Synthesis of chiral oxazolidinone derivatives through lipase-catalyzed kinetic resolution

Article abstract of DOI:10.1016/j.molcatb.2015.08.004

The synthesis of enantioenriched oxazolidinone derivatives through lipase-catalyzed kinetic resolution is described. The synthesis comprised a two-step, cascade acylation in one pot, resulting in a range of oxazolidinone derivatives in good yields and exc

Full text of DOI:10.1016/j.molcatb.2015.08.004

Accepted Manuscript
Title: Synthesis of Chiral Oxazolidinone Derivatives through
Lipase-Catalyzed Kinetic Resolution
Author: Yan Zhang Yang Zhang Yansong Ren Olof Ramstro¨m
PII:
S1381-1177(15)30042-4
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcatb.2015.08.004
MOLCAB 3213
To appear in:
Journal of Molecular Catalysis B: Enzymatic
Received date:
Revised date:
Accepted date:
23-4-2015
7-8-2015
7-8-2015
Please cite this article as: Y. Zhang, Y. Zhang, Y. Ren, O. Ramstrddotom,
Synthesis of Chiral Oxazolidinone Derivatives through Lipase-Catalyzed
Kinetic Resolution, Journal of Molecular Catalysis B: Enzymatic (2015),
http://dx.doi.org/10.1016/j.molcatb.2015.08.004
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Synthesis of Chiral Oxazolidinone Derivatives through Lipase-
Catalyzed Kinetic Resolution
Yan Zhang a,†, Yang Zhang a,†, Yansong Ren a and Olof Ramström a,*
a KTH - Royal Institute of Technology, Department of Chemistry, Teknikringen 30, S-10044, Stockholm, Sweden.
Highlights:
- Chiral oxazolidinone derivatives were synthesized with excellent enantiopurities.
- Lipase-catalyzed kinetic resolution of two-step, cascade acylation was described.
- Carbonates were used as double acyl donors for lipase-catalyzed cyclizations.
Abstract:
The synthesis of enantioenriched oxazolidinone derivatives through lipase-catalyzed kinetic resolution is
described. The synthesis comprised a two-step, cascade acylation in one pot, resulting in a range of
oxazolidinone derivatives in good yields and excellent enantiopurities
.
Keywords:
Lipases; kinetic resolution; oxazolidinone; asymmetric synthesis
1. Introduction
Oxazolidinone derivatives represent a class of important structures in organic and medicinal chemistry, for
example constituting the core structure of Evans’ auxiliaries for asymmetric synthesis [1-3]. This structural motif
exists in a variety of natural products and active pharmaceutical species, such as the antidepressant drug toloxatone,
the serotonin receptor agonist zolmitriptan, and the muscle relaxant metaxalone (Figure 1) [4-6]. In particular,
considerable attention has been put on the development of compounds with antibacterial activity, where the
oxazolidinone group of antibiotics has gained increasing interest [7-10]. For example, linezolid is a lead antibiotic
against gram-positive bacteria that are resistant to other antibiotics [11-13].
* Corresponding author. Tel. : +46 8 790 6915; fax : +46 8 7912333. E-mail address : ramstrom@kth.se
† These authors contributed equally to this study.
1
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O
O
N
F
O
N
O
N
O
OH
NHAc
Toloxatone
Linezolid
Figure 1. Structures of antidepressant toloxatone and antibiotic linezolid.
Owing to the importance of this heterocyclic structure, a variety of synthetic methods to enantioenriched
oxazolidinones have been developed and studied over the years [14-18]. In most of these approaches, the resulting
enantiopurity emanates from chiral starting materials or through the action of transition metal catalysts.
Biocatalysis, however, one of the most efficient routes to enantiopure compounds, has not been applied in the direct
synthesis of these core structures. One reason for this has been the lack of identified enzymes that catalyze these
processes. Compared to other catalysts, enzymes nevertheless possess several advantages, such as environmental
benignity, mild reaction conditions and high selectivity, making them attractive for synthetic processes [19-22].
