Parallel kinetic resolution of racemic oxazolidinones using quasi-enantiomeric active esters

Article abstract of DOI:10.1016/j.tetasy.2007.10.009

Racemic Evans' oxazolidinones were efficiently resolved using a combination of quasi-enantiomeric profens. The levels of stereocontrol were high, leading to products with predictable configurations.

Full text of DOI:10.1016/j.tetasy.2007.10.009

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2515–2530
Parallel kinetic resolution of racemic oxazolidinones using
quasi-enantiomeric active esters
Ewan Boyd,a Elliot Coulbeck,b Gregory S. Coumbarides,c Sameer Chavda,b Marco Dingjan,c
Jason Eames,b,* Anthony Flinn,d Majid Motevalli,c Julian Northend and Yonas Yohannesc
aSyngenta, Grangemouth Manufacturing Centre, Earls Road, Grangemouth, Scotland FX3 8XG, UK
bDepartment of Chemistry, University of Hull, Cottingham Road, Kingston upon Hull HU6 7RX, UK
cSchool of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, UK
dOnyx Scientific Limited, Units 97-98, Silverbriar, Sunderland Enterprise Park East, Sunderland SR5 2TQ, UK
Received 31 July 2007; accepted 4 October 2007
Available online 5 November 2007
Abstract—Racemic Evans’ oxazolidinones were efficiently resolved using a combination of quasi-enantiomeric profens. The levels of
stereocontrol were high, leading to products with predictable configurations.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Over the last few years, we have employed this PKR strat-
egy6 for the resolution of active esters, such as rac-14,7
using a pair of quasi-enantiomeric oxazolidinones (R)-12
and (S)-13 to give two separable diastereoisomerically pure
oxazolidinones syn,anti-15 and syn,anti-16 in moderate
yield and with high levels of diastereocontrol (Scheme 3).8
The separation of enantiomeric substrates using a parallel
kinetic resolution (PKR) is becoming a more popular
method.1 In recent years, attention has been focussed on
the use of traditional chiral auxiliaries as complementary
quasi-enantiomeric resolving agents.2 In particular, Davies3
has demonstrated this philosophy with resolution of a
racemic enone rac-3 using an equimolar combination of
quasi-enantiomeric lithium amides (S)-1 and (R)-2 (Scheme
1). The levels of enantiomer recognition were excellent
leading to separable b-amino esters syn,syn,anti-4 and
syn,syn,anti-5 in good yield with superb levels of diastereo-
isomeric control (Scheme 1).
2. Results and discussion
Herein, we report9 an extension of our methodology for the
complementary resolution of racemic Evans’10 oxazolidi-
nones, such as rac-A, using an equimolar combination of
quasi-enantiomeric profens [e.g., (R)-B and (S)-C] to give
the corresponding oxazolidinone adducts (R,S)-D and
(S,R)-E (Scheme 4). Simple separation and hydrolysis of
each adduct should lead to both individual enantiomers
of the original oxazolidinone (S)- and (R)-A, respectively
(Scheme 4).
Moreover, Fox4 has shown the use of a pair of quasi-enan-
tiomeric oxazolidinones (S)-6 and (R)-7 as resolving com-
ponents for the resolution of a racemic mixed anhydride
rac-8 to give the corresponding oxazolidinone adducts 9
and 10 with near perfect levels of stereocontrol (Scheme
2). These adducts were efficiently separated using a Vedejs’
post-modification strategy5 by the treatment of oxazolidi-
nones 9 and 10 with TBAF to give the more separable oxa-
zolidinones 9 and 11 (Scheme 2).
With this aim in mind, we first probed the kinetic resolu-
tion of a series of structurally related racemic oxazolidi-
nones rac-12, rac-13, rac-20, rac-21 and rac-22 using
two quasi-enantiomeric pentafluorophenyl active esters
(R)-14 and (S)-19 (Schemes 5–7). We initially chose to
use this combination of pentafluorophenyl active esters
(R)-14 and (S)-19 for synthetic ease, and the resulting
oxazolidinone adducts were also known to be separable
*
Corresponding author. Tel.: +44 1482 466401; fax: +44 1482 466410;
e-mail: j.eames@hull.ac.uk
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.009

