Enzyme- and ruthenium-catalyzed dynamic kinetic resolution involving cascade alkoxycarbonylations for asymmetric synthesis of 5-Substituted N-Aryloxazolidinones

Article abstract of DOI:10.1016/j.mcat.2019.03.020

Asymmetric synthesis of N-aryloxazolidinones via dynamic kinetic resolution was developed. A ruthenium-based catalyst was used in the racemization of β-anilino alcohols, while Candida antarctica lipase B (CAL-B) was applied for two selective alkoxycarbony

Full text of DOI:10.1016/j.mcat.2019.03.020

MolecularCatalysis470(2019)138–144
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
Enzyme- and ruthenium-catalyzed dynamic kinetic resolution involving
cascade alkoxycarbonylations for asymmetric synthesis of 5-Substituted N-
Aryloxazolidinones
⁎
⁎
Yang Zhanga, Sheng Xiea, Mingdi Yana,b, , Olof Ramströma,b,c,
a Department of Chemistry, KTH - Royal Institute of Technology, Teknikringen 30, S-10044 Stockholm, Sweden
b Department of Chemistry, University of Massachusetts Lowell, 1 University Avenue, Lowell, MA 01854, USA
c Department of Chemistry and Biomedical Sciences, Linnaeus University, SE-39182 Kalmar, Sweden
A R T I C L E I N F O
A B S T R A C T
Keywords:
Oxazolidinone
Dynamic kinetic resolution
Asymmetric synthesis
Candida Antarctica lipase B
Cascade alkoxycarbonylation
Asymmetric synthesis of N-aryloxazolidinones via dynamic kinetic resolution was developed. A ruthenium-based
catalyst was used in the racemization of β-anilino alcohols, while Candida antarctica lipase B (CAL-B) was applied
for two selective alkoxycarbonylations operating in cascade. Various N-aryloxazolidinone derivatives were ob-
tained in high yields and good enantiopurities.
Introduction
Experimental
N-Aryloxazolidinones constitute a class of attractive structures that
show wide presence in pharmaceuticals, such as antimicrobials, MAO
inhibitors, and HIV-1 protease inhibitors [1–5], Current syntheses of
enantiopure N-aryloxazolidinones are generally based on Cu-catalyzed
intermolecular N-arylation of chiral oxazolidinones [6–8], where the
parent oxazolidinones can be prepared by, e.g., cyclization of en-
antioenriched 1,2-aminoalcohols via the Mitsunobu reaction [9], in-
termolecular, stereospecific nucleophilic ring-opening of aziridine-2-
carboxamides [10], aminolytic kinetic resolution of epoxides [11], re-
gioselective alkylation-cyclization of aryl N-lithiocarbamates [12], or
enzymatic desymmetrization of N-Boc-serinols [13]. In these sequential
transformation processes, however, racemization of the compounds
were occasionally observed. Although the synthesis of racemic N-ar-
yloxazolidinones has been demonstrated [14], the direct, high-yielding
formation of the corresponding enantiopure structures, especially the 5-
substituted heterocycles, has not been established. This has been ad-
dressed in the present study, where, in continuation to our work on
enzyme-catalyzed heterocycle formations [15–23], we report a novel
asymmetric synthesis protocol of 5-substituted N-aryloxazolidinones
based on dynamic kinetic resolution (DKR) through racemization and
two sequential enzyme-catalyzed processes (Fig. 1).
General methods
DKR and racemization reactions were carried out under dry argon
atmosphere using standard Schlenk techniques. Reagents were obtained
from commercial suppliers and used as received. Candida antarctica li-
pase
B (CAL-B) preparation was purchased from Sigma-Aldrich.
Ruthenium catalyst 5 was synthesized according to a literature proce-
dure. [24] 1H and 13C NMR data were recorded on Bruker Avance 400
or Bruker Avance 500 spectrometers. Chemical shifts are reported as δ
values (ppm) with CHCl3/CDCl3 (1H NMR δ 7.26, 13C NMR δ 77.0) as
an internal references. J-values are given in hertz (Hz). Optical rota-
tions were measured with a polarimeter equipped with an Na lamp.
Analytical high performance liquid chromatography (HPLC) with chiral
stationary phase was performed on an HP-Agilent 1110 Series con-
troller and a UV detector, using a Daicel Chiralpak OD-H or Chiralcel
OJ column (4.6 × 250 mm, 10 μm). Solvents for HPLC use were of
spectrometric grade. Thin layer chromatography (TLC) was performed
on precoated Polygram® SIL G/UV 254 silica plates (0.20 mm, Ma-
cherey-Nagel), visualized with UV-detection. Flash column chromato-
graphy was performed on silica gel 60, 0.040-0.063 mm (SDS).
