Optically active amines by enzyme-catalyzed kinetic resolution

Article abstract of DOI:10.1055/s-2008-1078451

Chiral amines are resolved by an enzyme-catalyzed kinetic resolution. Key steps are the selective acylation of one enantiomer with isopropyl methoxyacetate, separation of the resulting amide from the unreacted antipode, and finally amide hydrolysis. The p

Full text of DOI:10.1055/s-2008-1078451

PAPER
2283
Optically Active Amines by Enzyme-Catalyzed Kinetic Resolution
E
nzyme-Catalyzed
l
K
ineti
a
c
R
esolutio
u
nof
A
miness Ditrich*
GVF – Fine Chemicals & Biocatalysis Research, BASF SE, Carl-Bosch-Str. 38, 67056 Ludwigshafen, Germany
Fax +49(621)6020440; E-mail: klaus.ditrich@basf.com
Received 11 April 2008
Dedicated to Professor Reinhard W. Hoffmann on the occasion of his 75th birthday
NH2
R2
O
Abstract: Chiral amines are resolved by an enzyme-catalyzed ki-
netic resolution. Key steps are the selective acylation of one enan-
tiomer with isopropyl methoxyacetate, separation of the resulting
amide from the unreacted antipode, and finally amide hydrolysis.
The process proceeds with excellent selectivity and is highly flexi-
ble with regard to substrates.
+
MeO
R1
OR
2
(RS)-1
lipase
O
Key words: amines, enzymes, enantiomeric resolution, kinetic
resolution
NH2
R2
HN
R1
+
R1
OMe
R2
(S)-1
(R)-3
Over the last years, single-enantiomer drugs and drug can-
didates became more and more important in the ‘life sci-
ence industry’. Therefore, industrially feasible methods
for the production of optically active intermediates and
building blocks are also of increasing importance. Of cen-
tral interest are optically active amines and alcohols,
which are frequently used as building blocks and in the
case of amines, as resolving agents and chiral auxiliaries.
Established commercial routes to the synthesis of these
classes of compounds were reviewed in a recently pub-
lished paper.1
Scheme 1 Enzyme-catalyzed kinetic resolution of amines
edge, these results can be rationalized by kinetic factors,
for example, suppression of nonspecific, nonenzyme-cat-
alyzed reactions. In the meantime this ‘secondary ester ef-
fect’ was confirmed by other groups.7 Finally, some
commercially available lipases like lipase B from Candi-
da antarctica, turned out to be almost as effective as our
Burkholderia plantarii lipase in the kinetic resolution of
racemic amines.5a,6,8 The most impressive feature of the
enzyme-catalyzed resolution methodology is the biocata-
lyst’s unique flexibility regarding substrates. Some typi-
cal examples are given in Table 1.
Enzyme-catalyzed resolutions of racemic amines were
first studied in the pioneering work of Klibanov2 and
Guthman.3 In the course of a research program aiming at
the discovery of new enzyme-catalyzed reactions, we
found at BASF in the early 1990s that the kinetic resolu-
tion of racemic amines (RS)-1 was catalyzed very effi-
ciently by a proprietary lipase from the soil bacteria
Burkholderia plantarii. In a typical example, 1-phenyl-
ethylamine (1, R1 = phenyl, R2 = CH3) was reacted with
ethyl methoxyacetate (2, R = ethyl) yielding an optically
active S-amine (S)-1 (ee = >99%) and an R-configured
amide (R)-3 (R1 = phenyl, R2 = CH3) of 93% ee (selectiv-
ity factor E = 150)4 (Scheme 1).
O
NH2
NH2
O
lipase
HN
+
+
MeO
R1
R2
R1
R2
O
Et2O
OMe
R1
R2
(RS)-1
2
(S)-1
(R)-3
Scheme 2 Enantioselective acylation of racemic amines with
isopropyl methoxyacetate; for conditions, see experimental section
Arylalkylamines are resolved without any restriction; het-
erocyclic compounds (RS)-1f, (RS)-1i are also accepted.
In the case of aliphatic amines containing long aliphatic
side chains (RS)-1g, the resolution process is in need of
improvement; if the difference in the steric bulkiness of
the substituents at the stereocenter is well pronounced as
in (RS)-1h, a perfect resolution is achieved. Usually, the
unreacted S-amines (S)-1 and R-amides (R)-3 are isolated
in excellent yields.
