Resolution of β-aminoalcohols and 1,2-diamines using fractional crystallization of diastereomeric salts of dehydroabietic acid

Article abstract of DOI:10.1016/j.tetasy.2003.08.033

(S)-(+)-1-Amino-3-phenyloxy-2-propanol, (R)-(-)-2-amino-1-phenylethanol, (S)-(+)-1-amino-2-propanol, (1S,2S)-(+)-2-aminocyclohexanol and (1S,2S)-(+)-1,2-diaminocyclohexane were resolved using dehydroabietic acid. It was shown that good to high enantiomeric purity, between 81～>99% ee, was obtained and that dehydroabietic acid could be easily and efficiently recovered in a reusable form.

Full text of DOI:10.1016/j.tetasy.2003.08.033

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3297–3300
Resolution of b-aminoalcohols and 1,2-diamines using fractional
crystallization of diastereomeric salts of dehydroabietic acid
Zhang Guangyou,† Liao Yuquing, Wang Zhaohui, Hiroyuki Nohira and Takuji Hirose*
Department of Applied Chemistry, Faculty of Engineering, Saitama University, 255 Shimo-ohkubo, Sakura, Urawa,
Saitama 338-8570, Japan
Received 30 May 2003; accepted 27 August 2003
Abstract—(S)-(+)-1-Amino-3-phenyloxy-2-propanol, (R)-(−)-2-amino-1-phenylethanol, (S)-(+)-1-amino-2-propanol, (1S,2S)-(+)-
2-aminocyclohexanol and (1S,2S)-(+)-1,2-diaminocyclohexane were resolved using dehydroabietic acid. It was shown that good to
high enantiomeric purity, between 81ꢀ>99% ee, was obtained and that dehydroabietic acid could be easily and efficiently
recovered in a reusable form.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Resolution and asymmetric synthesis are the major
methodologies1 used to obtain synthetic homochiral
compounds. The most practical and widely used
method is resolution. We have worked on resolution
using not only diastereomeric salt formation but also
preferential crystallization and developed various kinds
of chiral compounds useful as molecular recognition
reagents,2 liquid crystals and related materials.3 Among
chiral compounds, b-aminoalcohols and 1,2-diamines
are the most useful starting materials for the prepara-
tion of pharmaceuticals and ligands.4,5 As a result it is
important in asymmetric synthesis to search for rapid
and efficient resolving agents for aminoalcohols and
1,2-diamines.
A series of b-aminoalcohols, that is 1-amino-3-phenyl-
oxy-2-propanol 1, 2-amino-1-phenylethanol 2, 1-amino-
2-propanol
3
and 2-aminocyclohexanol 4, were
obtained via the reaction of ammonia with the corre-
sponding epoxides at 15–20°C. At higher temperatures,
more by-products were formed by the competing reac-
tion of the ammonia at the 1-position of the substituted
epoxides and/or by the reaction of the product
aminoalcohols with epoxides to give the 1:2 adduct.
1-Amino-3-phenyloxy-2-propanol was purified by
recrystallization from ethyl acetate. All other aminoal-
cohols were purified by distillation under vacuum. The
yield of 2-aminocyclohexanol was much higher than
other products, probably because it was more difficult
to react a second time with cyclohexene oxide to form
di(2-hydroxycyclohexyl)- amine due to its sterically hin-
dered character. Dehydroabietic acid was prepared
from disproportionated rosin according to the
literature6 as shown in Scheme 1.
Dehydroabietic acid, DAA, is one of the main compo-
nents of disproportionated rosin and is very easy to
obtain as an ethanolamine salt by fractional crystalliza-
tion.6 Compared with abietic acid, DAA is more stable
under acidic conditions and also withstands auto-oxida-
tion. To our knowledge, DAA has rarely been used as
a resolving agent. Herein it is shown that some b-
aminoalcohols and 1,2-diaminocyclohexane can be suc-
cessfully resolved.
The salts of b-aminoalcohols or 1,2-diaminocyclohex-
ane with DAA were easily recrystallized from various
organic solvents such as ethanol, methanol, acetonitrile,
2-propanol, THF and so on, but only crystals from
ethanol or methanol were of significantly higher enan-
tiomeric purity. The process and results of fractional
recrystallization are summarized in Scheme 2.
* Corresponding author. Tel./fax: +81-48-858-3522; e-mail:
hirose@apc.saitama-u.ac.jp
† Permanent address: Department of Chemical Engineering, Jinan
University, 106 Jiwei Road, Jinan, Shandon Province 25002, PR
China.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.033

