Development of dynamic kinetic resolution on large scale for (±)-1-phenylethylamine

Article abstract of DOI:10.3762/bjoc.6.97

Candida antarctica lipase B (CALB) and racemization catalyst 4 were combined in the dynamic kinetic resolution (DKR) of (±)-1- phenylethylamine (1). Several reaction parameters have been investigated to modify the method for application on multigram scale

Full text of DOI:10.3762/bjoc.6.97

Development of dynamic kinetic resolution
on large scale for (±)-1-phenylethylamine
Lisa K. Thalén and Jan-E. Bäckvall*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, 823–829.
Stockholm University, Department of Organic Chemistry, Arrhenius
Laboratory SE-106 91, Stockholm, Sweden
doi:10.3762/bjoc.6.97
Received: 02 June 2010
Email:
Accepted: 27 August 2010
Published: 13 September 2010
Jan-E. Bäckvall* - jeb@organ.su.se
* Corresponding author
Editor-in-Chief: J. Clayden
Keywords:
© 2010 Thalén and Bäckvall; licensee Beilstein-Institut.
License and terms: see end of document.
dynamic kinetic resolution; kinetic resolution; racemization; Shvo;
Candida antartica lipase B
Abstract
Candida antarctica lipase B (CALB) and racemization catalyst 4 were combined in the dynamic kinetic resolution (DKR) of (±)-1-
phenylethylamine (1). Several reaction parameters have been investigated to modify the method for application on multigram scale.
A comparison of isopropyl acetate and alkyl methoxyacetates as acyl donors was carried out. It was found that lower catalyst load-
ings could be used to obtain (R)-2-methoxy-N-(1-phenylethyl)acetamide (3) in good yield and high ee when alkyl methoxyacetates
were used as acyl donors compared to when isopropyl acetate was used as the acyl donor. The catalyst loading could be decreased
to 1.25 mol % Ru-catalyst 4 and 10 mg CALB per mmol 1 when alkyl methoxyacetates were used as the acyl donor.
Introduction
Chiral amines are important building blocks in the synthesis of achieved and that the remaining unreacted starting material
many pharmaceuticals, fragrances, and agricultural products, must be removed from the product mixture. However, by
and it is therefore important to develop methods for their racemizing the slower reacting enantiomer in situ, in a process
preparation that are applicable on multigram scale. They can be known as dynamic kinetic resolution (DKR) [11], a theoretical
prepared by resolution of amines, hydrogenation of prochiral yield of 100% can be achieved.
imines and enamines [1,2], alkylation of prochiral imines [3],
We have previously developed a highly efficient protocol for
the DKR of primary amines using Candida antarctica lipase B
(CALB) as the enzyme and 4 as the racemization catalyst (See
Scheme 1 for an example of the previously developed protocol
with isopropyl acetate as the acyl donor providing 2 as the
aminohydroxylation of alkenes [4], transamination of prochiral
ketones [5-7], and reductive amination of prochiral ketones [8].
Of these methods kinetic resolution using enzymes is often
favored due to its simplicity [9,10]. The main disadvantages of
kinetic resolution are that only a maximum yield of 50% can be
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Beilstein J. Org. Chem. 2010, 6, 823–829.
Scheme 1: Dynamic kinetic resolution of (rac)-1-phenylethylamine.
amide product) [12,13]. The Jacobs–De Vos group showed that Results and Discussion
palladium on an alkaline earth support in combination with an The previously reported [12,13] protocol for application of
enzyme can be used for practical DKR of benzylic amines [14- DKR on a 0.5 mmol scale was evaluated with the aim of devel-
16], while the Kim and Park group have combined a palladium oping a system that could be utilized on a larger scale
nanocatalyst with an enzyme for the DKR of amines [17]. Add- (10–50 mmol). The previously reported conditions for applica-
itional procedures for the chemoenzymatic DKR of amines in tion of DKR to 1 (Scheme 1) were as follows: 4 mol % racem-
which various racemization methods are combined with enzy- ization catalyst 4, 20 mg CALB, 6.8 equivalents isopropyl
matic resolution have been established [18-23]. We herein acetate (5) (Figure 1), and 20 mg sodium carbonate in 8 mL of
report the evaluation of our system for application on multi- toluene at 90 °C (Table 1, entry 1). These conditions were used
gram scale.
as a starting point and the reaction parameters were changed
Figure 1: Acyl donors and hydrogen donor used in DKR.