In the meantime many other acylating reagents have been
studied,1,5 but the esters of methoxyacetic acid are still un-
rivaled in terms of reactivity and selectivity.5b Another
important factor is the nature of the alcohol component in
the esters 2. Very soon it became apparent to us that esters
of secondary alcohols like isopropyl methoxyacetate (2,
R = isopropyl) led to a remarkable increase in selectivity
and reactivity;6 with excellent selectivity (E = >1000)
both reaction products, (S)-1 and (R)-3 were isolated in
nearly optically pure form (Scheme 2)! To our knowl-
A remaining task of the overall process was the hydrolysis
of the R-configured amides (R)-3. Whereas strongly acid-
ic cleavage9 in our hands led to the formation of undesired
by-products, we found that by applying appropriate con-
ditions, optically active amides like (R)-3 can be hydro-
SYNTHESIS 2008, No. 14, pp 2283–2287
x
x.
x
x
.
2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1078451; Art ID: C01108SS
© Georg Thieme Verlag Stuttgart · New York

2284
K. Ditrich
PAPER
Table 1 Enzyme-Catalyzed Resolution of Amines
Entry
1
Substrate
Yield of S-amine, ee (%)a of
Yield of R-amide, ee (%)a of
Selectivity E
1500
(S)-1 (%)
(S)-1
(R)-3 (%)
(R)-3
95
>99.9
90
99
NH2
(RS)-1a
(RS)-1b
2
93
89
>99.9
99.9
92
89
98.7
98.5
1200
1000
NH2
3b
NH2
Br
(RS)-1c
4b
95
99.8
87
98.1
700
NH2
Cl
Cl
(RS)-1d
5
6
92
93
>99.9
99.3
90
85
98.2
98.1
850
600
NH2
(RS)-1e
(RS)-1f
NH2
S
7
8
87
91
99.1
93
89
96.9
99.3
350
NH2
( )4
(RS)-1g
>99.9
>2000
NH2
(RS)-1h
9c
85
92
>99.9
99.5
94
93
99.5
99.1
>3000
1300
NH2
MeO
N
(RS)-1i
10
NH2
(RS)-1j
(RS)-1k
11
95
>99.9
90
99.1
1700
NH2
a The ee was determined by chiral GC or chiral HPLC.
b The reaction mixture was diluted by the addition of THF (100 mL).
c Amine (S)-1i and amide (R)-3i were separated from each other by bulb-to-bulb distillation (100 °C/0.5 mbar).
Synthesis 2008, No. 14, 2283–2287 © Thieme Stuttgart · New York

PAPER
Enzyme-Catalyzed Kinetic Resolution of Amines
2285
Table 2 Retention Times of Chiral Amines (Derivatized as Benzoic
Acid Amides)
lyzed without any undesired side reaction. Most important
was the addition of co-solvents like ethylene glycol or tri-
ethanolamine; in the presence of these compounds, the
hydrolysis occurred fast without formation of by-products
and without any racemization at the chiral center.6,10 By
applying inexpensive 50% aqueous NaOH as the hydro-
lyzing agent, the liberated R-amines (R)-1 were isolated in
nearly quantitative yields. A representative procedure
(Scheme 3) is given for the hydrolysis of 2-methoxy-N-
[(1R)-1-phenylethyl]acetamide [(R)-3a] liberating opti-
cally active (R)-1-phenylethylamine [(R)-1a] (Scheme 3).
Amine (RS)-1
tR (min) (R)-1
6.68
tR (min) (S)-1
8.90
1a
1b
1c
1d
1e
1f
5.94
7.79
7.98
13.05
13.12
8.63
7.73
6.36
9.12
12.31
4.81
O
1g
1h
1i
4.70
NH2
HN
OMe
3.14
4.59
6.86
8.23
(R)-1a
(R)-3a
1j
4.51
8.80
Scheme 3 Basic hydrolysis of optically active amides (R)-3;
Reagents and conditions: 50% aq (1.5 equiv) NaOH, triethanolamine,
120 °C, 6 h, yield: 93%
1k
6.26
9.53
HPLC Method for the Determination of the Optical Purity of
Chiral Amides (RS)-3
Amide (RS)-3 (0.1 g) was dissolved in n-hexane–CH2Cl2 (4:1, 25
mL) and injected in the chiral column as per the conditions above.