2516
E. Boyd et al. / Tetrahedron: Asymmetry 18 (2007) 2515–2530
OMe
OMe
Me
Me
N
Li
N
Li
(R)-2
(S)-1
Ar = 3,4-dimethoxyphenyl
Me
Ph
Ph
CO2Me
Me
Ph
Ar
(S)-1
(R)-2
CO2Me
N
CO2Me
N
THF
t-Bu
t-Bu
t-Bu
-78 oC
syn,syn,anti-4
syn,syn,anti-5
rac-3
39%, 95-97% d.e.
35%, 97-99% d.e.
Scheme 1. Parallel kinetic resolution of enone (rac)-3 using quasi-enantiomeric lithium amides 1 and 2.
(Scheme 5).9 The addition of pentafluorophenol to a
stirred solution of DCC and carboxylic acids, (R)-17 or
(S)-18, in dichloromethane gave the corresponding
enantiomerically pure active esters (R)-14 and (S)-19 in
85% and 84% yields, respectively (Scheme 5).
O
O
1. n-BuLi
THF, -78 oC
HN
O
HN
O
2.
Ph
CO2C6F5
(2 equiv.)
EtO2C
(R)-12
i-Pr
H CH3
(rac)-14
(S)-13
For this kinetic resolution study, we chose to use 2 equiv of
racemic oxazolidinone, as this would mirror our standard
parallel kinetic resolution conditions.8 The addition of
O
O
O
O
Ph
Me
Ph
O
N
O
O
N
Me
i-Pr
O
1. n-BuLi,
THF, -98 oC
H
H
HN
O
HN
O
EtO2C
2.
O
O
syn-: anti-15
syn-: anti-16
Ph
95:5; 60%
95:5; 49%
O
Scheme 3. Parallel kinetic resolution of active ester (rac)-14 using quasi-
enantiomeric oxazolidinones 12 and 13.
Ph
TBSO
(2 equiv.)
rac-8
(R)-7
(S)-6
n-BuLi to a stirred solution of oxazolidinones rac-12, rac-
13, rac-20, rac-21 and rac-22 in THF at ꢀ78 ꢁC, followed
by the addition of either enantiomerically pure active esters
(R)-14 or (S)-19, gave the corresponding oxazolidinone
adducts syn- and anti-15, syn- and anti-16, syn- and anti-
23, syn- and anti-24, and syn,syn- and anti,syn-25 [derived
from (R)-14—Scheme 6] and syn- and anti-26, syn- and
anti-27, syn- and anti-28, syn- and anti-29, and syn,syn-
and anti,syn-30 [derived from (S)-19—Scheme 7], respec-
tively. These active esters (R)-14 and (S)-19 proved to be
moderately diastereoselective favouring the formation of
the corresponding syn-oxazolidinone adduct (from 34%
to 64% de). Higher levels of diastereocontrol were preferred
for oxazolidinones, which contained a sterically demanding
group at its C(4) position; for example, when using
oxazolidinones rac-13 and rac-20, when R = i-Pr and Ph,
respectively (Schemes 6 and 7). The stereochemistry of
these adducts was assigned by comparison with known
derivatives.8,9
O
O
O
O
N
Ph
Ph
Ph
Ph
N
O
O
TBSO
10
9
O
O
O
O
Ph
Ph
Ph
TBAF
N
O
N
O
Ph
HO
11; 98% d.e.; 87%
9; 99% d.e.; 91%
With this information in hand, we next probed the parallel
kinetic resolution of this series of oxazolidinones rac-12,
Scheme 2. Parallel kinetic resolution of mixed anhydride (rac)-8 using
quasi-enantiomeric oxazolidinones 6 and 7.