⁎ Corresponding author
E-mail addresses: Mingdi_Yan@uml.edu (M. Yan), olof_ramstrom@uml.edu (O. Ramström).
https://doi.org/10.1016/j.mcat.2019.03.020
Received 9 October 2018; Received in revised form 16 March 2019; Accepted 18 March 2019
2468-8231/©2019ElsevierB.V.Allrightsreserved.

Y. Zhang, et al.
MolecularCatalysis470(2019)138–144
Fig. 1. DKR-based asymmetric synthesis of 5-substituted N-aryloxazolidinones.
General procedure for synthesis of β-aminoalcohols 1a-1i
(br, 1 H), 6.31 (d, J = 11.7 Hz, 1H, CH), 6.38˜6.43 (m, 2H, 2CH), 7.09
(q, J = 7.7 Hz, 1H, CH); 13C NMR (101 MHz, CDCl3, 25 °C) δ 21.0, 51.5,
66.5, 99.7, 100.0, 104.1, 104.3, 109.1, 109.2, 130.4, 130.5, 150.1,
150.3, 163.0, 165.4.
1-(2-fluorophenylamino)propan-2-ol (1 g) [31]. Brown oil, yield:
59%. 1H NMR (500 MHz, CDCl3, 25 °C) δ 1.27 (d, J = 6.3 Hz, 3H, CH3),
2.55 (br, 1 H), 3.03 (dd, J1 = 12.9 Hz, J2 = 8.4 Hz, 1H, CH2), 3.22 (dd,
J1 = 12.9 Hz, J2 = 3.5 Hz, 1H, CH2), 4.03 (m, 1H, CH), 6.64 (q,
J = 6.9 Hz, 1H, CH), 6.72 (t, J = 8.4 Hz, 1H, CH), 6.96˜7.01 (m, 2H,
2CH); 13C NMR (126 MHz, CDCl3, 25 °C) δ 20.9, 51.3, 66.5, 112.60,
112.62, 114.6, 114.7, 117.2, 117.3, 124.64, 124.67, 136.73, 136.82,
150.9, 152.8.
1-(4-methoxyphenylamino)propan-2-ol (1 h) [31]. Yellow solid,
yield: 62%. 1H NMR (400 MHz, CDCl3, 25 °C) δ 1.25 (d, J = 6.5 Hz, 3H,
CH3), 2.19 (br, 1 H), 2.94 (dd, J1 = 13.0 Hz, J2 = 8.6 Hz, 1H, CH2),
3.18 (dd, J1 = 12.7 Hz, J2 = 3.1 Hz, 1H, CH2), 3.75 (s, 3H, CH3), 3.99
(m, 1H, CH), 6.63 (d, J = 8.8 Hz, 2H, 2CH), 6.78 (d, J = 8.9 Hz, 2H,
2CH); 13C NMR (101 MHz, CDCl3, 25 °C) δ 20.9, 52.8, 55.8, 66.4, 114.8,
114.9, 142.4, 152.4.
1-chloro-3-(phenylamino)propan-2-ol (1i) [26]. White solid,
yield: 83%. 1H NMR (400 MHz, CDCl3, 25 °C) δ 3.14 (dd, J1 = 13.4 Hz,
J2 = 7.5 Hz, 1H, CH2), 3.30 (dd, J1 = 13.4 Hz, J2 = 4.4 Hz, 1H, CH2),
3.45 (br, 1 H), 3.56 (m, 2H, CH2), 3.99 (m, 1H, CH), 6.62 (d,
J = 8.4 Hz, 2H, CH), 6.75 (t, J = 6.9 Hz, 1H, CH), 7.18 (t, J = 7.5 Hz,
2H, 2CH); 13C NMR (101 MHz, CDCl3, 25 °C) δ 47.2, 47.6, 69.9, 113.3,
118.3, 129.4, 147.8.
LiBr (0.1 mmol) was added to a stirred mixture of respective ep-
oxide (2 mmol) and aniline (2 mmol) under nitrogen atmosphere, and
the solution was stirred at r.t. for 4 h. The reaction mixture was diluted
with water (10 mL) and extracted twice with diethyl ether (15 mL
each). The combined organic layer was dried over MgSO4 and removed
in vacuo. The crude products were purified using column chromato-
graphy (Hexane:EtOAc = 3:1).