Based upon the results of research and development, two
dedicated plants with tailor-made equipment were con-
structed. With an annual production capacity of >3000
tonnes/year, BASF is the world’s leading supplier for op-
tically active amines.
Enzyme-Catalyzed Resolution of 1-Phenylethylamine [(RS)-
1a]; Typical Procedure (TP1)
1-Phenylethylamine [(RS)-1; 12.1 g, 0.1 mol] and isopropyl meth-
oxyacetate [2 (R = i-Pr); 19.8 g, 0.15 mol] were dissolved in Et2O
(400 mL). After the addition of immobilized lipase B from Candida
antarctica (Novozyme 435®) (1 g), the turbid solution was stirred
(30 rpm) overnight at r.t. The progress of the reaction was moni-
tored by chiral HPLC and when the optical purity of the unreacted
S-enantiomer (S)-1a was >99.9% ee and the R-amide (R)-3a was
99% ee, the reaction was stopped. The solid material was removed
by filtration, the remainder was washed with Et2O (50 mL), and the
combined filtrates were stirred with 5% aq HCl (50 mL). The phases
were separated and the organic phase was washed with H2O (100
mL). The combined aqueous phases were re-extracted with Et2O
(3 × 70 mL) and the combined organic extracts were dried
(Na2SO4). The solvent was evaporated and from the remaining mix-
ture of R-amide (R)-3a and the unreacted isopropyl methoxyacetate
(2, R = i-Pr); the latter was removed by bulb-to-bulb distillation
(bath temperature: 90 °C/0.2 mbar). Upon standing, the remaining
amide (R)-3a solidified to a colorless solid; yield: 8.80 g (92%). An
analytical and optical pure sample was obtained by recrystallization
from cyclohexane; mp 63 °C.
All reactions were carried out under N2. Starting materials and sol-
vents were dried and purified according to standard procedures. Li-
pase B from Candida antarctica was purchased as an immobilisate
1
(Novozyme 435®) and used as such. All H NMR (500 MHz) and
13C NMR spectra (125 MHz) were recorded on a Varian Inova or
Bruker DAX 500 spectrometer. The chemical shifts d are reported
relative to SiMe4 (1H NMR) or to the solvent peaks (13C NMR). Op-
tical rotations refer to recrystallized or distilled samples and were
measured on a PerkinElmer 241 spectrometer. Melting points were
uncorrected and measured on a Dr. Tottoli (Büchi B-510) apparatus.
Chiral GCs were recorded on a Hewlett-Packard HP 6890 GC se-
ries, and chiral HPLCs were measured on an Agilent 1100 using a
Ciralcel-OD-column (Daicel Chemical Industries Ltd.) as the sta-
tionary phase.
HPLC Method for the Determination of the Optical Purity of
Chiral Amines (RS)-1
Amine (RS)-1 (0.5 g) was dissolved in Et2O (25 mL). The solution
was cooled in an ice-bath and benzoyl chloride (0.2 mL) was added
via a syringe. The mixture was stirred at r.t. for 30 min. The result-
ing white suspension was hydrolyzed by the addition of H2O (10
mL). After stirring for 10 min, the phases were separated. The upper
organic layer was washed successively with aq 10% HCl (10 mL),
H2O (10 mL) and aq sat. NaHCO3 (10 mL). Finally, the organic lay-
er was dried (Na2SO4). An aliquot of the ethereal solution (1 mL)
was diluted with n-hexane (5 mL) and the formed benzoic acid
amides were analyzed by HPLC (column: Chiralcel OD, Daicel
Chemical Industries Ltd.; operating temperature: r.t.; detection: ab-
sorbance at 214 nm; injection volume: 20 mL; mobile phase: n-hex-
ane–i-PrOH–EtOH (300:50:0.8), flow: 1.3 mL/min (approx. 40 kg/
cm2).
