Highly enantioselective enzymatic resolution of aromatic β-amino acid amides with Pd-catalyzed racemization

Article abstract of DOI:10.1016/j.tetasy.2013.09.022

The kinetic resolution of an aromatic β-amino acid amide 3a-d via N-acylation was explored with two lipases, Candida antarctica lipase A (CALA) and Pseudomonas stutzeri lipase (PSL). The PSL-catalyzed resolution proceeded with excellent enantioselectivity

Full text of DOI:10.1016/j.tetasy.2013.09.022

Tetrahedron: Asymmetry 24 (2013) 1449–1452
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly enantioselective enzymatic resolution of aromatic b-amino
acid amides with Pd-catalyzed racemization
⇑
⇑
Eunjeong Choi, Yunwoong Kim, Yangsoo Ahn, Jaiwook Park , Mahn-Joo Kim
Department of Chemistry, Pohang University of Science and Technology, San-31, Hyojadong, Pohang 790-784, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 August 2013
Accepted 18 September 2013
The kinetic resolution of an aromatic b-amino acid amide 3a–d via N-acylation was explored with two
lipases, Candida antarctica lipase A (CALA) and Pseudomonas stutzeri lipase (PSL). The PSL-catalyzed
resolution proceeded with excellent enantioselectivity (E = >400) to give both acylated products and
unreacted substrates in enantiopure forms. Three additional aromatic b-amino acid amides 3b–d were
also resolved by PSL with a high level of enantioselectivity (E = >200). The PSL-catalyzed resolution of
3a was coupled with a Pd-catalyzed racemization to obtain enantiopure N-acylated product (R)-4a
(>99% ee) in high yield (90%).
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
b-Amino acids and their simple derivatives are an interesting
class of chiral molecules due to their unique pharmacological
effects and their utility as building units for biologically active pep-
tidomimetics and natural products.1–4 For example, taxol, a power-
ful anticancer agent, has b-phenylisoserine as its side chain and
b-lactam antibiotics have a b-alanine unit as its four-membered
ring structure. A number of chemical methods are available for
the enantioselective synthesis of b-amino acids and their deriva-
Four different aromatic b-amino acid amides 3a–d were pre-
pared from the corresponding acids 1a–d via two steps: (i) the
esterification of 1a–d with methanol in the presence of thionyl
chloride; and (ii) the reaction of the resulting amino esters 2a–d
with ammonium hydroxide (Scheme 1). The two-step synthesis
proceeded smoothly with satisfactory yields.
The resolution of b-amino acid amides was explored first with
3a using Candida antarctica lipase A (CALA), which had been previ-
ously reported to show a good enantioselectivity (E = 75) in the
N-acylation of a b-amino acid ester.7b In a typical procedure, the
CALA-mediated resolution of 3a was carried out with a solution
containing 3a (0.3 mmol), vacuum-dried CALA (300 mg), and tri-
fluoroethyl butanoate (2 equiv) in dry THF at room temperature.
This reaction proceeded rather slowly and gave a modest resolu-
tion (Scheme 2; Table 1, entry 1).
We next examined PSL as an alternative enzyme for the resolu-
tion of 3a. In a typical procedure, the PSL-mediated resolution of 3a
was performed with a solution containing 3a (2 mmol), vacuum-
dried PSL (400 mg), and trifluoroethyl butanoate (2 equiv) in dry
THF at room temperature. The PSL-catalyzed resolution provided
a perfect resolution at a synthetically useful rate (entry 2). Both
the remaining substrate and acylated product were obtained in
enantiopure forms (>99% ee), thus indicating that PSL is highly
enantioselective (E = >400) relative to CALA. A similar level of high
enantioselectivity (E = >200) was also observed in the resolutions
of 3b–d (entries 3–5). These results suggest that PSL is a perfect
enzyme for the efficient resolution of aromatic b-amino acid
amides.11
tives, including asymmetric additions of amines to a,b-unsaturated
esters,5a asymmetric aldol-type reactions of imines,5b synthesis via
enantiomerically pure dihydropyrimidines,5c and the ring opening
of b-lactams.5d Enzymatic resolutions also provide useful routes to
non-racemic b-amino acids.6 In most of them, the substrates
resolved were b-amino acid esters and N-acyl-b-amino acid esters.