1-(phenylamino)propan-2-ol (1a) [25]. Yellow oil, yield: 86%. 1H
NMR (400 MHz, CDCl3, 25 °C) δ 1.25 (d, J = 6.2 Hz, 3H, CH3), 2.01 (br,
1 H), 2.98 (dd, J1 = 13.1 Hz, J2 = 8.6 Hz, 1H, CH2), 3.20 (dd,
J1 = 12.9 Hz, J2 = 3.4 Hz, 1H, CH2), 4.0 (m, 1H, CH), 6.66 (d,
J = 8.6 Hz, 2H, 2CH), 6.77 (t, J = 7.4 Hz, 1H, CH), 7.23 (t, J = 7.9 Hz,
2H, 2CH); 13C NMR (101 MHz, CDCl3, 25 °C) δ 20.8, 51.6, 66.3, 113.3,
117.8, 129.3, 148.2.
1-(phenylamino)butan-2-ol (1b) [26]. White solid, yield: 81%. 1H
NMR (400 MHz, CDCl3, 25 °C) δ 1.02 (t, J = 7.3 Hz, 3H, CH3), 1.56 (m,
2H, CH2), 2.57 (br, 1 H), 2.99 (dd, J1 = 12.9 Hz, J2 = 8.4 Hz, 1H, CH2),
3.26 (dd, J1 = 12.7 Hz, J2 = 3.2 Hz, 1H, CH2), 3.75 (m, 1H, CH), 3.97
(br, 1 H), 6.66 (d, J = 7.7 Hz, 2H, 2CH), 6.77 (t, J = 7.7 Hz, 1H, CH),
7.22 (t, J = 7.7 Hz, 2H, 2CH); 13C NMR (101 MHz, CDCl3, 25 °C) δ 10.0,
27.9, 49.9, 71.8, 113.4, 117.9, 129.3, 148.4.
1-(4-chlorophenylamino)butan-2-ol (1c) [27]. White solid, yield:
71%. 1H NMR (500 MHz, CDCl3, 25 °C) δ 1.01 (t, J = 7.5 Hz, 3H, CH3),
1.55 (m, 2H, CH2), 1.80 (br, 1 H), 2.98 (dd, J1 = 12.9 Hz, J2 = 8.5 Hz,
1H, CH2), 3.23 (dd, J1 = 12.8 Hz, J2 = 3.2 Hz, 1H, CH2), 3.76 (m, 1H,
CH), 4.01 (br, 1 H), 6.56 (d, J = 8.9 Hz), 7.12 (d, J = 8.9 Hz); 13C NMR
(126 MHz, CDCl3, 25 °C) δ 10.1, 28.2, 50.0, 71.9, 114.5, 122.6, 129.3,
147.1.
1-(4-chlorophenylamino)propan-2-ol (1d) [28]. Yellow solid,
yield: 77%. 1H NMR (500 MHz, CDCl3, 25 °C) δ 1.26 (d, J = 6.3 Hz, 3H,
CH3), 2.09 (br, 1 H), 2.98 (dd, J1 = 13.3 Hz, J2 = 8.7 Hz, 1H, CH2),
3.20 (dd, J1 = 13.0 Hz, J2 = 3.6 Hz, 1H, CH2), 4.03 (m, 1H, CH), 6.58
(d, J = 8.8 Hz, 2H, 2CH), 7.12 (d, J = 8.8 Hz, 2H, 2CH); 13C NMR
(126 MHz, CDCl3, 25 °C) δ 21.1, 52.1, 66.5, 114.6, 122.9, 129.3, 146.8.
1-(4-fluorophenylamino)propan-2-ol (1e) [29]. Yellow solid,
yield: 50%. 1H NMR (400 MHz, CDCl3, 25 °C) δ 1.26 (d, J = 6.3 Hz, 3H,
CH3), 2.06 (br, 1 H), 2.95 (dd, J1 = 12.5 Hz, J2 = 8.6 Hz, 1H, CH2),
3.18 (dd, J1 = 13.1 Hz, J2 = 3.3 Hz, 1H, CH2), 3.87 (br, 1 H), 4.0 (m,
1H, CH), 6.58 (q, J = 4.5 Hz, 2H, 2CH), 6.89 (t, J = 8.8 Hz, 2H, 2CH);
13C NMR (101 MHz, CDCl3, 25 °C) δ 21.0, 52.4, 66.4, 114.2, 114.3,
115.7, 115.9, 144.7, 155.0, 157.3.
General procedure for synthesis of racemic N-aryloxazolidinones 4a-4i
β-aminoalcohol 1a-1i (0.08 mmol), diphenyl carbonate (0.1 mmol),
NaH (0.16 mmol, 60% in oil) and THF (1 mL) were added into a 5 mL
flask. The solution was stirred at r.t. for 6 h. TLC was used to monitor
the reaction progress. CH2Cl2 was subsequently added, and the aqueous
layer was extracted three times (3 mL CH2Cl2 each). The combined
organic layer was dried over MgSO4 and removed in vacuo. The crude
products
were
purified
using
column
chromatography
(Hexane:EtOAc = 6:1).