With cooling in an ice bath, the aqueous extracts from above were
rendered alkaline (pH 13) by the addition of 50% aq NaOH. Et2O
(75 mL) was added and the phases were separated. The aqueous
phase was extracted with Et2O (2 × 75 mL) and the combined ex-
tracts were dried (Na2SO4). The solvent was evaporated and the re-
maining S-amine (S)-1a was purified by bulb-to-bulb distillation
(bath: 50 °C/0.2 mbar). (S)-1-Phenylethylamine [(S)-1a] (5.75 g,
95%) was obtained as a colorless liquid, chiral HPLC indicated an
optical purity of >99.9%ee.
2-Methoxy-N-[(1R)-1-phenylethyl]acetamide [(R)-3a]
Following TP1, the amide (R)-3a was obtained as colorless crystals;
chiral HPLC: tR = 4.89 min (R), 5.74 min (S); mp 63 °C;
[a]D25 +110.4 (c = 2.0, MeOH).
Retention times of the derivatized chiral amines are listed in
Table 2.
Synthesis 2008, No. 14, 2283–2287 © Thieme Stuttgart · New York

2286
K. Ditrich
PAPER
1H NMR (500 MHz, CDCl3): d = 1.50 (d, J = 7.4 Hz, 3 H,
CH3CHN), 3.40 (s, 3 H, CH2OCH3), 3.84 and 3.90 (AB-system,
JA,B = 15.0 Hz, 2 H, CH2OCH3), 5.18 (quint, J = 7.4 Hz, 1 H,
CH3CHNH), 6.80 (br s, 1 H, CONH), 7.23–7.50 (m, 5 H).
13C NMR (125 MHz, CDCl3): d = 21.9, 48.0, 59.1, 72.0, 126.1,
127.4, 128.7, 143.0, 168.5.
(AB-system, JA,B = 15.0 Hz, 2 H, CH2OCH3), 5.23 (m, 1 H,
CHNH), 6.83 (br s, 1 H, CONH), 6.99–7.06 (m, 1 H), 7.08–7.15 (m,
2 H), 7.21 (dd, J = 2.0, 8.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 22.8, 28.5, 46.1, 59.1, 71.9,
124.5, 126.8, 128.1, 130.3, 132.4, 133.6, 168.6.
2-Methoxy-N-[(2R)-2-nonyl]acetamide [(R)-3g]
2-Methoxy-N-[(1R)-1-phenylpropyl]acetamide [(R)-3b]
Following TP1, the amide (R)-3b was obtained as colorless crystals;
chiral HPLC: tR = 4.60 min (R), 5.46 min (S); mp 75 °C;
[a]D25 +107.4 (c = 2.0, MeOH).
Following TP1, the amide (R)-3g was obtained as colorless crystals;
chiral GC (column: Chiraldex-GTA, 20 m × 0.25 mm × 0.12 mm,
constant flow: 0.8 mL/min, program: 140/20/10/180/20): tR = 9.59
min (S), 10.11 min (R); mp 58 °C; [a]D25 +5.3 (c = 2.0, MeOH).
1H NMR (500 MHz, CDCl3): d = 0.90 (t, J = 7.3 Hz, 3 H, CH3CH2),
1.80–1.92 (m, 2 H, CH3CH2CNH), 3.38 (s, 3 H, CH2OCH3), 3.83
and 3.92 (AB-system, JA,B = 15.0 Hz, 2 H, CH2OCH3), 4.93 (q,
J = 7.3 Hz, 1 H, CH2CHNH), 6.80 (br s, 1 H, CONH), 7.18–7.35
(m, 5 H).
13C NMR (125 MHz, CDCl3): d = 10.7, 29.2, 54.1, 59.1, 72.0,
126.6, 127.3, 128.6, 142.0, 168.7.
1H NMR (500 MHz, CDCl3): d = 0.88 (t, J = 7.2 Hz, 3 H, CH3CH2),
1.18 (d, J = 7.3 Hz, 3 H, CH3CHNH), 1.22–1.38 (m, 12 H), 1.43–
1.50 (m, 2 H), 3.40 (s, 3 H, CH2OCH3), 3.85 (s, 2 H, CH2OCH3),
4.05 (sext, J = 7.2 Hz, 1 H, CHNH), 6.30 (br s, 1 H, CONH).
13C NMR (125 MHz, CDCl3): d = 13.1, 20.0, 21.7, 25.1, 28.3, 28.5,
31.0, 36.0, 43.7, 58.1, 71.2, 167.7.