Their resolution was achieved via ester hydrolysis, transesterifica-
tion, N-acylation, or deacylation.7 To the best of our knowledge,
few studies have been carried out on the resolution of b-amino acid
amides. As part of our continuing efforts toward the development
of procedures for the chemoenzymatic dynamic kinetic resolution
(DKR) of amines8 and amino acids,9 we have explored the enzy-
matic resolution of b-amino acid amides. Herein we report that
aromatic b-amino acid amides were efficiently resolved by
Pseudomonas stutzeri lipase (PSL; trade name, lipase TL) to give
both unreacted substrates and N-acylated products in highly-
enantioenriched forms.10
It was found that the signs of the specific rotations for the PSL-
resolved products were opposite to those for the CALA-resolved
⇑
Corresponding authors. Tel.: +82 54 279 2112; fax: +82 54 279 0654 (M.-J.K.).
E-mail address: mjkim@postech.ac.kr (M.-J. Kim).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.09.022

1450
E. Choi et al. / Tetrahedron: Asymmetry 24 (2013) 1449–1452
NH3+Cl-
NH2
NH2
NH4OH
rt
SOCl2
CO2H
CO2Me
CONH2
MeOH
70° C
R
R
R
3a d
-
2a d
-
1a R = H, 1b R = F
1c R = Me, 1d R = OMe
Scheme 1. Synthesis of b-amino acid amides.
NHCOPr
NH2
CONH2
CONH2
CALA
+
PrCO2CH2CF3
(S)-4a
3a
(R)-
NH2
[α]D25 = +25
[α]D25 = -30
CONH2
NHCOPr
NH2
3a
CONH2
CONH2
PSL
+
PrCO2CH2CF3
3a
4a
(S)-
(R)-
[α]D25 = -51
[α]D25 = +59
Scheme 2. Lipase-catalyzed N-acylation of a b-amino acid amide.
products (Scheme 2), thus indicating that the stereopreference of
PSL was opposite to that of CALA. The enantioselectivity of PSL in
the resolution of 3a should be (R) because CALA has been known
to be (S)-selective in the resolution of the corresponding b-amino
acid ester.7b The (R)-selectivity of PSL is in agreement with the
empirical rule proposed by Kazlauskas et al. for predicting the
enantioselectivity of a lipase (Fig. 1).12,13 The enantiocomplemen-
tary relationship between PSL and CALA was also previously
observed in the resolution of 1,2-diphenylethanamine and 1,
2-diphenylethanol.14,15
(>99% ee) with 90% isolated yield. Recently, Bäckvall et al.
reported the (S)-selective DKR of an ester analogue of 3a by the
combination of CALA and a Ru-based racemization catalyst.18 This
and our process thus constitute as a pair of enantiocomplementa-
ry procedures for the synthesis of optically active b-amino acids
and their simple derivatives.19
Table 1
Lipase-catalyzed N-acylation of b-amino acid amides
The perfect enantioselectivity of PSL in the kinetic resolution
of 3a encouraged us to explore a high-yielding synthesis of enan-
tiopure 3a via a DKR.16 PSL as the resolution catalyst was com-
bined with Pd/AlO(OH),8c a Pd nanocatalyst entrapped in an
AlO(OH) matrix, as the racemization catalyst to perform the
DKR of 3a. Since the optimum temperature for the Pd-catalyzed
racemization of 3a was 70 °C, the first DKR reaction was carried
out at the same temperature but gave poor results because PSL
lost its activity quickly at the elevated temperature.17 The DKR
reactions at lower temperatures (40–60 °C) were also unsuccess-
ful due to the low thermal stability of PSL and the slow Pd-
catalyzed racemization. We next carried out the PSL-catalyzed
resolution and the Pd-catalyzed racemization alternatively at
two different temperatures in one pot. The enzymatic resolution
was first performed at room temperature for 12 h and then the
Pd-catalyzed racemization at 70 °C for 12 h (Scheme 3). The
sequential resolution–racemization process was repeated once
with the addition of a portion of fresh enzyme. Finally, another
portion of fresh enzyme was added to achieve only the enzymatic
resolution at room temperature for 12 h. Overall, the whole pro-
cess took 60 h with a total of 800 mg of enzyme/mmol of sub-
strate and 5 mol % of Pd nanocatalyst to give enantiopure (R)-4a
Entry
Substrate
Lipase
Time (h)
ees
eep
c
E
1
2
3
4
5
3a
3a
3b
3c
3d
CALAa
PSLb
PSLb
PSLb
PSLb
37
12
12
4
62
>99
>99
96
76
>99c
96c
45
50
51
49
47
14
>400
>200
>200
>200
99c
7
88
>99c
a
b
c
1 g enzyme/mmol of substrate.