Procedure for kinetic resolution
β-aminoalcohol 1a-1i (0.05 mmol), diphenyl carbonate (0.15 mmol)
and dry toluene (0.6 mL) were added into a 1.5 mL sealed-cap vial
containing CAL-B (30 mg) and 4 Å molecular sieves (20 mg). CAL-B was
dried under vacuum for at least two days before use. The vial was kept
at r.t. without stirring, and 1H NMR was used to monitor the reaction
progress. After a specific time, the reaction mixture was filtered through
a cotton-stoppered pipette. CH2Cl2 was subsequently added, and the
aqueous layer was extracted three times (3 mL CH2Cl2 each). The
1-(3-fluorophenylamino)propan-2-ol (1f) [30]. Colorless oil,
yield: 42%. 1H NMR (400 MHz, CDCl3, 25 °C) δ 1.25 (d, J = 6.3 Hz, 3H,
CH3), 2.19 (br, 1 H), 2.96 (dd, J1 = 13.2 Hz, J2 = 8.4 Hz, 1H, CH2),
3.18 (dd, J1 = 13.0 Hz, J2 = 3.3 Hz, 1H, CH2), 4.01 (m, 1H, CH), 4.18
139

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MolecularCatalysis470(2019)138–144
combined organic layer was dried over MgSO4 and removed in vacuo.
The crude products were purified using column chromatography
(Hexane:EtOAc = 6:1).
3-(4-fluorophenyl)-5-methyloxazolidin-2-one (4e) [30]. Con-
version: quant., enantiomeric excess (ee): 84%, determined by HPLC
analysis: Chiral OJ, Hex:iPrOH = 8 : 2, 0.5 mL/min, detection 210 nm,
tR1 = 42.7 min, tR2 = 46.2 min, white solid. 1H NMR (400 MHz, CDCl3,
25 °C) δ 1.54 (d, J = 6.2 Hz, 3H, CH3), 3.61 (t, J = 8.0 Hz, 1H, CH2),
4.09 (t, J = 8.6 Hz, 1H, CH2), 4.79 (m, 1H, CH), 7.07 (t, J = 8.5 Hz, 2H,
2CH), 7.49 (dd, J1 = 88 Hz, J2 = 4.7 Hz, 2H, 2CH); 13C NMR (100 MHz,
CDCl3, 25 °C) δ 20.9, 52.3, 69.7, 115.8, 116.0, 120.0, 120.1, 134.6,
134.7, 155.2, 158.2, 160.6.
Racemization of (S)-1a
Ruthenium catalyst 5 (1.2 mg, 0.0019 mmol) was added to a
Schlenk tube. Dry toluene (0.4 mL) was added, and the resulting solu-
tion was stirred. A THF solution of t-BuOK (3.75 μL, 0.5 M in dry THF,
0.0019 mmol) was added to the reaction mixture. After 6 min stirring,
(S)-1-(phenylamino)propan-2-ol ((S)-1a) (5.7 mg, 0.0375 mmol) dis-
solved in dry toluene (0.1 mL) was added to the reaction mixture, and
the reaction was heated to the appropriate temperature. Samples for
HPLC analysis were collected with a syringe after 2, 5, 10, 30, 60, and
90 min. HPLC: Chiralpak OD-H column, Hex:iPrOH = 9 : 1, 0.5 mL/
min, tR1 = 25.3 min, tR2 = 30.7 min.
3-(3-fluorophenyl)-5-methyloxazolidin-2-one (4f) [30]. Conver-
sion: 97%, enantiomeric excess (ee): 78%, determined by HPLC ana-
lysis: Chiral OD-H, Hex:iPrOH = 9 : 1, 0.5 mL/min, detection 210 nm,
tR1 = 28.2 min, tR2 = 31.7 min, yellow oil. 1H NMR (400 MHz, CDCl3,
25 °C) δ 1.54 (d, J = 6.1 Hz, 3H, CH3), 3.60 (t, J = 7.8 Hz, 1H, CH2),
4.11 (t, J = 8.4 Hz, 1H, CH2), 4.80 (m, 1H, CH), 6.84 (td, J1 = 8.3 Hz,
J2 = 2.1 Hz, 1H, CH2), 7.23 (d, J = 8.9 Hz, 1H, CH), 7.31 (q,
J = 7.5 Hz, 1H, CH), 7.42 (dt, J1 = 11.8 Hz, J2 = 2.2 Hz, 1H, CH); 13C
NMR (101 MHz, CDCl3, 25 °C) δ 20.9, 52.0, 69.8, 105.8, 106.0, 110.7,
110.9, 113.3, 113.4, 130.3, 130.4, 140.1, 140.2, 154.7, 162.0, 164.5.