2-Methoxy-N-[(1R)-1,2,2-Trimethylpropyl]acetamide [(R)-3h]
Following TP1, the amide (R)-3h was obtained as a colorless oil;
chiral HPLC: tR = 2.99 min (R), 3.48 min (S); bp 101 °C/10 Torr;
[a]D25 –2.4 (c = 2.0, MeOH).
1H NMR (500 MHz, CDCl3): d = 0.90 [s, 9 H, (CH3)3CH], 1.05 (d,
J = 7.1 Hz, 3 H, CH3CHN), 3.42 (s, 3 H, CH2OCH3), 3.85 (s, 2 H,
CH2OCH3), 3.88 (q, J = 7.2 Hz, 1 H, CH3CHNH), 6.40 (br s, 1 H,
CONH).
N-[(1R)-1-(4-Bromophenyl)ethyl]-2-methoxyacetamide [(R)-3c]
Following TP1, the amide (R)-3c was obtained as colorless crystals;
chiral HPLC: tR = 6.30 min (R), 6.90 min (S); mp 94 °C; [a]D25 +104
(c = 2.0, MeOH).
1H NMR (500 MHz, CDCl3): d = 1.49 (d, J = 7.4 Hz, 3 H, CH3CH),
3.38 (s, 3 H, CH2OCH3), 3.85 and 3.91 (AB-system, JA,B = 15.0 Hz,
2 H, CH2OCH3), 5.12 (quint, J = 7.4 Hz, 1 H, CHNH), 6.75 (br s, 1
H, CONH), 7.20 and 7.45 (AA¢BB¢-system, J = 8 Hz, 4 H)
13C NMR (125 MHz, CDCl3): d = 16.1, 26.2, 34.2, 52.2, 59.2, 72.1,
168.7.
13C NMR (125 MHz, CDCl3): d = 21.8, 47.5, 59.1, 71.9, 121.1,
127.9, 131.7, 142.2, 168.6.
2-Methoxy-N-[(1R)-1-(6-methoxypyridin-3-yl)ethyl]acetamide
[(R)-3i]
N-[(1R)-1-(2,4-Dichlorophenyl)ethyl]-2-methoxyacetamide
[(R)-3d]
Following TP1, amide (R)-3d was obtained as colorless crystals;
chiral HPLC: tR = 5.38 min (R), 5.79 min (S); mp 90 °C;
[a]D25 +48.5 (c = 2.0, MeOH).
1H NMR (500 MHz, CDCl3): d = 1.50 (d, J = 7.2 Hz, 3 H, CH3CH),
3.40 (s, 3 H, CH2OCH3), 3.86 and 3.92 (AB-system, JA,B = 15.0 Hz,
2 H, CH2OCH3), 5.38 (quint, J = 7.2 Hz, 1 H, CHNH), 6.92 (br s, 1
H, CONH), 7.22 (dd, J = 1.2, 8 Hz, 1 H), 7.20–7.28 (m, 2 H), 7.37
(d, J = 1.2 Hz, 1 H).
Following TP1, the mixture of amine (S)-1i and amide (R)-3i ob-
tained were separated from each other by bulb-to-bulb distillation
(100 °C/0.5 Torr). The amide (R)-3i was obtained as colorless crys-
tals; chiral HPLC: tR = 5.95 min (R), 6.25 min (S); mp 83 °C;
[a]D25 +104.8 (c = 2.0, MeOH).
1H NMR (500 MHz, CDCl3): d = 0.90 (t, J = 7.4 Hz, 3 H, CH3CH2),
1.78–1.95 (m, 2 H, CH3CH2), 3.40 (s, 3 H, CH2OCH3), 3.82 and
3.90 (AB-system, JA,B = 15.0 Hz, 2 H), 3.90 (s, 3 H, OCH3), 4.87 (q,
J = 8.0 Hz, 1 H, CHNH), 6.75 (br s, 1 H, CONH), 6.75 (d, J = 8.0
Hz, 1 H), 7.50 (dd, J = 2.0, 8.0 Hz, 1 H), 8.09 (d, J = 2.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 20.9, 46.0, 59.2, 72.0, 127.4,
128.0, 129.8, 133.5, 133.6, 139.2, 168.6.