E. Boyd et al. / Tetrahedron: Asymmetry 18 (2007) 2515–2530
2517
O
O
O
O
O
1. n-BuLi
THF, -78oC
Ar1
Me
Ar2
Me
HN
R
O
N
O
N
O
1
2.
Ar
CO2C6F5
H
H
R
R
Me H
(R)-B
Ar2
CO2C6F5
rac-A
(S,R)-syn-E
(R,S)-syn-D
(2 equiv.)
LiOH
LiOH
THF, H2O
THF, H2O
Me H
(S)-C
O
O
HN
O
HN
R
O
R
(S)-A
(R)-A
Scheme 4. Proposed parallel kinetic resolution of oxazolidinone (rac)-A using active esters (R)-B and (S)-C.
Ph
Me
(R)-17
CO2H DCC, C6F5OH
Ph
Me
CO2C6F5
CH2Cl2
H
H
(R)-14; 85%
MeO
MeO
CO2C6F5
CO2H
Me
(S)-18
DCC, C6F5OH
CH2Cl2
H
Me
H
(S)-19; 84%
Scheme 5. Synthesis of active esters (R)-14 and (S)-19.
O
O
O
O
O
O
1. n-BuLi
THF, -78oC
Ph
Ph
Me
HN
O
N
O
N
O
HN
R
O
2.
Ph
Me H
(R)-14
CO2C6F5
H
Me
H
R
anti-
Me
rac-22
Ph
R
rac-
syn-
(2 equiv.)
rac-12; R = CO2Et
rac-21; R = CH2Ph
rac-13; R = i-Pr
rac-20; R = Ph
rac-22
Oxazolidinone
syn,syn-25: anti,syn-25
syn-15: anti-15
syn-16: anti-16
syn-23: anti-23
syn-24: anti-24
Products
Ratio
78:22
74:26
80:20
67:33
74:26
Yield
59%
60%
61%
71%
74%
Scheme 6. Kinetic resolution of oxazolidinones (rac)-12, 13 and 20–22 using active ester (R)-14.
rac-13, rac-20, rac-21 and rac-22 using an equimolar
combination of quasi-enantiomeric active esters (R)-14
and (S)-19 (Scheme 8). The addition of an equimolar
mixture of active esters (R)-14 and (S)-19 to a stirred solu-
tion of the lithiated racemic oxazolidinones derived from
rac-12, rac-13, rac-20, rac-21 and rac-22 (2 equiv) in THF
at ꢀ78 ꢁC, gave the corresponding oxazolidinone adducts
syn-15, syn-16, syn-23, syn-24, and syn,syn-25 [derived from
(R)-14] and the complementary syn-26, syn-27, syn-28, syn-
29 and syn,syn-30 [derived from (S)-19] as the major diaste-
reoisomers, respectively (Scheme 8). These oxazolidinones
were efficiently separated by column chromatography to
give the diastereoisomerically pure adducts (Scheme 8).11
The levels of diastereocontrol (and consequently enantio-
mer selection) were near perfect for the oxazolidinones
rac-12, rac-13 and rac-20 (Scheme 8). Whereas, for those
oxazolidinones, such as rac-21 and rac-22, which were ste-
rically less demanding at their C(4)-position, lower levels of

2518
E. Boyd et al. / Tetrahedron: Asymmetry 18 (2007) 2515–2530
O
O
O
O
O
1. n-BuLi
THF, -78oC
Ar
Ar
N
O
N
O
HN
R
O
2.
Ar
CO2C6F5
H Me
(S)-19
H
Me
H
Me
R
R
rac-
syn-
anti-
(2 equiv.)
rac-21; R = Bn
rac-12; R = CO2Et
rac-13; R = i-Pr
rac-20; R = Ph
rac-22
Oxazolidinone
syn,syn-30: anti,syn-30
syn-29: anti-29
syn-26: anti-26
syn-27: anti-27
syn-28: anti-28
Products
Ratio
73:27
67:33
79:21
79:21
82:18
79%
51%
Yield
78%
69%
67%
Scheme 7. Kinetic resolution of oxazolidinones (rac)-12, 13 and 20–22 using active ester (S)-19.
MeO
O
O
O
O
O
O
1. n-BuLi
THF, -78 oC
Ph
Me
N
O
N
HN
R
O
2. (R)-14
(S)-19
H
H Me
R
R
syn-
rac-
syn-
(2 equiv.)
Products
[derived from (S)-19]
Entry
1
[derived from (R)-14]
Oxazolidinone
syn-26:anti-26; 95:5; 59%
syn-27:anti-27; 95:5; 59%
rac-12; R = CO2Et
syn-15:anti-15; 95:5; 55%
rac-13; R = i-Pr
rac-20; R = Ph
rac-21; R = Bn
rac-22
syn-16:anti-16; 95:5; 57%
syn-23:anti-23; 95:5; 65%
syn-24:anti-24; 72:28; 47%
2
3
4
5
syn-28:anti-28; 95:5; 61%
syn-29:anti-29; 70:30; 42%
syn-25:anti-25; 82:18; 44% syn-30:anti-30; 85:15; 49%
Scheme 8. The parallel kinetic resolution of oxazolidinones (rac)-12, 13 and 20–22 using quasi-enantiomeric oxazolidinones (R)-14 and (S)-19.
a stirred solution of ibuprofen (R)-31 and pentafluorophe-
nol in dichloromethane (Scheme 9). The treatment of a
CO2C6F5
CO2H
DCC, C6F5OH
CH2Cl2
solution of oxazolidinones rac-12, rac-13 and rac-20
(2 equiv) in THF at ꢀ78 ꢁC with n-BuLi, followed by the
addition of a stirred solution of active esters (R)-32 and
(S)-19 in THF, gave the required pair of complementary
quasi-enantiomeric adducts syn-33 and syn-26 [derived
from rac-12] syn-34 and syn-27 [derived from rac-12], and
syn-35 and syn-28 [derived from rac-20], respectively with
high levels of stereocontrol (Scheme 10). These adducts
were efficiently separated by column chromatography to
give the corresponding diastereoisomerically pure adducts
in good yields (Scheme 10).
Me
H
Me
H
(R)-32; 82%
(R)-31
Scheme 9. Synthesis of active ester (R)-32.
complementary enantiomer selection were obtained
(Scheme 8).
Our attention next turned to the use of naproxen (S)-19
and ibuprofen (R)-31 as complementary quasi-enantio-
meric resolving agents for the resolution of racemic oxazol-
idinones (Schemes 9 and 10). We chose to focus on this
particular combination of quasi-enantiomeric active esters
(S)-19 and (R)-32, as these would have greater adducts sep-
aration (Scheme 10).12 The required active ester, (R)-32,
was synthesised in 82% yield by the addition of DCC to
In an attempt to gain a greater understanding of this recog-
nition process, we next focussed our attention on the
mutual kinetic separation of an equimolar mixture of two
complementary oxazolidinones, such as (S)-13 and (R)-
20, using two quasi-enantiomeric active esters (R)-14 and
(S)-19 (Scheme 11). The addition of an equimolar solution