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Z. Guangyou et al. / Tetrahedron: Asymmetry 14 (2003) 3297–3300
of the aminoalcohols and diamine. The unchanged
enantiomeric purity of the resolving agent was con-
firmed by measuring the specific rotation.
Enantiomerically enriched 2, 3, 4 and 5 were further
derived to 6, 7, 8 and 9, respectively, for HPLC analy-
sis. The enantiomeric purities of 6 and 7 were 81% and
82% ee, respectively and the result which after only one
recrystallization was not satisfactory. It is noteworthy
however, that the small and flexible aminoalcohol 4 was
resolved in good yield and reasonable purity. The rigid
structure of DAA seems to be one source of its resolu-
tion ability. However the absolute configurations of 1, 2
and 3 are not consistent in spite of their structural
similarities. At the present time, rigidity or bulkiness
around the asymmetric center is expected to affect the
chirality discrimination. This is consistent with the flexi-
bility of 1 and 3 versus the rigidity of 2 due to its
phenyl group. The purity of 8 was >99% ee, which
means that the preparative yield and purity of (1S,2S)-
(+)-4 is as good as that of the enzymatic method
reported by Takada et al.8
Scheme 1. Preparation of dehydroabietic acid (DAA).
The absolute configurations of the resolved b-aminoal-
cohols and 1,2-diaminocyclohexane were determined by
comparing their specific rotation signs with those in the
literature.7 The enantiomeric purities were determined
by chiral HPLC analysis.
The absolute configurations of resolved 1, 2, 3, 4 and 5
were found to be (S)-(+), (R)-(−), (S)-(+), (1S,2S)-(+)
and (1S,2S)-(+), respectively, as follows. Resolved (S)-
(+)-1 was directly analyzed with HPLC and the enan-
tiomeric purity was determined to be >99% ee. This
result showed that the entire process was an easy and
practical method to obtain (S)-(+)-1. The resolving
agent was easily recovered as a precipitate by acidifica-
tion of the aqueous solution obtained during liberation
It is well known that chiral 1,2-diaminocyclohexane is a
versatile synthon of chiral salen complexes.9 The high
enantiomeric purity of 9 (>99% ee) shows that the
preparation of enantiomerically pure (1S,2S)-(+)-5 pre-
sented here is also efficient practically.10 However, the
Scheme 2. Optical resolution of b-chiral aminoalcohols and 1,2-diamine by dehydroabietic acid and their derivation. a: Based on
half the amount of racemate.