Table 1: Investigation of individual DKR parameters.a
Entry
4 (mol %)
5 (equiv)
Conc (M)
ee (%)
Yieldb (%)
1
2
3
4
5
6
7
4
4
4
3
2
1
4
6.8
3.4
1.5
6.8
6.8
6.8
6.8
0.06
0.06
0.06
0.06
0.06
0.06
0.13c
98
98
99
98
98
97
98
90
67
51
84
81
72
93
aConditions: 0.50 mmol of 1, Ru-catalyst 4, 20 mg of CALB, 20 mg of Na2CO3, isopropyl acetate (5), 8 mL of toluene, 90 °C, 72 h; bdetermined by GC
analysis; c4 mL of toluene.
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Beilstein J. Org. Chem. 2010, 6, 823–829.
individually and then concurrently in a continuing attempt to indicating that the racemization was slower than the transesteri-
find the ideal conditions for a large scale reaction. The reaction fication at these catalyst loadings. An increase in the selectivity
parameters evaluated included catalyst loading, concentration of was observed when the amount of acyl donor was decreased,
the reaction, and the quantity of acyl donor used.
however this also coincided with deceleration of the reaction
rate (Table 2, entries 4–6). The concentration of the reaction
Changes of individual reaction parameters were examined first. was increased to 2.5 M, resulting in a faster yet less selective
It was found that a marked decrease in the reaction rate was reaction (Table 2, entry 7). In a final attempt to obtain 2 in high
observed when the excess of acyl donor 5 was decreased from yield and ee, the Ru-catalyst loading was again increased to
6.8 equiv to 1.5 equiv (Table 1, entries 1–3). It was possible to 2 mol %. Amide 2 was obtained in 64% isolated yield with
decrease the Ru-catalyst loading to 1 mol % and still obtain 2 in 97% ee (Table 2, entry 8). Further attempts to find appropriate
72% yield with 97% ee (Table 1, entry 6). The reaction was conditions at high concentrations (1–3 M) resulted in signifi-
then concentrated to see if there was an effect on the rate of the cant byproduct formation.
reaction and on byproduct formation. It was found that the reac-
tion was slightly accelerated and only small amounts of Since it proved difficult to obtain both a high enantiomeric
byproduct were observed when the reaction mixture was excess value and a high yield at a reduced catalytic loading, and
concentrated from 0.06 M to 0.13 M (Table 1, entries 1 and 7, that the amount of acyl donor used played a key role in the
respectively).
outcome of the results, another acyl donor was tested.
The parameters were then changed concurrently to find a A 200-fold acceleration in the kinetic resolution of 1 has been
balance between the rate of acylation and racemization at lower observed with methyl methoxyacetate 6 (Figure 1) as the acyl
catalyst loadings. When the Ru-catalyst loading was decreased donor instead of methyl butyrate [24]. However, it is also
to 2 mol % and the reaction concentration was increased to known that an uncatalyzed chemical acylation of the substrate
0.25 M, the amide 2 could be obtained in 77% yield with occurs at elevated temperatures when using acyl donors of this
99% ee (Table 2, entry 1). When the Ru-catalyst loading was type in the DKR of primary amines. This has been overcome by
further decreased to 1 mol%, and the amount of CALB or acyl initially adding one equivalent of the acyl donor followed by a
donor was increased, a decrease in the enantioselectivity of the later addition of 0.1 equiv of the acyl donor to allow the reac-
reaction was observed (Table 2, entries 2 and 3, respectively) tion to go to completion [22].