3-(2-fluorophenyl)-5-methyloxazolidin-2-one (4 g) [30]. Con-
version: quant., enantiomeric excess (ee): 85%, determined by HPLC
analysis: Chiral OJ, Hex:iPrOH = 8 : 2, 0.5 mL/min, detection 210 nm,
tR1 = 31.1 min, tR2 = 33.9 min, yellow solid. 1H NMR (500 MHz, CDCl3,
25 °C) δ 1.54 (d, J = 6.3 Hz, 3H, CH3), 3.66 (t, J = 8.0 Hz, 1H, CH2),
4.12 (t, J = 8.3 Hz, 1H, CH2), 4.82 (m, 1H, CH), 7.11˜7.19 (m, 2H,
2CH), 7.23 (t, J = 5.6 Hz, 1H, CH), 7.55 (td, J1 = 7.8 Hz, J2 = 1.5 Hz,
1H, CH); 13C NMR (101 MHz, CDCl3, 25 °C) δ 20.7, 53.9, 71.3, 116.7,
116.9, 124.8, 125.6, 127.2, 128.2, 128.3, 156.0, 156.2, 157.9.
3-(4-methoxyphenyl)-5-methyloxazolidin-2-one (4 h) [35].
Conversion: 88%, enantiomeric excess (ee): 81%, determined by HPLC
analysis: Chiral OD-H, Hex:iPrOH = 9 : 1, 0.5 mL/min, detection
210 nm, tR1 = 47.4 min, tR2 = 50.8 min, white solid. 1H NMR
(400 MHz, CDCl3, 25 °C) δ 1.52 (d, J = 6.2 Hz, 3H, CH3), 3.59 (t,
J = 7.7 Hz, 1H, CH2), 3.80 (s, 3H, CH3), 4.08 (t, J = 8.5 Hz, 1H, CH2),
4.77 (m, 1H, CH), 6.90 (d, J = 9.1 Hz, 2H, 2CH), 7.42 (d, J = 9.1 Hz,
2H, 2CH); 13C NMR (100 MHz, CDCl3, 25 °C) δ 20.8, 52.5, 55.7, 69.6,
114.4, 120.3, 131.7, 155.4, 156.4.
Procedure for dynamic kinetic resolution
Ruthenium catalyst 5 (4.8 mg, 0.0075 mmol), CAL-B (15 mg), and
CaCl2 (8.3 mg, 0.075 mmol) were added to a Schlenk tube. Dry toluene
(0.7 mL) was added, and the resulting solution was stirred. A THF so-
lution of t-BuOK (15 μL, 0.5 M in dry THF, 0.0075 mmol) was added to
the reaction mixture. After 6 min of stirring, rac-1 (0.075 mmol) dis-
solved in dry toluene (0.1 mL) was added to the reaction mixture. After
an additional 4 min, diphenyl carbonate (48.2 mg, 0.225 mmol) dis-
solved in dry toluene (0.2 mL) was added. SiO2 was added under flow of
dry nitrogen and the resulting reaction was heat to 50 °C. After a certain
time, the reaction mixture was filtered and solvent was removed in
vacuo. The crude products were purified using column chromatography
(Hexane:EtOAc = 6:1).
5-methyl-3-phenyloxazolidin-2-one (4a) [32]. Conversion: 100%,
enantiomeric excess (ee): 90%, determined by HPLC analysis: Chiral
OD-H, Hex:iPrOH = 9
:
1, 0.5 mL/min, detection 210 nm,
tR1 = 27.7 min, tR2 = 34.0 min, white solid. 1H NMR (400 MHz, CDCl3,
25 °C) δ 1.54 (d, J = 6.3 Hz, 3H, CH3), 3.63 (t, J = 8.1 Hz, 1H, CH2),
4.12 (t, J = 8.5 Hz, 1H, CH2), 4.79 (m, 1H, CH), 7.14 (t, J = 7.5 Hz, 1H,
CH), 7.38 (t, J = 7.5 Hz, 2H, 2CH), 7.53 (d, J = 8.1 Hz, 2H, 2CH); 13C
NMR (100 MHz, CDCl3, 25 °C) δ 21.0, 52.1, 69.8, 118.3, 124.1, 129.3,
138.5, 155.0.