Moreover, enzyme-catalyzed kinetic resolution (KR) schemes are commonly applied in asymmetric synthesis,
where high enantiopurities can be obtained [23-26]. In the present study, we have taken advantage of these features
and present an efficient synthesis to chiral oxazolidinone derivatives through enzyme-catalyzed kinetic resolution.
Lipases [EC 3.1.1.3], have generally evolved to catalyze the hydrolysis of triglycerides, although some lipases
are known to participate in other biological processes. This family of enzymes is however also widely used in
organic synthesis owing to the commercial availability, structural stability, solvent tolerance, broad substrate scope
and good catalytic activity [27, 28]. In organic solvents, the enzymes generally catalyze different acylation reactions
to provide esters, thiolesters and amides [26, 29-30]. In addition to intermolecular acylations, some lipases are
furthermore able to catalyze promiscuous [31-33], intramolecular reactions. We have thus preciously reported
different cyclization reactions catalyzed by lipases, resulting in facile synthesis of chiral 1,3-oxathiolan-5-one
derivatives [34, 35], substituted Thiolanes [36], oxathiazinanones [37], and thiazolidinones [38]. The exploration of
enzyme substrate- and reaction promiscuity for the synthesis of heterocycles is however an ongoing quest [39, 40],
where new, efficient transformations are evaluated. In the present study, carbonate diesters were used as double acyl
donors [41-42], enabling the possibility of a two-step cascade acylation in one pot.
2. Results and discussion
At the outset, different α-hydroxy, α-mercapto, and α-amino alcohols were tested for lipase-catalyzed
cyclizations, all of which successfully undergoing double acylation to the respective heterocyclic products. Of these,
the reactions with α-amino alcohols provided the desired oxazolidinone products, also showing promising
enantiomeric excesses (ees). Of the α-amino alcohols, 2-(methylamino)-1-phenylethanol (1a) was chosen as the
model substrate for further evaluation of the lipase-catalyzed transformation (Scheme 1).
Scheme 1. Synthesis of compound 3a through lipase-catalyzed kinetic resolution.
To identify the best catalyst for the transformation, different lipase preparations were screened, including lipases
from Burkholderia (Pseudomonas) cepacia (PS-IM and PS), Pseudomonas fluorescens (PFL), and Candida
antarctica (CAL-B). Among these, PS and CAL-B did not produce any products, while both PS-IM and PFL
catalyzed the reaction. PS-IM was subsequently chosen for further evaluation owing to the faster substrate
transformation with this enzyme preparation compared to PFL.
The impact of the solvent on the reaction was next evaluated. Between toluene and tert-butyl methyl ether
(TBME), the two most commonly used solvents in our previous studies, TBME was proven more efficient in the
catalysis of the reaction, providing considerably better conversions within the same time scale. Different carbonate
diesters (2), such as diphenyl carbonate and methyl phenyl carbonate were furthermore tested in reactions with
compound 1a. The results showed that the reactions with diphenyl carbonate proceeded smoothly, providing both
good yields and ees. Methyl phenyl carbonate, on the other hand, did not result in any products, probably due to the
lipase inactivation effect of methanol released as the side product.37
2
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In order to elucidate the role of the enzyme in the two-step reaction process, control experiments were carried
out in the absence of lipase. Under the conditions used, acylation of the amine could be detected within one hour,
after which the reaction stopped without any further acylation or cyclization. This is indicative of a relatively rapid
carbamation step between the carbonate diester and the α-amino alcohol, with no subsequent reaction ensuing from
the resulting carbamate structure. Therefore, a kinetically controlled first-step carbamation followed by a lipase-
catalyzed second-step cyclization mechanism can be proposed, leading to the enantioenriched oxazolidinone
products (Scheme 2).
Scheme 2. Lipase-catalyzed, double acylation process through carbamate intermediate.