0.2 g enzyme/mmol of substrate.
The absolute configuration of the product is (R) according to the stereospeci-
ficity of PSL described in Figure 1.
X
L
M
X = OH or NH2
Figure 1. The enantiomer shown reacts more rapidly than the other in the lipase-
catalyzed acylation if a secondary alcohol or a primary amine as its isostere has a
medium-sized (M) and a relatively larger substituent (L) at the stereogenic center.

E. Choi et al. / Tetrahedron: Asymmetry 24 (2013) 1449–1452
1451
O
PSL
NH2
O
NH
O
NH2
O
C3H7CO2CH2CF3
+
NH2
NH2
NH2
THF, 12 h, rt
3a
(S)-3a
4a
(R)-
Pd/AlO(OH), 12 h, 70 °C
Scheme 3. PSL-catalyzed resolution of b-phenylalanine amide coupled with Pd-catalyzed racemization.
4.3. Kinetic resolution of 3a–d with PSL
3. Conclusion
b-Amino acid amide 3a (328.4 mg, 2 mmol) was added to dry
THF (20 mL, 0.1 M) with vacuum-dried PSL (400 mg, 200 mg/
mmol). 2,2,2-Trifluoroethyl butanoate (608 lL, 2 equiv) was then
We have demonstrated that aromatic b-amino acid amides are
accepted by PSL with high enantioselectivity, thus allowing for
their efficient kinetic resolution. The PSL-catalyzed resolution can
be coupled with a Pd-catalyzed racemization to convert racemic
b-amino acid amides completely into single enantiomeric
products. This process thus provides a useful alternative for the
synthesis of enantioenriched b-amino acids and their derivatives.
added and the mixture was stirred at rt. After 12 h, the reaction
was stopped by filtering off the enzyme. The solvent was evapo-
rated off and the residue was purified by column chromatography
(methylene chloride/methanol = 15/1) to afford (R)-4a (225 mg,
0.96 mmol, 48% yield) and (S)-3a (90 mg, 0.56 mmol, 28% yield).