5-(chloromethyl)-3-phenyloxazolidin-2-one (4i) [32]. Conver-
sion: 87%, enantiomeric excess (ee): 71%, determined by HPLC ana-
lysis: Chiral OD-H, Hex:iPrOH = 9 : 1, 0.5 mL/min, detection 210 nm,
tR1 = 40.5 min, tR2 = 44.1 min, yellow solid. 1H NMR (500 MHz, CDCl3,
25 °C) δ 3.77 (m, 2H, CH2), 3.98 (dd, J1 = 9.2 Hz, J2 = 5.7 Hz, 1H,
CH2), 4.18 (t, J = 9.2 Hz, 1H, CH2), 4.88 (m, 1H, CH), 7.16 (t,
J = 7.6 Hz, 1H, CH), 7.40 (t, J = 7.9 Hz, 2H, 2CH), 7.55 (d, J = 7.9 Hz,
2H, 2CH); 13C NMR (126 MHz, CDCl3, 25 °C) δ 44.7, 48.4, 71.0, 118.5,
124.6, 129.4, 137.9, 154.1.
5-ethyl-3-phenyloxazolidin-2-one (4b) [33]. Conversion: 96%,
enantiomeric excess (ee): 95%, determined by HPLC analysis: Chiral
OD-H, Hex:iPrOH = 9
:
1, 0.5 mL/min, detection 210 nm,
tR1 = 25.6 min, tR2 = 32.5 min, yellow oil. 1H NMR (500 MHz, CDCl3,
25 °C) δ 1.08 (t, J = 7.3 Hz, 3H, CH3), 1.74˜1.94 (m, 2H, CH2), 3.67 (t,
J = 7.8 Hz, 1H, CH2), 4.09 (t, J = 8.6 Hz, 1H, CH2), 4.59 (m, 1H, CH),
7.13 (t, J = 7.4 Hz, 1H, CH), 7.38 (t, J = 7.9 Hz, 2H, 2CH), 7.54 (d,
J = 7.9 Hz, 2H, 2CH); 13C NMR (101 MHz, CDCl3, 25 °C) δ 8.9, 28.2,
50.3, 74.3, 118.3, 124.2, 129.2, 138.5, 155.1.
Results and discussion
3-(4-chlorophenyl)-5-ethyloxazolidin-2-one (4c) [30]. Conver-
sion: quant., enantiomeric excess (ee): 92%, determined by HPLC ana-
lysis: Chiral OJ, Hex:iPrOH = 8 : 2, 1 mL/min, detection 210 nm,
tR1 = 19.0 min, tR2 = 23.3 min, white solid. 1H NMR (400 MHz, CDCl3,
25 °C) δ 1.07 (t, J = 7.6 Hz, 3H, CH3), 1.85 (m, 2H, CH2), 3.64 (t,
J = 7.8 Hz, 1H, CH2), 4.06 (t, J = 8.6 Hz, 1H, CH2), 4.59 (m, 1H, CH),
7.33 (d, J = 8.9 Hz, 2H, 2CH), 7.50 (d, J = 9.0 Hz, 2H, 2CH); 13C NMR
(101 MHz, CDCl3, 25 °C) δ 8.9, 28.2, 50.2, 74.3, 119.4, 129.2, 129.3,
137.2, 155.0.
3-(4-chlorophenyl)-5-methyloxazolidin-2-one (4d) [34]. Con-
version: quant., enantiomeric excess (ee): 84%, determined by HPLC
analysis: Chiral OJ, Hex:iPrOH = 8 : 2, 1 mL/min, detection 210 nm,
tR1 = 27.6 min, tR2 = 32.3 min, white solid. 1H NMR (500 MHz, CDCl3,
25 °C) δ 1.54 (d, J = 6.3 Hz, 3H, CH3), 3.60 (t, J = 7.9 Hz, 1H, CH2),
4.10 (t, J = 8.5 Hz, 1H, CH2), 4.79 (m, 1H, CH), 7.33 (d, J = 8.9 Hz,
2H, 2CH), 7.48 (d, J = 8.9 Hz, 2H, 2CH); 13C NMR (126 MHz, CDCl3,
25 °C) δ 20.9, 52.0, 69.8, 119.5, 129.3, 137.2, 154.9.