With the identified reaction conditions, the double acylation process catalyzed by PS-IM proceeded well in
TBME, providing product 3a at good yield (46%) and excellent ee (92%), with an absolute (S)-configuration of the
major enantiomer according to polarimetry data [43]. In addition, starting material 1a was fully consumed, and the
carbamation intermediate (1a’) from the kinetic resolution process was detected with a high ee of 94%. However,
one drawback with these conditions was the lengthy reaction times to reach full conversion of the selected
enantiomer. Thus, several Lewis basic- and acidic additives were screened to improve the reaction rates (Table 1).
The results showed that Et3N had almost no effect on the process, where both the yield and the ee of the product
remained the same as without any additives. The other two organic bases: 4-methylmorpholine and 1-
methylimidazole, led to very low yields to the product, while maintaining high ees. On the other hand, two of the
Lewis acids tested, ZnBr2 and SiO2, increased the reaction yield in solution (entry 5 and 6), although the presence of
ZnBr2 resulted in substantially reduced product ee during the process. Fortunately, SiO2 did not affect the
enantioselectivity of the lipase-catalysis process, and the reaction was considered accelerated. The appeared reaction
time was thus shortened from 4 d to 3 h, while maintaining a product ee of 95%.
Table 1. Effect of additivesa
3
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Entry
1
Additive
-
Time
4 d
Yield (%)b
46
ee (%)c
92
2
3
4
5
6
Et3N
4 d
4 d
4 d
3 h
2 d
47
30
21
47
52
93
91
93
95
9
O
N
N
N
SiO2
ZnBr2
a Reactions were carried out with 0.05 mmol of 1a, 3 equiv. of 2, 0.5 equiv. of additives, 20 mg of 4 Å MS and 50 mg of PS-
IM in 0.6 mL TBME at rt; b Determined by 1H NMR spectroscopy; c Determined by HPLC analysis using a Daicel Chiralpak
OD-H column
Following identification of optimized reaction conditions with respect to lipase preparation, solvent, carbonate
structure and additives, a range of substrates was evaluated in the process (Table 2). Interestingly, the tested
substrates resulted in different solution distributions when the reactions reached full conversions to the products.
Besides the cyclized oxazolidinone products,
intermediates 1’ in the solution, while more sterically hindered substrates (1e
materials 1e 1g. The determined ees for all constituents are shown in Table 2, where the unbalanced ratios between
N
-substituted methyl, ethyl and butyl substrates gave only
,
1f and 1g) mainly provided starting
-
the enantiomers can be attributed to the irreversible interactions between the substrates and SiO2 (cf. ESI). On the
other hand, the benzyl-substituted substrate 1h was not affected by the addition of SiO2, presenting a typical pattern
for kinetic resolution. In some cases, the enantioenriched intermediate 1’ was not stable under the reaction
conditions, and partially reverted back to starting material
With respect to the enantioselective cyclization, the majority of the oxazolidinone products were obtained with
good total yields and high enantiopurities. Changing the phenyl group for a -chlorophenyl moiety (1b) led to a
1.
p
slightly lower reaction rate, but resulted in good yield and excellent ee. Replacing the amine methyl group for an
ethyl functionality (1c) showed only minor effects, and the reaction rate and ee remained high. However, upon
increasing the size of the amine substituent further by applying a butyl group (1d), the ee decreased to some extent,
likely due to less optimal fit of the longer aliphatic chain into the enzyme active site. Aliphatic rings were also
applied as amine substituents, including cyclopropyl (1e) and cyclopentyl (1f) groups. The reaction process
proceeded well for the cyclopropyl group, resulting in good yield (50 %) and ee (92 %). However, increasing the
ring size to the larger cyclopentyl group, led to longer reaction time and considerably lower ee. For the substrate
with a tert-butyl group as amine substituent (1g), poor enantioselectivity and longer reaction time were recorded. In
addition to the aliphatic groups, a phenyl substituent was also probed on the amine side (1h). Although longer time
was required for this reaction to reach good yield, a high ee of the product was nevertheless obtained.