Table 2: Investigation of concurrent changes of DKR parameters with 5 as acyl donor.a
CALB/Na2CO3
(mg/mmol 1)
Entry
1 (mmol)
4 (mol %)
5 (equiv)
Conc (M)
ee (%)
Yieldb (%)
1
2
0.5
2.5
5
2
1
1
1
1
1
1
2
6.8
7
0.25
0.25
0.25
0.20
0.25
0.50
2.5
40/40
80/60
40/40
10/20
40/60
40/60
40/40
30/30
99
90
89
98
>99
99
93
97
77
86 (73)
76 (72)
53
3
10
3
4c
5
1
2.5
2.5
5
1.5
1.15
3
40
6
55d
7
(61)e
(64)f
8
10
1.5
2.9
aConditions: 40 mg of CALB per mmol 1, Ru-catalyst 4, isopropyl acetate (5), toluene, 90 °C, 72 h; bdetermined by GC, isolated yields in paranthesis;
c2.5 mmol of hydrogen donor 9 (Figure 1); d18% byproduct formation; e6% byproduct formation; f21% byproduct formation.
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Beilstein J. Org. Chem. 2010, 6, 823–829.
Table 3: Investigation of concurrent changes of DKR parameters with 7 as acyl donor.a
Ethyl methoxyacetate (7) (equiv)
Hydrogen donor 9 CALB/Na2CO3
Entry
ee (%)
Yield (%)b
(mmol)
(mg)
0 h
24 h
48 h
1
2
1.5
1
—
0.5
—
—
—
—
—
0.2
—
—
—
2.5
2.5
2.5
1
20/40
20/40
10/20
20/40
20/40
20/40
10/20
10/20
10/20
83
86
90
74
97
96
95
97
94
99
79
97
88
87
83
70
91
73
3
1
0.5
4d
5c
6c
7
1
0.5
1
0.1
1
1
—
1
1
0.15
0.15
0.35
1.25
2.5
2.5
8e
9
1
0.75
aConditions: 1 mmol of 1, 1 mol % of 4, 10 mg of CALB, 20 mg of Na2CO3, ethyl methoxyacetate (7), 2.5 mmol of hydrogen donor 9, 5 mL of toluene,
90 °C, 72 h; bdetermined by GC; c10 mL of toluene; d2 mL of toluene; e100 °C.
The addition of 1.5 equiv of ethyl methoxyacetate 7 (Figure 1) entry 6). The addition of 1 equiv 7 was then compared to the
in one portion in the application of DKR to 1 with 1 mol % 4 addition of 0.75 equiv 7 at the beginning of the reaction. A
and 20 mg CALB at 90 °C was tested. As expected, the product sample was taken after 24 hours and enantiomeric excesses of
amide 3 was obtained with a low ee (83%) after 72 hours 97% and 99%, respectively were obtained for 3. Subsequently,
(Table 3, entry 1). The consecutive addition of 7 in different 0.15 equiv and 0.35 equiv 7, respectively were added. After a
ratios at 0, 24, and 48 hours was then tested. The amount of reaction time of 72 hours, 3 was obtained in 95% and 94% ee,
hydrogen donor 9 (Figure 1), CALB, sodium carbonate and the respectively (Table 3, entry 7 and 9). The higher ee observed
concentration of the reaction was varied concurrently. Alcohol after 24 h indicates that a smaller portionwise addition was ad-
9 was added as a hydrogen donor to suppress byproduct forma- vantageous. Furthermore, when the reaction temperature was
tion [25]. Some general trends could be observed. The concen- increased to 100 °C both the enantiomeric excess and the yield
tration of the reaction had a large impact on the rate of uncat- improved (Table 3, entry 8).
alyzed acylation. This could be seen in the decrease of enan-
tiomeric excess observed when going from a concentration of Additionally, methoxyacetate type acyl donors 6–8, which
0.2 M to 0.5 M (Table 3, entries 2 and 4). Also, a decrease in differ in the leaving group, were investigated. When acyl donor
the amount of enzyme to compensate for the decrease in loading 6 was used in the DKR of 1, amide 3 was obtained with the
of racemization catalyst gave both a better enantiomeric excess highest ee (97%) and in 89% yield (Table 4, entry 1). However,
value and a better yield (Table 3, entries 2–3). Addition of when acyl donor 8 was used in the DKR of 1, amide 3 was
1 equiv acyl donor 7, followed by addition of 0.5 equiv after obtained with a lower ee (88%) but in higher yield (97%,
24 hours led to unsatisfactory ee values (Table 3, entry 2–4). By Table 4, entry 3). When 7 was employed as acyl donor, 3 was
only adding 0.1 equiv 7 after 24 hours, an enantiomeric excess obtained in 91% yield with an ee of 95%. Thus, an increase in
of 97% could be obtained (Table 3, entry 5).
