FPhA salt precipi-
tated after 3 h (ee: 49%, F: 0.46) and 15 h (ee: 83%, F:
0.73), respectively.
0.4
3 h
0.21
a Enantiomeric excess based on specific rotation.
b Yield.
c Fogassy-parameter characterizing the efficiency of the resolution;
When (R)-(+)-PhEA resolving agent was used in acetone,
significant enantiomer separation could not be achieved.
F = ee · Y.10
OH
COOH
(S)-BAB·(R)-FPhA
(S)-BAB·(R)-FPhA
+
NHCHOH
(S)-FPhA
crystal
N
H
+
(S)-BAB
in solution
COOH
O
C
(S)-BAB.(R)-FPhA
OH
H3C
CH3
NHCHO
(R)-FPhA
(S)-BABHA·(R)-FPhA (S)-BAB HA·(S)-FPhA
+
N
+
CH3
HO CH3
(S)-BABHA
Figure 4. A possible explanation of improving effect of acetone.

2534
E. Pa´lovics et al. / Tetrahedron: Asymmetry 18 (2007) 2531–2536
Table 2. Results of the resolutions of FPhA with (S)-(+)-BAB using (R)-
(+)-PhEA as chiral additive
Solvent
Water
Molar ratio
ee (%)
Y (%)
F
FPhA:(S)-BAB:(R)-PhEA
1:0.5:0.5
28
21
0.06
0.41
Acetone
(5% water)
FPhA:(S)-BAB:(R)-PhEA
1:0.5:0.5
81
51
phase has a kinetic advantage.13 In acetone, the precipita-
tion of (S)-(+)-BABÆ(R)-(ꢀ)-FPhA could be promoted by
the selective interactions of the diastereoisomeric salts with
the acetone solvent.
2.6. Resolution of N-formylphenylalanine with (S)-(+)-2-
benzylaminobutanol using benzylamine achiral additive
Figure 5. DSC curve of the (S)-(+)-BABÆ(S)-(+)-FPhA diastereomer that
shows the reversible polymorphic phase transition at 353.6 K and the
melting of the salt.
When half of the resolving agent (S)-(+)-BAB was replaced
with achiral benzylamine (BA), (R)-(ꢀ)-FPhAÆ(S)-(+)-
BAB precipitated from the acetone solution, with almost
zero diastereomeric excess (ee 2%, F = 0.01, Table 3). In
other words, BA achiral additive ruins the resolution with
(S)-(+)-BAB. The effect of (R)-(+)-PhEA and BA on the
resolution with (S)-(+)-BAB resolving agent is remarkably
different despite their high structural similarity.
2.4. Polymorphism of the more soluble (S)-(+)-BABÆ(S)-(+)-
FPhA diastereomer
We have also observed that the more soluble (S)-(+)-BABÆ
(S)-(+)-FPhA diastereomer has two polymorphic modifica-
tions in an enantiotopic relationship. The equilibrium
temperature is 353.6 K (Fig. 5). The polymorphic phase
transition is reversible, at room temperature the less stable
modification transforms back to the stable form in a few
hours and the polymorphic transition of the sample can
be observed again by DSC. When polymorphism occurs
in a given system, then the probability that kinetic effects
could be expressed is increased, since the number of possi-
ble crystallization routes is increased.11,12
When the (R)-(+)-PhEA resolving agent was applied
together with the BA additive in a 1:1 ratio, the results were
similar to that obtained during the resolution with half an
equivalent of (R)-(+)-PhEA resolving agent.14 In the pre-
cipitated diastereoisomeric salt, the BA/(R)-(+)-PhEA
ratio was approximately 1:4; presumably the similar
molecular structures of the two agents made solid solution
formation possible. The presence of the achiral BA hardly
influences the chiral recognition phenomena when the
structural differences between the resolving agent and the
additive are slight. This is what we would expect whilst
BA can replace (R)-(+)-PhEA in its molecular interactions
but cannot express a chiral effect.
2.5. Dutch resolution of N-formylphenylalanine using (S)-
(+)-2-benzylaminobutanol and (R)-(+)-1-phenylethylamine
resolving agents
In water, using a mixture of (S)-(+)-BAB and (R)-(+)-
PhEA resolving agents in a 1:1 ratio, (R)-(+)-1-phenylethyl-
ammonium (R)-(ꢀ)-N-formylphenylalaninate [(R)-(+)-
PhEAÆ(R)-(ꢀ)-FPhA] was precipitated in low diastereo-
meric excess and low efficiency. The presence of (S)-(+)-
BAB decreased the efficiency when compared to what
could be achieved with pure (R)-(+)-PhEA resolving agent.
Consequently the structural similarity of the two resolving
agents was lower than needed for a favourable interaction.
2.7. Complex solid–liquid equilibrium of the N-formylphen-
ylalanine enantiomers
A binary phase diagram of the mixture of N-formylphenyl-
alanine enantiomers was also constructed on the basis of
thermoanalytical data (Fig. 6).15 At room temperature, a
conglomerate form seemed to be stable. At higher temper-
atures, an unstable racemic compound formed and then it
transformed into a stable racemic compound form that
melts at 167 ꢁC (Table 4).