4
Page 4 of 10

Table 2. Kinetic resolution of different substrates a
Conversion
(%)b
Yield
(%)c
ee1
ee1’
ee3
Entry
1
Substrate
Time
3 h
(%)d (%)e (%)f
OH
H
N
> 99
47
n.d.g
--h
14
4
95
1a
OH
H
N
2
4.5 h
58
45
> 99
1b
Cl
OH
H
N
3
4
5
6
7
8
3.5 h
1.5 h
1.5 h
3 d
> 99
> 99
50
50
42
50
48
57
46
n.d.
n.d.
44
--
12
58
97
88
92
28
10
90
1c
OH
H
N
1d
OH
H
N
n.d.
n.d.
n.d.
99
1e
OH
H
N
48
1f
OH
H
N
3 d
57
--
1g
OH
H
N
5 d
96
3
1h
a Reactions were carried out with 0.05 mmol of 1, 3 equiv. of 2, 0.5 equiv. of SiO2, 20 mg of 4 Å MS and 50 mg of PS-IM in
1
c
0.6 mL TBME at rt; b The total conversion of starting material 1. Determined by H NMR spectroscopy; The yield from
starting material 1 to product 3. ee of starting material 1 when the reaction reached aforementioned conversion. e ee of
d
f
intermediate 1’ when the reaction reached aforementioned conversion. All ees were determined by HPLC analysis using a
Daicel Chiralpak OD-H column. g No corresponding compound was detected when the reaction was quenched. No chiral
h
separation method was found.
3. Conclusions
A kinetic resolution protocol for the synthesis of enantioenriched oxazolidinone derivatives has been
successfully developed using carbonate donors and lipase catalysis. Following an initial carbamation step, lipase-
catalyzed cyclization provided the oxazolidinone structures in good yields and with excellent enantiopurities. The
use of carbonates as double acyl donors for lipase-catalyzed cyclizations has been successfully illustrated in a
cascade reaction process, representing an efficient method for chiral oxazolidinone synthesis.
4. Experimental
4.1 General methods
Reagents were obtained from commercial suppliers and used as received. Lipase PS “Amano” IM [EC 3.1.1.3]
was purchased from Amano Enzyme Inc. Lipases from Pseudomonas fluorescens (PFL), Burkholderia
(Pseudomonas) cepacia (PS), Candida antarctica (CAL-B) were purchased from Sigma-Aldrich. 1H and 13C NMR
data were recorded on a Bruker Avance 400 (100) MHz and/or a Bruker Avance 500 (125) MHz, respectively.
Chemical shifts are reported as δ values (ppm) with CDCl3 (1H NMR δ 7.26, 13C NMR δ 77.0) as an internal
standard. J values are given in Hertz (Hz). Analytical high performance liquid chromatography (HPLC) with chiral
stationary phase was performed on an HP-Agilent 1110 Series controller and a UV detector, using a Daicel
Chiralpak OD-H column (4.6 × 250 mm, 10 µm). Solvents for HPLC use were of spectrometric grade. Thin layer
5
Page 5 of 10

chromatography (TLC) was performed on precoated Polygram® SIL G/UV 254 silica plates (0.20 mm, Macherey-
Nagel), visualized with UV-detection. Flash column chromatography was performed on silica gel 60, 0.040-0.063
mm (SDS).
4.2 General procedure for the synthesis of α-amino alcohols (1a-1h)
Styrene oxide or 2-(4-chlorophenyl)oxirane (2 mmol), was added to a flask together with methylamine (8 mmol, 40 %
aqueous solution) or other amines (8 mmol) in ethanol (2 mL). Then the solution was stirred at 60 °C for 7 h. The solvent was
subsequently evaporated, and the crude product was purified using column chromatography (EtOAc, followed by
EtOAc:MeOH = 10:1).