the enantiomeric excess of 3 corresponded with a decrease in
the size of the leaving group (i.e. 6 > 7 > 8), and an increase in
The substrate amine was no longer racemic after 24 hours, indi- the yield corresponded with an increase in the size of the
cating that the racemization was the slower of the two reactions. leaving group (i.e. 6 < 7 < 8, Table 4, entries 1–3).
In order to allow the racemization more time, acyl donor 7 was
added after 48 hours instead of after 24 hours; however, this did Acyl donors 6 and 7 were both evaluated in the DKR of 1 on
not improve the overall outcome of the reaction (Table 3, 10 mmol scale. First, a two portion addition of the acyl donor in
826

Beilstein J. Org. Chem. 2010, 6, 823–829.
Table 4: Acyl donor screening.a
Entry
1
Acyl donor
R
Time (h)
ee (%)
Yieldb (%)
6
OMe
24
72
24
72
24
72
99
97
98
95
94
88
70
89
73
96
74
97
2
3
7
8
OEt
O-iPr
aConditions: 1 mmol of 1, 1 mol % of 4, 10 mg of CALB, 20 mg of Na2CO3, 1 mmol of acyl donor (0.15 mmol added after 24 h), 2.5 mmol of hydrogen
donor 9, 5 mL of toluene, 90 °C, 72 h; bdetermined by GC.
0.75 equiv and 0.35 equiv aliquots was tested. Under these (Table 5, entry 4). A two portion addition of acyl donor 6 and
conditions, use of acyl donor 6, provided amide 3 with a CALB provided 3 in 83% isolated yield with an ee of 98%
slightly higher ee than with the corresponding addition of acyl (Table 5, entry 5).
donor 7 (Table 5, entries 1 and 3). Also, a three portion add-
ition of acyl donor 7 provided the product 3 with a higher ee Conclusion
than from a two portion addition (Table 5, entries 1–2). Since a The application of DKR to (±)-1-phenylethylamine (1) has been
slightly higher ee was obtained with acyl donor 6, it was used in investigated for use on multigram scale. A comparison of iso-
the DKR of 1 on 45 mmol scale. When using a three portion propyl acetate and alkyl methoxyacetates as the acyl donor was
addition of acyl donor 6 and a three portion addition of CALB, carried out. It was found that lower catalyst loadings could be
amide 3 was obtained with 98% ee and in 68% isolated yield used to obtain (R)-2-methoxy-N-(1-phenylethyl)acetamide (3)
Table 5: Scale up of dynamic kinetic resolution.a
Acyl donor (equiv)
Entry
1 (mmol)
Acyl donor
8 (equiv)
ee (%)
Yield (%)b
0 h
24 h
48 h
1
2
10
10
10
45
45
7
7
6
6
6
0.75
0.4
0.35
0.35
0.35
0.35
0.35
—
0.35
—
2.5
2.5
97
99
98
98
98
93 (90)
91
3
0.75
0.4
1.25
1.25
1.25
(74)
(68)
(83)
4c
5d
0.35
—
0.75
aConditions: 1, 1.25 mol % of 4, 100 mg of CALB, 200 mg of Na2CO3, acyl donor, hydrogen donor 9, 50 mL of toluene, 100 °C, 72 h; bdetermined by
GC, isolated yield in parenthesis; c225 mg of CALB, addition of 113 mg of CALB after 24 and 48 h; d340 mg of CALB, addition of 110 mg of CALB
after 24 h.