When the above mentioned resolving agent mixture was
used, now in acetone (5% water), the precipitating diaste-
reomer changed to (S)-(+)-BABÆ(R)-(ꢀ)-FPhA and the effi-
ciency of the resolution was satisfactory (ee 81%, F = 0.41)
but it was much smaller than the efficiency of the resolution
with the pure (S)-(+)-BAB (Table 2). The change in the
precipitating diastereomer caused by the change of solvent
is noteworthy. The crystalline phases did not combine with
each other as they do in regular Dutch resolution experi-
ments, but competition was observed between them.
Table 3. Comparison of the resolutions using BA achiral additive with
(S)-(+)-BAB and (R)-(+)-PhEA resolving agents
Solvent
Resolving
agent
Molar ratio
(racemate:resolving (%) (%)
agent:additive)
ee
Y
F
Water
Acetone
(5% water)
(R)-(+)-PhEA 1:0.5:0.5
(S)-(+)-BAB 1:0.5:0.5
75
2
35
59
0.26
0.01
It had been formerly demonstrated that in aqueous solvent,
the formation of (R)-(+)-PhEA. (R)-(ꢀ)-FPhA crystalline

E. Pa´lovics et al. / Tetrahedron: Asymmetry 18 (2007) 2531–2536
2535
Table 5. Results of enantiomeric enrichment experiments
Enantiomeric excess
a
a
a
ee0 (%)
ee1 (%)
ee2 (%)
Fractional crystallization
Neutral solution/HCl
Recrystallization from water
49.6
73.4
75.0
19.3
70.8
73.4
75.0
68.0
74.5
a ee0, ee1 and ee2: ee values of the starting material, the first isolated and
the second isolated fraction, respectively.
3. Conclusions
A detailed investigation of the resolution of N-formylphen-
ylalanine with (S)-N-benzylaminobutanol in water and
in acetone has allowed us to develop a new method for
the enantiomer separation of FPhA. The efficiency of the
resolution, carried out with (S)-BAB in acetone, was signi-
ficantly higher (F = 0.73) than that described in the litera-
ture method [(R)-PhEA resolving agent, F = 0.42]14 and
higher than the calculated value (F = 0.51) of the resolv-
ability expected on the basis of thermoanalytical data.
The success was attributed to a special effect of the solvent
(acetone) which can form a hemiaminal derivative of (S)-
BAB resulting in an in situ formation of a relative resolving
agent ((S)-BABHA) in the reaction mixture. Time-depen-
dent experiments confirmed our hypothesis: prolonged
crystallization time caused the best separation when it
was long enough to achieve the diffusion-controlled
equilibrium of the proposed multicomponent equilibrium
system. In addition, two polymorphic forms of the more
soluble diastereoisomeric salt ((S)-BAB-(S)-FPhA) were
detected.
The structural similarity of (S)-N-benzylaminobutanol was
not enough to make it able to cooperate with another
structurally related benzylamine-derivative resolving agent
[(R)-PhEA]. Instead, a competition was observed between
the salts of the two resolving agents and the efficiency of
the resolution, using the mixture of the resolving agents,
was worse than it was with the use of the individual
compounds.
Figure 6. Binary phase diagram and DSC curves of the N-formylphenyl-
alanine enantiomeric mixtures.
In order to find a good purification method for FPhA
enantiomeric mixtures, three types of enantiomeric enrich-
ment experiments were accomplished in our laboratory:
fractional crystallization, parietal hydrochloride salt for-
mation and recrystallization from water. The results are
summarized in Table 5.
The achiral benzylamine additive did not influence the
chiral recognition process when its molecular structure
was close to that of the resolving agent. In the case of
(S)-N-benzylaminobutanol where the structural differences
were more expressed, the negative effect of benzylamine on
the enantiomer separation was significant.
It can be seen from the experimental data that the FPhA
enantiomeric mixtures can be purified until reaching the eu-
tectic composition, however further purification is only
possible with another derivative or using a chiral agent (re-
peated resolution).
Thermoanalytical investigations of FPhA enantiomeric
mixtures showed a temperature-dependent conglomerate
versus racemate formation. The presence of the thermo-
dynamically more stable racemate strictly determines the
efficiency of the enantiomeric enrichment processes: the
ee cannot improve above the eutectic composition by these
methods.
Table 4. Characteristic data of the conglomerate and racemic forms of
FPhA enantiomeric mixtures
Conglomerate
Racemic
Racemic
compound 1
compound 2
Eutectic
0.50
0
0.61
0.78
composition (R/S)
Enantiomeric
excess (%)
22
56
4. Experimental
Eutectic
temperature (ꢁC)
132.6
142.1
154.6
Chemicals were products of Aldrich. Optical rotations were
determined on a Perkin Elmer 241 polarimeter. DSC

2536
E. Pa´lovics et al. / Tetrahedron: Asymmetry 18 (2007) 2531–2536
measurements were performed by TA Instruments DSC
2920 in the 290–420 K temperature range with 5 K minꢀ1
heating rate. Samples were placed in a hermetically sealed
pan, the measuring cell was purged with 60 ml minꢀ1 nitro-
gen gas.
in water (5 cm3). After 2 days the diastereomeric salt pre-
cipitated. It was filtrated and washed with water
(2 · 0.3 cm3). Then it was treated with concd HCl (2 cm3)
20
in water (5 cm3) to give 0.2 g (R)-(ꢀ)-1, ½aꢁD ¼ ꢀ20:8 (c
2, ethanol).