2-(Methylamino)-1-phenylethanol (1a) [44]
Light yellow solid, yield: 34 %. 1H NMR (500 MHz, CDCl3, 25 oC) δ 2.48 (s, 3H, CH3), 2.73 (dd, J1 = 12.1 Hz, J2 = 8.9 Hz,
1H, CH2), 2.84 (dd, J1 = 12.1 Hz, J2 = 3.7 Hz, 1H, CH2), 4.73 (dd, J1 = 8.9 Hz, J2 = 3.7 Hz, 1H, CH), 7.25-7.30 (m, 1H, CH),
7.32-7.40 (m, 4H, 4CH); 13C NMR (125 MHz, CDCl3, 25 oC) δ 36.1, 59.3, 71.5, 125.9, 127.7, 128.5, 142.6.
1-(4-Chlorophenyl)-2-(methylamino)ethanol (1b) [44]
1
Yellow oil, yield: 54 %. H NMR (500 MHz, CDCl3, 25 oC) δ 2.44 (s, 3H, CH3), 2.66 (dd, J1 = 12.1 Hz, J2 = 9.2 Hz, 1H,
CH2), 2.76 (dd, J1 = 12.1 Hz, J2 = 3.5 Hz, 1H, CH2), 4.72 (dd, J1 = 9.2 Hz, J2 = 3.5 Hz, 1H, CH), 7.27-7.33 (m, 4H, 4CH);
13C NMR (125 MHz, CDCl3, 25 oC) δ 36.0, 59.1, 70.7, 127.4, 128.7, 133.3, 141.2.
2-(Ethylamino)-1-phenylethanol (1c) [44]
White solid, yield: 47 %. 1H NMR (500 MHz, CDCl3, 25 oC) δ 1.18 (t, J = 7.2 Hz, 3H, CH3), 3.30-3.46 (m, 3H, CH2CH2),
3.92 (t, J = 8.4 Hz, 1H, CH2), 5.49 (t, J = 8.4 Hz, 1H, CH), 7.34-7.43 (m, 5H, 5CH); 13C NMR (125 MHz, CDCl3, 25 oC) δ
12.7, 39.1, 51.8, 74.4, 125.6, 128.9, 129.1, 139.0, 157.8.
2-(Butylamino)-1-phenylethanol (1d) [45]
White solid, yield 36 %. 1H NMR (500 MHz, CDCl3, 25 oC) δ 0.93 (t, J = 7.3 Hz, 3H, CH3), 1.31-1.40 (m, 2H, CH2), 1.44-
1.52 (m, 2H, CH2), 2.58-2.75 (m, 3H, CHCH2), 2.88 (dd, J1 = 12.1 Hz, J2 = 3.5 Hz, 1H, CH2), 4.74 (dd, J1 = 9.2 Hz, J2 = 3.5
Hz, 1H, CH), 7.27-7.31 (m, 1H, CH), 7.34-7.41 (m, 4H, 4CH); 13C NMR (125 MHz, CDCl3, 25 oC) δ 14.1, 20.4, 32.5, 49.3,
57.3, 71.7, 126.0, 127.5, 128.5, 142.9.
2-(Cyclopropylamino)-1-phenylethanol (1e) [46]
Colorless oil, yield: 44 %. 1H NMR (500 MHz, CDCl3, 25 oC) δ 0.32-0.53 (m, 4H, 2CH2), 2.14-2.10 (m, 1H, CH), 2.80 (dd,
J1 = 12.1 Hz, J2 = 9.1 Hz, 1H, CH2), 3.01 (dd, J1 = 12.1 Hz, J2 = 3.7 Hz, 1H, CH2), 4.73 (dd, J1 = 9.1 Hz, J2 = 3.7 Hz, 1H,
CH), 7.25-7.30 (m, 1H, CH), 7.32-7.39 (m, 4H, 4CH); 13C NMR (125 MHz, CDCl3, 25 oC) δ 6.3, 7.1, 30.4, 57.3, 71.9, 126.0,
127.6, 128.5, 142.7.