We previously reported the sequential kinetic resolution (KR) of 1,2-
anilinoalcohols towards cyclic N-aryloxazolidinones, where diphenyl
carbonate acts as a double acyl donor [36]. The reaction was shown to
possess wide substrate compatibility, however displaying some limita-
tions due to the applied KR protocol. To address this challenge, an
additional racemization catalyst was introduced in the present process
(Scheme 1, yellow part), leading to an improved dynamic kinetic re-
solution protocol. DKR can in this context lead to high conversions
while maintaining high enantiopurities, and has been widely applied in
organic synthesis and used for large-scale production in industry
[37–42]. However, no reports on DKR-systems for 1,2-anilinoalcohols
have been presented. A major issue in chemoenzymatic DKR is the
compatibility of the racemization catalyst, which may be deactivated by
the enzyme, the substrates/products, or the reaction conditions. For
example, in the development of a DKR-protocol for aminoalcohols,
Bäckvall and co-workers found severe deactivation of the ruthenium-
based racemization catalyst [43,44], which could be attributed to
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MolecularCatalysis470(2019)138–144
compatibility of the ruthenium racemization catalyst with 1,2-anili-
noalcohols. The racemization process was subsequently performed at
different temperatures: room temperature, 30 °C, 50 °C and 70 °C, and
monitored by HPLC. As indicated in Fig. 2, higher temperatures led to
acceleration of the racemization process, with the transformation at
70 °C being finished within 20 min. This is comparable to the results for
other alcohols using the same catalyst [47,48].
Next, the DKR protocol was optimized with respect to enzyme
loading, additives, and temperature (Table 1). In general, transforma-
tion of the starting material (1a) into intermediate 3a was observed
within 8 h, whereas the cyclization process of the intermediate to the
final oxazolidinone product proceeded slower. The temperature screen
indicated an optimal temperature at 50 °C, with full conversion to the
oxazolidinone and 88% ee within 66 h (Table 1, entries 1–4). Interest-
ingly, the ee of intermediate 3a was recorded to 60% after complete
conversion of the starting material. The considerably higher ee of the
final product thus indicates an enzyme-catalyzed, stereospecific cycli-
zation process in addition to the stereoselective alkoxycarbonylation
step. Either lowering or increasing the catalyst loading led to lower
conversions or poorer ees (Table 1, entries 5–6).
The additive salts (K2CO3, Na2CO3, Na2SO4, CaCl2) influenced the ee
only slightly, but otherwise increased the reaction rates to some extent.
For enzymatic reactions in nonpolar organic solvents, inorganic salts
have been reported to impact the selectivities of the enzymes, mediated
by tuning the water content (described as the water activity, aw) via
their equilibria between free water molecules and salt-hydrate pairs
[49–51]. The use of calcium chloride (aw ˜ 0.04 at 20 °C) [51], instead
Fig. 2. Racemization of (S)-1a at different temperatures.
bidentate coordination of the substrates to the ruthenium center
[45,46]. Thus, protection of the amino group was required for the
transformation to proceed successfully. In the present study, however,
we reasoned that this complication would be less pronounced, owing to
the weaker coordination of anilines to the ruthenium center, compared
to alkyl amines. The presence of the aryl ring would thus prohibit po-
tential bidentate coordination towards the ruthenium center due to
enhanced steric hindrance as well as the reduced nucleophilicity.
Sterically crowded ruthenium-based catalysts would then be applicable
in the present case.
of sodium carbonate (aw ˜ 0.7 at 20 °C) [51], potassium carbonate (aw
˜
0.4 at 20 °C) [52], or sodium sulfate (aw ˜ 0.8 at 20 °C), thus resulted in
slightly higher enantiopurities (Table 1, entries 6, 8, 10, 11). Of the
salts evaluated, CaCl2 displays the lowest aw, indicating that the en-
antioselectivity of CAL-B increased at lower aw in toluene (Table 1,
entries 6, 8–10). This is consistent with the trends in previous reports
[53,54]. The presence of SiO2 also produced positive effects on the
chiral discrimination (Table 1, entries 6–7, 12–13), as shown in similar
enzymatic heterocylizations [15].
To support this hypothesis, enantioenriched 1,2-anilinoalcohol (S)-
1a (84% ee) was examined in toluene with ruthenium catalyst 5, con-
veniently and efficiently prepared in 86% isolated yield [24]. No by-
products were detected by 1H NMR within 24 h, thus indicating good
Although the cyclization step displayed lower rates, it proved to be a
Table 1
Optimization of the DKR process of 1-(phenylamino)propan-2-ol (1a).a.
Entry
Lipase (mg)
Additive
T (°C)
Time (h)
Conv. (%)b
ee (%)c
1
2
3
4
5
6
7
15
15
15
15
7.5
30
30
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3,
SiO2
70
60
50
40
70
70
70
43
58
66
97
17
17
19
98
97
85
86
88
74
81
82
84
quant.
quant.
25
quant.
99
8
9
10
11
12d
30
30
30
30
15
CaCl2
70
70
70
70
50
23
22
23
23
18
quant.
97
quant.
quant.
quant.