Compound (S)-3a was acetylated by treatment with acetic anhy-
dride to (S)-4a for the determination of its ee value by HPLC:
(R,R)-Whelk-O1, n-hexane/2-propanol = 80/20, flow rate = 1.5 mL/
min, UV = 217 nm, (S)-form: 7.9 min., (R)-form; 13.7 min. (S)-3a:
4. Experimental
4.1. Synthesis of aromatic b-amino acid amides 3a–d
mp 105–107 °C; ½a 25
¼ ꢁ51 (c 0.5, THF) >99% ee. (R)-4a: mp
ꢀ
¼Dþ59 (c 0.1, THF) >99% ee; 1H NMR
The procedure for the synthesis of 3a is described as a represen-
tative one. Thionyl chloride (1.45 mL, 20 mmol) was dropwise
added to a mixture of 3-amino-3-phenylpropanoic acid (1.65 g,
10 mmol) and dry methanol (15 mL) in a 2-neck round bottom
flask connected with a condenser. After being refluxed overnight
at 70 °C, the mixture was cooled to ambient temperature, and
methanol was removed by evaporation. The salt precipitate was
washed with ethyl acetate and then dissolved in aqueous ammo-
nium hydroxide (20 mL). The resulting mixture was stirred at room
temperature overnight and extracted with CH2Cl2. The organic
layer was dried over Na2SO4 and evaporated under reduced pres-
sure to obtain 3a as a white solid (1.195 g, 7.28 mmol, 73%): mp
99–101 °C (lit.20 mp 110.1 °C); the data of 1H and 13C NMR were
in good agreement with the literature data.20 Compound 3b: mp
118–122 °C; 1H NMR (300 MHz, CDCl3, ppm): d 1.8 (2H, br s,
NH2), 2.51–2.53 (2H, m, CH2CH), 4.36–4.40 (1H, m, CHNH2), 5.7
(1H, br s, CONH2), 6.7 (1H, br s, CONH2), 7.00–7.07 (2H, m, C6H4),
7.27–7.34 (2H, m, C6H4). 13C NMR (75 MHz, CDCl3, ppm): d 45.1,
52.2, 115.6(d), 127.5(d), 140.7(d), 160.4, 163.7, 173.5. 3c: mp
123–126 °C; the data of 1H and 13C NMR were in good agreement
with the literature data.20 3d: mp 102–105 °C; the data of 1H and
13C NMR were in good agreement with the literature data.20
222–225 °C;
½
a 2D5
ꢀ
(300 MHz, CDCl3, ppm): d 0.95 (3H, t, J = 7.37 Hz, CH2CH2CH3),
1.67 (2H, m, CH2CH2CH3), 2.23 (2H, t, J = 7.49 Hz, CH2CH2CH3),
2.78 (2H, m, CHCH2CO), 5.2 and 5.7 (1H each, br s, CONH2),
5.39 (1H, m, CHCH2CO), 7.0 (1H, br s, CHNHCO), 7.27–7.35 (5H,
m, C6H5); 13C NMR (75 MHz, CDCl3 with a trace of methanol-d4,
ppm): d 13.7, 19.2, 38.7, 41.2, 49.9, 126.3, 127.6, 128.8, 140.9,
173.7, 174.0; Analysis Calcd for C13H18N2O2: C 66.64; H 7.74; N
11.96. Found: C 66.60; H 7.58; N 11.54. (S)-3b: mp 119–122 °C;
½
a 2D5
a 2D5
ꢀ
¼ ꢁ41:5 (c 0.24, CHCl3; >99% ee). (R)-4b: mp 232–234 °C;
½
ꢀ
¼ þ118 (c 0.1, MeOH; 96% ee); 1H NMR (300 MHz, DMSO-
d6, ppm): d 0.81 (3H, t, J = 7.37 Hz, CH2CH2CH3), 1.48 (2H, m, CH2-
CH2CH3), 2.04 (2H, t, J = 7.2 Hz, CH2CH2CH3), 2.46 (2H, m, CHCH2-
CO), 5.19 (1H, m, CHCH2CO), 6.8 and 7.3 (1H each, br s, CONH2),
7.08–7.14 (2H, m, C6H4), 7.29–7.34 (2H, m, C6H4), 8.25 (1H, d,