2-(Cyclopentylamino)-1-phenylethanol (1f) [47]
White solid, yield: 56 %, 1H NMR (500 MHz, CDCl3, 25 oC) δ 1.12 (s, 9H, 3CH3), 2.62 (dd, J1 = 12.1 Hz, J2 = 8.8 Hz, 1H,
CH2), 2.91 (dd, J1 = 12.1 Hz, J2 = 3.5 Hz, 1H, CH2), 4.64 (dd, J1 = 8.8 Hz, J2 = 3.5 Hz, 1H, CH), 7.25-7.29 (m, 1H, CH),
7.33-7.40 (m, 4H, 4CH); 13C NMR (125 MHz, CDCl3, 25 oC) δ 24.0, 24.1, 33.2, 33.6, 56.0, 59.7, 72.2, 125.9, 127.6, 128.5,
142.9.
2-(tert-Butylamino)-1-phenylethanol (1g) [48]
Light yellow solid, yield: 9 %. 1H NMR (500 MHz, CDCl3, 25 oC) δ 1.29-1.39 (m, 2H, CH2), 1.49-1.59 (m, 2H, CH2), 1.63-
1.73 (m, 2H, CH2), 1.79-1.88 (m, 2H, CH2), 2.67 (dd, J1 = 12.4 Hz, J2 = 9.2 Hz, 1H, CH2), 2.92 (dd, J1 = 12.4 Hz, J2 = 3.7 Hz,
1H, CH2), 3.08-3.15 (m, 1H, CH), 4.68 (dd, J1 = 9.2 Hz, J2 = 3.7 Hz, 1H, CH), 7.24-7.30 (m, 1H, CH), 7.32-7.40 (m, 4H,
4CH); 13C NMR (125 MHz, CDCl3, 25 oC) δ 29.3, 50.4, 50.6, 72.3, 126.0, 127.5, 128.5, 143.1.
1-Phenyl-2-(phenylamino)ethanol (1h) [49]
Yellow oil, yield: 30.8 %. 1H NMR (500 MHz, CDCl3, 25 oC) δ 3.31 (dd, J1 = 13.3 Hz, J2 = 8.7 Hz, 1H, CH2), 3.45 (dd, J1 =
13.3 Hz, J2 = 3.7 Hz, 1H, CH2), 4.95 (dd, J1 = 8.7 Hz, J2 = 3.7 Hz, 1H, CH), 6.69 (d, J = 8.1 Hz, 2H, 2CH), 6.75 (t, J = 7.3
Hz, 1H, CH), 7.20 (t, J = 8.1 Hz, 2H, CH), 7.33 (t, J = 7.1 Hz, 1H, CH), 7.37-7.45 (m, 4H, 4CH); 13C NMR (125 MHz,
CDCl3, 25 oC) δ 52.0, 72.7, 113.6, 118.2, 126.0, 128.2, 128.8, 129.5, 142.2, 148.0.
4.3. General procedure for the synthesis of racemic oxazolidinones (3a-3h)
6
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α-Amino alcohol 1a-1h (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. Then 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).
4.4. General procedure for kinetic resolution of oxazolidinones (3a-3h)
α-Amino alcohol 1a-1h (0.05 mmol), diphenyl carbonate (0.15 mmol) and dry TBME (0.6 mL) were added into a 1.5 mL
sealed-cap vial containing PS-IM (50 mg), silica gel (20 mg) and 4Å molecular sieves (20 mg). PS-IM was dried under
1
vacuum for at least two days before use. The vial was kept at r.t. without stirring, and H NMR was used to monitor the
reaction progress. After a certain 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 combined organic layer was
dried over MgSO4 and removed in vacuo. The crude products were purified using column chromatography (Hexane:EtOAc =
6:1).