4.1. Resolution of N-formylphenylalanine by (S)-(+)-2-
benzylaminobutanol (1:1) in water
The mother liquor was acidified with concd HCl (2 cm3)
20
and the precipitate filtrated to give 1.3 g (S)-(+)-1, ½aꢁD
¼
þ4:9 (c 2, ethanol).
A mixture of racemic FPhA (1.93 g, 10.0 mmol) and (S)-
(+)-BAB (1.8 g, 10.9 mmol) was dissolved in water
(5 cm3) under heating. After 12 days, the (S)-(+)-BABÆ
(R)-(ꢀ)-FPhA salt precipitated. This was filtered out and
washed with water (2 · 0.3 cm3), after which it was reacted
with concd HCl (2 cm3) in water (6 cm3). The precipitated
(R)-(ꢀ)-FPhA was filtered off and washed with water
Acknowledgement
The Hungarian OTKA Foundation (Project Nos.: T042725
and F037814) is gratefully acknowledged for financial
support.
(2 · 0.5 cm3). The process yielded 0.64 g of (R)-(ꢀ)-FPhA
20
(66%) ½aꢁD ¼ ꢀ19:3 (c 2, ethanol).
References
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with concd HCl (2 cm3), the precipitated (S)-(+)-FPhA
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was filtered off and washed with water (2 · 0.5 cm3), the
20
mass of the dried product was 1.0 g. ½aꢁD ¼ þ12:5 (c 2,
ethanol).
4.2. Resolution of N-formylphenylalanine by (S)-(+)-2-
benzylaminobutanol (1:1) in acetone
(a) A mixture of racemic FPhA (19.3 g, 0.1 mol) and
(S)-(+)-BAB (17.9 g, 0.1 mol) was dissolved in hot
acetone (10 cm3). After one night (15 h), the (S)-
(+)-BABÆ(R)-(ꢀ)-FPhA diastereomer salt precipitate
was filtrated and washed with acetone (2 · 1 cm3). It
was reacted with concd HCl (2 · 1 cm3) in water
(5 cm3). The precipitated (R)-(ꢀ)-FPhA was filtered
and washed by water (2 · 0.5 cm3). The process
20
yielded 0.85 g (R)-(ꢀ)-FPhA (88.0%) ½aꢁD ¼ ꢀ62:3
(c 2, ethanol), ee: 83.0%.
The mother liquor of the diastereomeric salt was
evaporated and acidified with concd HCl (3 cm3).
The precipitated (S) -(+)-FPhA was filtered and
7. Overby, L. R.; Ingersoll, A. W. J. Am. Chem. Soc. 1951, 73,
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washed by water (2 · 0.5 cm3), the mass of the dried
20
product was 0.95 g, (98%), ½aꢁD ¼ þ58:1 (c 2,
´
9. Kozma, D.; Pokol, G.; Acs, M. J. Chem. Soc., Perkin Trans.
ethanol).
2 1992, 435.
´
(b) The work is similar to that described before, but the
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L. Tetrahedron Lett. 1980, 21, 647.
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Chem. Soc. 2002, 124, 13139.
12. Courvoisier, L.; Mignot, L.; Petit, M. N.; Coquerel, G. Org.
Process Res. Dev. 2003, 7, 1007.
The process yielded 0.90 g (R)-(ꢀ)-FPhA (93.3%)
20
½aꢁD ¼ ꢀ36:8 (c 2, ethanol), ee: 49.1%. The mass of
the dried (S)-(+)-FPhA separated from mother liquor
20
was 0.66 g, (68.5%), ½aꢁD ¼ þ41:8 (c 2, ethanol).
13. Bereczki, L.; Palovics, E.; Bombicz, P.; Pokol, G.; Fogassy,
E. Tetrahedron: Asymmetry 2007, 18, 260.
14. Fogassy, E.; Palovics, E.; Schindler, J. 10th International
Conference of Chemistry, Cluj, 2004; p 342.
4.3. Resolution of N-formylphenylalanine by (S)-(+)-2-benz-
ylaminobutanol and (R)-(+)-1-phenylethylamine (1:0.5:0.5)
in water
15. Marchand, P.; Lefebvre, L.; Querniard, F.; Cardinael, P.;
Perez, G.; Counioux, J. J.; Coquerel, G. Tetrahedron:
Asymmetry 2004, 15, 2455.
Racemic-1 (1.93 g, 10.0 mmol), (S)-(+)-3 (0.67 g,
5.5 mmol) and (R)-(+)-2 (0.9 g, 5.5 mmol) were dissolved