Z. Guangyou et al. / Tetrahedron: Asymmetry 14 (2003) 3297–3300
3299
resolution of 1,2-diaminopropane failed in spite of the
results with 3, 4 and 5.
tion and then 96 mL for the second to obtain crystals
(4.11 g) in 63.1% yield based on half the amount of
racemate, [h]2D3=+40.9 (c 1.0, methanol).
In summary it has been shown that DAA is a useful
resolving agent. Its versatility is probably due to the
following factors: (1) Face discrimination by one car-
boxyl group and two axial methyl groups; (2) its rather
rigid planar structure, and (3) its aromatic structure as
an additional interacting part for amines like 1 and 2
which have an aromatic group. Although the resolu-
tions of some o-aminomethylphenols were tried using
DAA, satisfactory results have yet to be obtained.
The salts of (R)-(−)-2 (1.94 g) and DAA (4.24 g): 80%
methanol (50 and 25 mL) was used for every 1 g of the
salt to give a yield of 40.5% (82.3% ee) based on half
the amount of racemate, [h]2D5=+20.5 (c 1.0, methanol).
The salts of (S)-(+)-3 (2.50 g) and DAA (10.00 g): 95%
methanol (40 and 20 mL) was used for every 1 g of the
salt to give a yield of 60.4% based on half the amount
of racemate, [h]2D2=+44.4 (c 1.0, methanol).
3. Experimental
3.1. General
The salts of (1S,2S)-(+)-4 (2.77 g) and DAA (7.23 g):
90% methanol (50 mL and then 20 mL) was used to
obtain crystals (2.52 g) in 48.2% yield (81.1% ee) based
on half the amount of racemate, [h]2D3=+37.9 (c 1.0,
methanol).
1H NMR spectra were recorded in CDCl3 on a Bruker
AM-400 spectrometer. Enantiomeric excess determina-
tions were carried out using a set of JASCO LC 900
series with a chiral column ‘Chiralcel OB-H’ (Daicel
Chem. Ind. Ltd., 4.6 mm×250 mm). Optical rotations
were measured with a JASCODIP-370 polarimeter.
Melting temperatures were determined on a Mel-Temp
melting point apparatus (Laboratory Devices, MA) and
are reported uncorrected. For recrystallization, all sol-
vents were used as received.
The salts of (1S,2S)-(+)-5 (1.14 g) and DAA (3.01 g):
95% ethanol (20 and 10 mL) was used for every 1 g of
the salt to give a yield of 47.1% based on half the
amount of racemate, [h]2D3=+50.7 (c 1.0, methanol).
3.5. Liberation of resolved aminoalcohols and 1,2-
diaminocyclohexane from their salts of DAA
General method: 1 mmol of the crystals obtained was
dissolved in 20 mL of methanol after which 2.5 mmol
(3.5 mmol in case of 1,2-diaminocyclohexane) c. HCl
aq. was added. After the evaporation of methanol, 10
mL of water was added and the mixture was stirred for
10 min. Dehydroabietic acid was filtered off and
washed with 10 mL of water. To the filtrate, 2.5 mmol
(3.5 mmol in case of 1,2-diaminocyclohexane) NaOH
was added. After the evaporation of water from the
mixture, precipitated NaCl was removed by filtration
and washed with THF. The THF solution was dried
over K2CO3 and removed by filtration. The solvent was
removed to yield either the resolved b-aminoalcohol or
1,2-diaminocyclohexane.
3.2. Preparation of DAA
Dehydroabietic acid was prepared according to the
literature,6 mp 170–171.5°C, [h]2D0=+62.5 (c 2.0, 95%
ethanol). (Lit.6: mp 170–171.5°C, [h]2D0=+62.5.)
3.3. General method for the preparation of b-
aminoalcohols
Epoxide (0.1 mol) and 25% NH3 aq. (1 mol) were
mixed together after which methanol was added until
the reaction mixture became clear with stirring. The
reaction mixture was then further stirred overnight at
15–20°C. Methanol, water and excess NH3 were
removed under reduced pressure. The residue was
recrystallized for 1 and distilled under vacuum for 2, 3
and 4. Pure 1 was obtained from ethyl acetate in 71%
yield. The yields of 2, 3 and 4 were 32, 45 and 90%,
respectively.
(S)-(+)-1; 96.2% yield, [h]2D9=+2.4 (c 1.0, methanol),
>99% ee (OD-H, hexane:2-propanol=7:3).
(R)-(−)-2; 97.0% yield, [h]2D6=−31.6 (c 1.0, methanol).
(S)-(+)-3; 94.2% yield, [h]2D6=+5.4 (c 1.0, methanol).
3.4. Fractional recrystallization of b-aminoalcohols and
1,2-diaminocyclohexane dehydroabietate
(1S,2S)-(+)-4; 95.6% yield, [h]2D4=+8.2 (c 1.0,
methanol).
DAA (10 mmol) was dissolved in methanol (50 mL),
and then either b-aminoalcohols or 5 (10 mmol) added.
After the evaporation of methanol, the residue was
recrystallized from the solvent. The crystals were iso-
lated, dried under vacuum, and recrystallized once
more. Ordinarily recrystallization overnight was
required. The other salts were resolved in the same way
with various solvent systems (Scheme 2).
(1S,2S)-(+)-5, yield in 95.4%, [h]3D0=+41.2 (c 1.0,
methanol).
3.6. Reaction of resolved b-aminoalcohols and 2,4-
dinitrofluorobenzene8
b-Aminoalcohol (0.5 mmol), 2,4-dinitrofluorobenzene
(1.0 mmol) and triethylamine (1.0 mmol) were added to
chloroform (20 mL) and the mixture stirred at room
temperature for 2 h. Chloroform was removed by evap-
The salts of (S)-(+)-1 (3.34 g) and DAA (6.01 g): 190
mL of 80% ethanol was used for the first recrystalliza-

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Z. Guangyou et al. / Tetrahedron: Asymmetry 14 (2003) 3297–3300
oration and the residue purified by chromatography
(silica gel, chloroform:ethyl acetate=5:1). After concen-
tration of the eluent, the residue was washed with water
and then with methanol, and fed to HPLC analysis.
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6; 70.5% yield, 81.1% ee (Chiralcel OB-H, 25% 2-
propanol in hexane).
7; 66.8% yield, 82.3% ee (Chiralcel OB-H, 30% 2-
propanol in hexane).
8; 74.2% yield, >99% ee (Chiralcel OB-H, 30% 2-
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3.7. Benzoylation of (1S,2S)-(+)-1,2-diaminocyclo-
hexane
(1S,2S)-(+)-1,2-Diaminocyclohexane (0.5 mmol), ben-
zoyl chloride (1.2 mmol) and triethylamine (1.2 mmol)
were added to THF (20 mL) and the mixture stirred at
room temperature for 2 h. The mixture was then
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Acknowledgements
The authors deeply appreciate the helpful discussion
and English editing by Professor Bruce W. Baldwin of
Spring Arbor University.
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