(S)-3-Methyl-5-phenyloxazolidin-2-one ((S)-3a) [50]
Yield: 47%, enantiomeric excess (ee): 95%, determined by HPLC analysis (Daicel Chiralpak OD-H column) 90:10
Hex:iPrOH, 0.5 mL/min; tR 38.0 min; tR 48.6 min. 1H NMR (500 MHz, CDCl3, 25 oC) δ 2.93 (s, 3H, CH3), 3.45 (t, J = 7.9 Hz,
1H, CH2), 3.92 (t, J = 8.6 Hz, 1H, CH2), 5.49 (t, J = 8.1 Hz, 1H, CH), 7.33-7.43 (m, 5H, 5CH); 13C NMR (125 MHz, CDCl3,
25 oC) δ 31.2， 54.6， 74.3， 121.9, 125.7, 128.9, 129.0, 138.9; [α]25D = +30 (c 1.0, CHCl3, ee: 87%).
(S)-5-(4-Chlorophenyl)-3-methyloxazolidin-2-one ((S)-3b)
Yield: 45%, enantiomeric excess (ee): > 99%, determined by HPLC analysis (Daicel Chiralpak OD-H column) 90:10
Hex:iPrOH, 0.5 mL/min; tR 41.3 min; tR 48.3 min. 1H NMR (500 MHz, CDCl3, 25 oC) δ 2.93 (s, 3H, CH3), 3.40 (t, J = 8.1 Hz,
1H, CH2), 3.91 (t, J = 8.8 Hz, 1H, CH2), 5.46 (t, J = 8.1 Hz, 1H, CH), 7.28 (d, J = 8.4 Hz, 2H, 2CH), 7.38 (d, J = 8.4 Hz, 2H,
2CH); 13C NMR (125 MHz, CDCl3, 25 oC) δ 31.3, 54.5, 73.6, 127.1, 129.3, 134.9, 137.4, 158.1; [α]25D = +34 (c 1.0, CHCl3,
ee: 92%); HRMS: found 212.04692, calc. for C10H11Cl1N1O2 [M+H+] 212.04728.
(S)-3-Ethyl-5-phenyloxazolidin-2-one ((S)-3c) [50]
Yield: 50%, enantiomeric excess (ee): 97%, determined by HPLC analysis (Daicel Chiralpak OD-H column) 90:10
Hex:iPrOH, 0.5 mL/min; tR 31.0 min; tR 38.1 min. 1H NMR (500 MHz, CDCl3, 25 oC) δ 1.18 (t, J = 7.2 Hz, 3H, CH3), 3.29-
3.46 (m, 3H, CH2CH2), 3.92 (t, J = 8.8 Hz, 1H, CH2), 5.49 (t, J = 8.2 Hz, 1H, CH), 7.34-7.43 (m, 5H, 5CH); 13C NMR
(125 MHz, CDCl3, 25 oC) δ 12.6, 38.9, 51.8, 74.3, 125.7, 128.9, 129.1, 139.0, 157.9.
(S)-3-Butyl-5-phenyloxazolidin-2-one ((S)-3d) [50]
Yield: 42%, enantiomeric excess (ee): 88%, determined by HPLC analysis (Daicel Chiralpak OD-H column) 90:10
Hex:iPrOH, 0.5 mL/min; tR 25.0 min; tR 29.8 min. 1H NMR (500 MHz, CDCl3, 25 oC) δ 0.94 (t, J = 7.5 Hz, 3H, CH3), 1.31-
1.40 (m, 2H, CH2), 1.50-1.59 (m, 2H, CH2), 3.23-3.38 (m, 2H, CH2), 3.40-3.45 (m, 1H, CH2), 3.91 (t, J = 8.8 Hz, 1H, CH2),
5.48 (t, J = 8.1 Hz, 1H, CH), 7.33-7.43 (m, 5H, 5CH); 13C NMR (125 MHz, CDCl3, 25 oC) δ 13.8, 19.9, 29.5, 44.1, 52.3, 74.5,
125.6, 128.9, 129.0, 139.0, 158.0.