J = 8.4 Hz, CHNHCO). 13C NMR (75 MHz, DMSO-d6, ppm): d 13.5,
18.7, 37.3, 42.1, 49.0, 114.7 (d), 128.3 (d), 139.4 (d), 159.4,
162.6, 171.0, 171.2; Analysis Calcd for C13H17FN2O2: C, 61.89; H,
6.79; N, 11.10. Found: C, 61.89; H, 6.86; N, 10.77. (S)-3c: mp
124–127 °C; ½a 2D5
ꢀ
¼ ꢁ43 (c 0.25, CHCl3; 96% ee). (R)-4c: mp
246–248 °C;
½ ꢀ
a 2D5
¼ þ92 (c 0.2, MeOH; 99% ee); 1H NMR
(300 MHz, DMSO-d6, ppm): d 0.82 (3H, t, J = 7.37 Hz, CH2CH2CH3),
1.48 (2H, m, CH2CH2CH3), 2.04 (2H, t, J = 7.14 Hz, CH2CH2CH3),
2.26 (3H, s, C6H4CH3), 2.45 (2H, m, CHCH2CO), 5.16 (1H, m,
CHCH2CO), 6.8 and 7.2 (1H each, br s, CONH2), 7.08–7.19 (4H,
m, C6H4), 8.2 (1H, d, J = 8.4 Hz, CHNHCO). 13C NMR (75 MHz,
DMSO-d6, ppm): d 14.0, 19.2, 21.1, 37.9, 42.6, 49.8, 126.8, 129.1,
136.1. 140.7, 171.4, 171.9; Analysis Calcd for C14H20N2O2: C,
67.71; H, 8.12; N, 11.28. Found: C, 67.49; H, 8.35; N, 11.23. (S)-
4.2. Kinetic resolution of 3a with CALA
Experimental procedure: Trifluoroethyl butanoate (92 lL,
2 equiv) was added to a solution containing 3a (49.3 mg, 0.3 mmol)
and vacuum-dried CALA (300 mg, 1000 mg/mmol) in dry THF
(6 mL, 0.05 M). The resulting mixture was stirred at rt for 37 h
and then the enzyme was removed by filtration. The filtrate was
evaporated under reduced pressure and the residue was purified
by column chromatography (methylene chloride/methanol = 15/
1) to afford (R)-3a (12 mg, 0.075 mmol, 25% yield) and (S)-4a
(30 mg, 0.12 mmol, 40% yield). Compound (R)-3a was acetylated
by treatment with acetic anhydride to (R)-4a for the determination
3d: mp 102–104 °C; ½a 25
¼ ꢁ33 (c 0.29, CHCl3; 88% ee). (R)-4d:
ꢀ
mp 236–239 °C; ½a D25
ꢀ
¼Dþ85 (c 0.1, MeOH; >99% ee); 1H NMR
(300 MHz, DMSO-d6, ppm): d 0.81 (3H, t, J = 7.37 Hz, CH2CH2CH3),
1.48 (2H, m, CH2CH2CH3), 2.03 (2H, t, J = 7.08 Hz, CH2CH2CH3),
2.45 (2H, m, CHCH2CO), 3.71 (3H, s, C6H4OCH3), 5.15 (1H, m,
CHCH2CO), 6.7 and 7.2 (1H each, br s, CONH2), 6.83–7.23 (4H,
m, C6H4), 8.2 (1H, d, J = 8.4 Hz, CHNHCO). 13C NMR (75 MHz,
DMSO-d6, ppm): d 13.5, 18.7, 37.4, 42.2, 48.9, 55.0, 113.4, 127.6,
of its ee value by HPLC. (R)-3a: ½a D25
¼ þ25 (c 0.1, THF) 62% ee.
ꢀ
(S)-4a: ½a 2D5
¼ ꢁ30 (c 0.1, THF) 76% ee. See (R)-4a for its analytical
ꢀ
data.

1452
E. Choi et al. / Tetrahedron: Asymmetry 24 (2013) 1449–1452
8. (a) Kim, M.-J.; Kim, W.-H.; Han, K.; Choi, Y. K.; Park, J. Org. Lett. 2007, 9, 1157–
1159; (b) Han, K.; Park, J.; Kim, M.-J. J. Org. Chem. 2008, 73, 4302–4304; (c) Kim,
Y.; Park, J.; Kim, M.-J. Tetrahedron Lett. 2010, 51, 5581–5584.
135.2, 158.0, 170.9, 171.4; Analysis Calcd for C14H20N2O3: C,
63.62; H, 7.63; N, 10.60. Found: C, 64.07; H, 7.83; N, 9.80.
9. Choi, Y. K.; Kim, Y.; Han, K.; Park, J.; Kim, M.-J. J. Org. Chem. 2009, 74, 9543–
9545.