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Beilstein J. Org. Chem. 2010, 6, 823–829.
in good yield and with high ee when alkyl methoxyacetates 126.3, 72.1, 59.3, 48.1, 22.0. Chiral GC-analysis (CP-Chirasil-
were used as the acyl donor than when isopropyl acetate was DEX CB column (25 m Ø × 0.32 mm)): Injector 250 °C
used as the acyl donor. The catalyst loading could be decreased Program: 100 °C / 5 min / 155 °C / 3 °C min−1, 5 min / 200°C /
to 1.25 mol % Ru-catalyst 4 and 10 mg CALB per mmol 1 20 °C min−1, 5 min. tS= 20.44 min, tR= 21.00 min. [α]27D =
when alkyl methoxyacetates were used as the acyl donor. Appli- + 91.3 (c = 1.0, CDCl3).
cation of DKR with these catalyst loadings and either ethyl
methoxyacetate (7) or methyl methoxyacetate (6) as the acyl 10 mmol scale: (R)-2-methoxy-N-(1-phenylethyl)acetamide, 3.
donor provided (R)-2-methoxy-N-(1-phenylethyl)acetamide (3) A flame dried 250 mL Schlenk tube was charged with
in 90% yield and with 97% ee (10 mmol scale) and 83% yield Novozym 435 (100 mg), Na2CO3 (200 mg), and Ru-complex 4
with 98% ee (45 mmol scale), respectively.
(166 mg, 0.125 mmol). The vessel was evacuated and back-
filled with argon three times. Toluene (50 mL), (±)-1-
phenylethylamine (1, 1.3 mL, 10 mmol), 2,4-dimethyl-3-
pentanol (3.5 mL, 25 mmol), and ethyl methoxyacetate (1.6 mL,
Experimental
General
Unless otherwise noted, all manipulations were performed 7.5 mmol) were added subsequently via syringe. The mixture
under an argon atmosphere. Toluene was dried with a VAC was stirred at 100 °C. After 24 h the reaction vessel was
solvent purifier. Flash chromatography was carried out on 60 Å allowed to cool for 10 min at rt. Ethyl methoxyacetate
(35–70 µm) silica gel. 1H and 13C NMR spectra were recorded (3.5 mmol, 410 μL) was added. The reaction mixture was then
at 400 MHz and at 100 MHz, respectively. Chemical shifts (δ) stirred at 100 °C. After a reaction time of 72 h, the reaction was
are reported in ppm, using the residual solvent peaks in CDCl3 cooled to rt and the solids were removed by filtration through a
(δH 7.26 and δC 77.00) as internal standards, and coupling sintered glass funnel. The solvent and other volatiles were
constants (J) are given in Hz. The enantiomeric excess was subsequently removed in vacuo. The crude product was puri-
determined by analytical GC employing a CP-Chirasil-DEX CB fied by column chromatography (DCM:MeOH:NH3, 98:2:0.1 to
column (25 m Ø × 0.32 mm). Racemic compounds were used as 90:10:0.1) to afford 1.73 g (90%) of (R)-2-methoxy-N-(1-
references.
phenylethyl)acetamide (3) in 97% ee.
Dynamic Kinetic Resolution
Acknowledgements
45 mmol scale: (R)-2-methoxy-N-(1-phenylethyl)acetamide, 3. Financial support from the European FP7 network INTENANT
A flame dried 1 L two-necked round-bottomed flask was (“Integrated synthesis and purification of single enantiomers”)
charged with Novozym 435 (340 mg), Na2CO3 (900 mg, is gratefully acknowledged. Christine Rösch (née Hoben) is
8.5 mmol), and Ru-complex 4 (745 mg, 0.56 mmol). The vessel gratefully acknowledged for her contribution to some of the
was evacuated and backfilled with argon three times. Toluene initial studies with isopropyl acetate as the acyl donor.
(225 mL), (±)-1-phenylethylamine (1, 5.8 mL, 45 mmol), 2,4- Novozymes is gratefully acknowledged for their donation of
dimethyl-3-pentanol (8 mL, 57 mmol), and methyl methoxy- Novozym 435.
acetate (3.4 mL, 34 mmol) were added subsequently via
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