(S)-3-Cyclopropyl-5-phenyloxazolidin-2-one ((S)-3e) [50]
Yield: 50%, enantiomeric excess (ee): 92%, determined by HPLC analysis (Daicel Chiralpak OD-H column) 90:10
Hex:iPrOH, 0.5 mL/min; tR 36.3 min; tR 46.0 min. 1H NMR (500 MHz, CDCl3, 25 oC) δ 0.68-0.87 (m, 4H, 2CH2), 2.55-2.60
(m, 1H, CH), 3.44 (t, J = 8.5 Hz, 1H, CH2), 3.89 (t, J = 8.7 Hz, 1H, CH2), 5.43 (t, J = 8.1 Hz, 1H, CH), 7.31-7.43 (m, 5H,
5CH); 13C NMR (125 MHz, CDCl3, 25 oC) δ5.7, 6.2, 26.0, 53.6, 74.6, 125.6, 128.9, 129.0, 138.7, 158.2.
(S)-3-Cyclopentyl-5-phenyloxazolidin-2-one ((S)-3f)
Yield: 48%, enantiomeric excess (ee): 28%, determined by HPLC analysis (Daicel Chiralpak OD-H column) 90:10
1
Hex:iPrOH, 0.5 mL/min; tR 27.1 min; tR 32.6 min. H NMR (500 MHz, CDCl3, 25 oC) δ 1.49-1.67 (m, 6H, 3CH2), 1.88(m,
2H, CH2), 3.39 (t, 1H, CH2), 3.88 (t, 1H, CH2), 4.29(m, 1H, CH), 5.47 (t, 1H, CH), 7.26-7.41 (m, 5H, 5CH); 13C NMR
(125 MHz, CDCl3, 25 oC) δ 24.0, 24.1, 28.8, 29.3, 48.7, 54.8, 74.6, 125.6, 128.9, 129.1, 139.1, 157.7; [α]25 = +3 (c 1.0,
D
CHCl3, ee: 26%); HRMS: found 232.1332; calc. for C14H17NO2 [M+H]+ 232.1338.
(S)-3-tert-Butyl-5-phenyloxazolidin-2-one ((S)-3g) [50]
Yield: 57%, enantiomeric excess (ee): 10%, determined by HPLC analysis (Daicel Chiralpak OD-H column) 90:10
Hex:iPrOH, 0.5 mL/min; tR 19.2 min; tR 26.8 min. 1H NMR (500 MHz, CDCl3, 25 °C) δ; 1.41 (s, 9H, 3CH3), 3.46 (t, J = 8.3
7
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Hz, 1H, CH2), 3.96 (t, J = 8.6 Hz, 1H, CH2), 5.38 (t, J = 8.3 Hz, 1H, CH), 7.33-7.43 (m, 5H, 5CH); 13C-NMR (125 MHz,
CDCl3, 25 °C) δ 27.5, 51.3, 53.8, 73.7, 125.8, 128.8, 129.1, 139.1, 156.9.
(S)-3,5-Diphenyloxazolidin-2-one ((S)-3h) [50]
Yield: 46%, enantiomeric excess (ee): 90%, determined by HPLC analysis (Daicel Chiralpak OD-H column) 90:10
Hex:iPrOH, 0.5 mL/min; tR 25.5 min; tR 28.3 min. 1H NMR (500 MHz, CDCl3, 25 °C) δ; 3.97 (t, J = 8.1 Hz, 1H, CH2), 4.39
(t, J = 9.1 Hz, 1H, CH2), 5.65 (t, J = 8.1 Hz, 1H, CH), 7.15 (t, J = 7.3 Hz, 1H, CH), 7.35-7.47 (m, 7H, 7CH), 7.56 (d, J = 7.7
Hz, 2H, 2CH); 13C-NMR (125 MHz, CDCl3, 25 °C) δ 52.9, 74.2, 118.4, 124.3, 125.8, 129.2, 129.3, 138.2, 138.3, 154.8.
Acknowledgements
This work was supported in part by the Swedish Research Council and the Royal Institute of Technology. YZ
and YZ thank the China Scholarship Council for special scholarship awards.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.molcatb.
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