4.4. PSL-catalyzed kinetic resolution of 3a coupled with Pd-cata-
lyzed racemization
10. For recent studies on kinetic resolution with PSL, see: (a) Aoyagi, Y.; Agata, N.;
Shibata, N.; Horiguchi, M.; Williams, R. M. Tetrahedron Lett. 2000, 41, 10159–
10162; (b) Aoyagi, Y.; Iijima, A.; Williams, R. M. J. Org. Chem. 2001, 66, 8010–
8014; (c) Aoyagi, Y.; Saitoh, Y.; Ueno, T.; Horiguch, M.; Takeya, K.; Williams, R.
M. J. Org. Chem. 2003, 68, 6899–6904; (d) Yamamoto, T.; Shibata, N.;
Takashima, M.; Nakamura, S.; Toru, T.; Matsunaga, N.; Hara, H. Org. Biomol.
Chem. 2008, 6, 1540–1543; (e) Wang, M.-H.; Yang, G.; Yang, L.-R. Chin. J. Org.
Chem. 2008, 28, 1398–1403.
To a Schlenk-type flask equipped with a grease-free high vac-
uum stopcock were added 3a (33 mg, 0.2 mmol), Pd/AlO(OH)
(130 mg, 5 mol % Pd), vacuum-dried PSL (80 mg, 400 mg/mmol),
sodium carbonate (80 mg, 400 mg/mmol), dry THF (2 mL, 0.1 M),
11. Herein, only p-substituted substrates were tested, but it is expected that o- and
m-substituted substrates could also be resolved enantioselectively because o-
and m-substituted benzoins were resolved enantioselectively in previous
work.16d
12. (a) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org.
Chem. 1991, 56, 2656–2665; (b) Jing, Q.; Kazlauskas, R. J. Chirality 2008, 20,
724–735.
13. For other empirical rules or active-site models for predicting the
enantioselectivity of lipase, see: (a) Xie, Z.-F.; Suemune, H.; Sakai, K.
Tetrahedron: Asymmetry 1990, 1, 395–402; (b) Burgess, K.; Jennings, L. D. J.
Am. Chem. Soc. 1991, 113, 6129–6139; (c) Kim, M.-J.; Cho, H. J. Chem. Soc., Chem.
Commun. 1992, 1411–1413; (d) Naemura, K.; Fukuda, R.; Takahashi, N.;
Konishi, M.; Hirose, Y. Tetrahedron: Asymmetry 1993, 4, 911–918; (e) Naemura,
K.; Fukuda, R.; Konishi, M.; Hirose, K.; Tobe, Y. J. Chem. Soc., Perkin Trans. 1
1994, 1253–1256; (f) Naemura, K.; Fukuda, R.; Murata, M.; Konishi, M.; Hirose,
K.; Tobe, Y. Tetrahedron: Asymmetry 1995, 6, 2385–2394; (g) Naemura, K.;
Murata, M.; Tanaka, R.; Yano, M.; Hirose, K.; Tobe, Y. Tetrahedron: Asymmetry
1996, 7, 3285–3294.
and trifluoroethyl butanoate (61 lL, 2 equiv) in sequence. The
mixture was stirred at rt for 12 h to induce the enzymatic reaction
smoothly and then at 70 °C for 12 h to promote the Pd-catalyzed
racemization. The reaction mixture was then cooled down to rt
and a portion of fresh PSL (40 mg, 200 mg/mmol) was added. The
second cycle of resolution–racemization was performed at rt for
12 h and then at 70 °C for 12 h. It should be noted that the conver-
sion was 50% after the first cycle and increased to 80% after the
second cycle. Finally, the last portion of fresh PSL (40 mg,
200 mg/mmol) was added and, after stirring at rt for 12 h, the reac-
tion was stopped by filtering off the catalysts. The filtrate was
evaporated under reduced pressure and the residue was purified
by column chromatography (methylene chloride/methanol = 15/
1) to afford (R)-4a (42 mg, 0.18 mmol, 90% yield; >99% ee).
14. Kim, S.; Choi, Y. K.; Hong, J.; Park, J.; Kim, M.-J. Tetrahedron Lett. 2013, 54, 1185–
1188.
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immobilization on
immobilization of PSL herein.
a
solid support.16b However, we did not try the
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