13C NMR (125 MHz, CDCl3): d = 10.7, 28.8, 51.6, 53.5, 59.2, 72.0,
110.9, 130.2, 137.2, 145.2, 163.6, 168.8.
N-[(1R)-2,3-Dihydro-1H-inden-1-yl]-2-methoxyacetamide [(R)-
3e]
Following TP1, the amide (R)-3e was obtained as colorless crystals;
chiral HPLC: tR = 4.81 min (R), 6.71 min (S); mp 94 °C;
[a]D25 +112.4 (c = 2.0, MeOH).
2-Methoxy-N-[(1R)-(1-naphthyl)ethyl]acetamide [(R)-3j]
Following TP1, the amide (R)-3j was obtained as colorless crystals;
chiral HPLC: tR = 3.79 min (R), 6.83 min (S); mp 80 °C;
[a]D25 +30.8 (c = 2.0, MeOH).
1H NMR (500 MHz, CDCl3): d = 1.78–1.88 (m, 1 H), 2.58–2.68 (m,
1 H), 2.82–2.95 (m, 1 H), 2.98–3.08 (m, 1 H), 3.38 (s, 3 H,
CH2OCH3), 3.85 and 3.91 (AB-system, JA,B = 15.0 Hz, 2 H,
CH2OCH3), 5.53 (dd, J = 7, 9 Hz, 1 H, CHNH), 6.85 (br s, 1 H,
CONH), 7.18–7.29 (m, 4 H).
1H NMR (500 MHz, CDCl3): d = 1.68 (d, J = 7.6 Hz, 3 H, CH3CH),
3.38 (s, 3 H, CH2OCH3), 3.84 and 3.92 (AB-system, JA,B = 15.0 Hz,
2 H, CH2OCH3), 5.98 (quint, J = 7.6 Hz, 1 H, CHNH), 6.80 (br s, 1
H, CONH), 7.48 (m, 4 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.85 (d, J = 8.0
Hz, 1 H), 8.11 (d, J = 8 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 30.3, 34.0, 53.9, 59.1, 72.0,
124.0, 124.8, 126.8, 128.0, 143.0, 143.4, 169.3.
13C NMR (125 MHz, CDCl3): d = 21.0, 43.9, 59.0, 71.9, 122.5,
123.4, 125.2, 125.8, 126.5, 128.3, 128.8, 131.1, 133.9, 138.2, 168.3.
N-[(4R)-3,4-Dihydro-2H-1-benzothiopyran-4-yl]-2-methoxy-
acetamide [(R)-3f]
Following TP1, the amide (R)-3f was obtained as colorless crystals;
chiral HPLC: tR = 6.91 min (R), 7.84 min (S); mp 117 °C;
[a]D25 +130.2 (c = 2.0, MeOH).
2-Methoxy-N-[(1R)-1-(4-methylphenyl)ethyl]acetamide
[(R)-3k]
Following TP1, the amide (R)-3k was obtained as colorless crystals;
chiral HPLC: tR = 4.35 min (R), 5.01 min (S); mp 54 °C; [a]D25 +124
(c = 2.0, MeOH).
1H NMR (500 MHz, CDCl3): d = 2.05–2.18 (m, 1 H), 2.30–2.42 (m,
1 H), 2.90–3.15 (m, 2 H), 3.35 (s, 3 H, CH2OCH3), 3.90 and 3.92
1H NMR (500 MHz, CDCl3): d = 1.50 (d, J = 7.4 Hz, 3 H, CH3CH),
2.33 (s, 3 H, ArCH3), 3.37 (s, 3 H, CH2OCH3), 3.84 and 3.90 (AB-
Synthesis 2008, No. 14, 2283–2287 © Thieme Stuttgart · New York

PAPER
Enzyme-Catalyzed Kinetic Resolution of Amines
2287
system, JA,B = 15.0 Hz, 2 H, CH2OCH3), 5.15 (quint, J = 7.4 Hz, 1
H, CHNH), 6.76 (br s, 1 H, CONH), 7.14 and 7.20 (AA¢BB¢-system,
J = 8 Hz, 4 H).
13C NMR (125 MHz, CDCl3): d = 21.0, 21.8, 47.8, 59.1, 72.0,
126.1, 129.3, 137.0, 140.0, 168.4.