86
79
81
75
90
4 Å MS
K2CO3
Na2SO4
CaCl2
SiO2
13
15
15
CaCl2
SiO2
CaCl2
50
50
69
65
quant.
quant.
89
26
14e
SiO2
a
Reaction conditions: compound 1 (0.075 mmol), compound 2 (0.225 mmol), Ru-catalyst 5 (0.0075 mmol), t-BuOK (0.5 M in THF), CAL-B preparation, additives
d
(0.075 mmol or 20 mg [4 Å MS or SiO2]), in toluene (1 mL). Determined by 1H NMR. Determined by HPLC analysis using Chiralpak OD-H chiral column.
Temperature increased to 70 °C following complete conversion of all starting materials to intermediate. Reaction performed without Ru-catalyst and t-BuOK.
b
c
e
141

Y. Zhang, et al.
MolecularCatalysis470(2019)138–144
Table 2
DKR of different substrates.a.
Entry
1
Substrate
Product
Time
18 h
Conv.(%)b
ee (%)c
quant. (89d)
90
4a
1a
2f
3
42 h
47 h
96
95
92
4b
1b
quant.
4c
1c
4
5
27 h
42 h
quant.
quant.
84
84
4d
1d
4e
1e
1f
6
7
8
42 h
7 d
97
78
85
81
4f
quant.
88
4 g
1 g
30 h
4 h
1 h
9
a
6 d
87
71
4i
1i
Reaction conditions: compound 1 (0.05 mmol), compound 2 (0.15 mmol), SiO2 (20 mg), CAL-B preparation (15 mg), Ru-catalyst 5 (0.0075 mmol), t-BuOK (0.5 M
in THF), CaCl2 (20 mg) in toluene (1 mL) at 50 °C. Average values, each reaction carried out ≥ 2 times. Determined by 1H NMR. Determined by HPLC analysis
using Chiralpak OD-H or OJ chiral column. Isolated yield from reaction at 0.4 mmol scale. For substrates 1c, 1d, 1e, 1f, 1i, temperature increased to 70 °C
following complete conversion of starting materials to intermediate. 30 mg CAL-B preparation.
b
c
d
e
f
CAL-B-catalyzed process that could be accelerated at higher tempera-
ture. Thus, an increase in reaction temperature to 70 °C, following
complete conversion from the substrate aniline to intermediate 3a, led
to a significantly shortened overall process time without loss of reaction
selectivity (Table 1, entry 12). In comparison, the process performed in
the absence of the ruthenium catalyst resulted in product formation
with only 26% ee.
Finally, the developed DKR protocol was applied to a range of other
1,2-anilinoalcohol derivatives to further evaluate the scope of the
process. The results are displayed in Table 2, and as can be seen, most of
the substrates could be transformed into the corresponding ox-
azolidinone species through the DKR process with excellent conversions
and up to excellent ees. Under the conditions developed, the protocol
displayed the best results for the O-ethyl substrate (95% ee, Table 2,
entry 2). Halogen substituents at different positions of the aniline ring
also proved highly compatible with the protocol (Table 2, entries 3–7).
These results show high tolerance of halogen atoms in the phenyl ring,
thus enabling further modification of the enantioenriched N-arylox-
azolidinones. Interestingly, the ortho-fluorine substrate was con-
siderably more sluggishly transformed in the process, however still
resulting in excellent conversion and good ee (85%, Table 2, entry 7). A
para-methoxy group on the aniline ring led to a comparably good ee
value, albeit slight deactivation of the racemization catalyst was ex-
pected, also resulting in lower conversion (Table 2, entry 8).
Conclusions
In summary, a DKR protocol for the transformation of 1,2-anili-
noalcohol substrates to enantioenriched 5-substituted N-arylox-
azolidinones was developed. The protocol employed a ruthenium
complex as racemization catalyst, combined with CAL-B-catalyzed
inter- and intramolecular alkoxycarbonylation in two stereoselective
steps. Various N-aryloxazolidinone analogs carrying different func-
tional groups were obtained with up to excellent ees and generally
excellent conversions. Aniline structures showed high compatibility
with the ruthenium-catalyzed racemization process, enabling direct
application of 1,2-aminoalcohols in DKR without pre-protection. In
combination with directed evolution-type protocols, the developed DKR
protocol shows high potential for further optimization of the en-
antioenrichment process. Furthermore, 1,3-anilinoalcohol substrates
may be applied to obtain oxazinanones, a venue we are currently
pursuing.
Acknowledgments
The study was in part supported by the Swedish Research Council.
YZ and SX thank the China Scholarship Council for special scholarship
awards.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
142

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MolecularCatalysis470(2019)138–144
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