(2) (a) Zaks, A.; Klibanov, A. M. Proc. Natl. Acad. Sci. U.S.A.
1985, 82, 3192. (b) Kitaguchi, H.; Fitzpatrick, P. A.; Huber,
J. E.; Klibanov, A. M. J. Am. Chem. Soc. 1989, 111, 3094.
(c) Klibanov, A. M. Acc. Chem. Res. 1990, 23, 114.
(3) Guthman, A. L.; Meyer, E.; Kalerin, E.; Polyak, F.; Sterling,
J. Biotechnol. Bioeng. 1992, 40, 760.
(4) (a) Balkenhohl, F.; Ditrich, K.; Hauer, B.; Ladner, W.
J. Prakt. Chem./Chem.-Ztg. 1997, 339, 381.
Hydrolysis of 2-Methoxy-N-[(1R)-1-phenylethyl]acetamide
[(R)-3a]; (R)-1-Phenylethylamine [(R)-1a]; Typical Procedure 2
(TP 2)
(b) Balkenhohl, F.; Hauer, B.; Ladner, W.; Pressler, U.;
Nübling, C. BASF AG, WO 95/08636, 1993; Chem. Abstr.
1995, 122, 289035.
A mixture of (R)-3a (500 g, 4.13 mol, ee: 99%) and triethanolamine
(250 g) was heated to 115 °C. Aq 50% NaOH (500 g, 6.25 mol) was
added and the biphasic mixture was stirred vigorously at 120 °C.
After 6 h, GC indicated complete conversion of the starting amide
(R)-3a. The mixture was diluted by the addition of H2O (300 mL)
and cooled to r.t. Toluene (1 L) was introduced and the phases were
separated. The aqueous phase was extracted with toluene (2 × 200
mL), the combined organic extracts were washed with H2O (50 mL)
and subjected to distillation. Upon removal of a H2O/toluene-azeo-
trope (bp 85 °C) and toluene, the R-amine (R)-1a was collected at
64 °C/10 Torr as a colorless liquid (465 g, 93%); chiral HPLC indi-
cated an optical purity of 99% ee.
(5) (a) Nechab, M.; Azzi, N.; Vanthuyne, N.; Bertrand, M.;
Gastaldi, S.; Gil, G. J. Org. Chem. 2007, 72, 6918.
(b) Cammenberg, M.; Hult, K.; Park, S. ChemBioChem
2006, 7, 1745.
(6) Ditrich, K.; Balkenhohl, F.; Ladner, W. BASF AG, DE
19534208, 1995; Chem. Abstr. 1997, 126, 277259.
(7) (a) Reeve, C. D. Zeneca Ltd., UK, WO 9931264, 1999;
Chem. Abstr. 1999, 131, 43668. (b) Reeve, C. D.; Holt, R.
A.; Rigby, S. R.; Hazell, K. Chim. Oggi 2001, 19 (7/8), 31.
(c) Veld, M. A. J.; Hult, K.; Palmans, A. R. A.; Meijer, E. W.
Eur. J. Org. Chem. 2007, 5416.
(8) (a) Gill, I. I.; Das, J.; Patel, R. N. Tetrahedron: Asymmetry
2007, 18, 1330. (b) Iglesias, L. E.; Sanchez, V. M.;
Rebolledo, F.; Gotor, V. Tetrahedron: Asymmetry 1997, 8,
1330. For reviews see: (c) Gotor-Fernandez, V.; Busto, E.;
Gotor, V. Adv. Synth. Catal. 2006, 348, 797.
Acknowledgment
The important contributions of F. Balkenhohl, B. Hauer and W.
Ladner, and the skillful work of B. Böhl, A. Gering, E. Magin and
U. Reuther are gratefully acknowledged.
(d) van Rantwijk, F.; Sheldon, R. A. Tetrahedron 2004, 60,
501.
(9) (a) Amoroso, R.; Cardillo, G.; Tomasini, C. Tetrahedron
Lett. 1990, 31, 6413. (b) Rao, A. V. R.; Gurjar, M. K.;
Lakshmipathi, P.; Reddy, M. M.; Nagarajan, M.; Sarma, B.
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References
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Synthesis 2008, No. 14, 2283–2287 © Thieme Stuttgart · New York