E. Boyd et al. / Tetrahedron: Asymmetry 18 (2007) 2515–2530
2519
O
O
N
O
O
Me
H
O
R
1. n-BuLi
syn-
THF, -78 oC
HN
R
O
2.
(R)-32
(S)-19
MeO
O
O
rac-
N
(2 equiv.)
H
Me
R
syn-
Products
Entry
1
[derived from (R)-32]
[derived from (S)-19]
Oxazolidinone
syn-26:anti-26; 96:4; 41%
syn-33:anti-33; 96:4; 41%
rac-12; R = CO2Et
rac-13; R = i-Pr
rac-20; R = Ph
syn-34:anti-34; 95:5; 70%
syn-35:anti-35; 97:3; 54%
syn-27:anti-27; 95:5; 74%
syn-28:anti-28; 95:5; 48%
2
3
Scheme 10. Parallel kinetic resolution of oxazolidinone (rac)-12, 13 and 20 using quasi-enantiomeric active esters (S)-19 and (R)-32.
of active esters (R)-14 and (S)-19 in THF to a stirred solu-
tion of lithiated oxazolidinones in THF at ꢀ78 ꢁC [derived
from the treatment of (S)-13 and (R)-20 with n-BuLi
(2 equiv)], gave the corresponding oxazolidinone adducts
syn-16 and syn-28 in good yield and with excellent levels
of mutual recognition (Scheme 11).13 From this study, it
was evident that oxazolidinone (S)-13 preferentially recog-
nised the (R)-enantiomer of the active ester 14 (to give syn-
16), whereas the complementary oxazolidinone (R)-20
recognised the (S)-enantiomer of enantiomer of the active
ester 19 (to give syn-28), and vice versa (Scheme 11). The
relative amounts of the mismatched adducts anti-23 and
anti-27 were determined by 1H NMR spectroscopy (by
comparison with known adducts). For the remaining oxa-
MeO
O
O
O
O
O
O
1. n-BuLi
THF, -78oC
N
O
N
O
HN
O
HN
Ph
O
2.
(R)-14
(S)-19
Me
H
H
Me
Ph
i-Pr
i-Pr
syn-28: anti-23
syn-16: anti-27
(S)-13
(R)-20
95:5; 67%
95:5; 67%
MeO
MeO
O
O
O
O
O
O
1. n-BuLi
THF, -78oC
N
O
N
O
HN
O
HN
EtO2C
O
2. (R)-14
(S)-19
Me
H
H
Me
EtO2C
i-Pr
i-Pr
(S)-13
syn-26: anti-15
(S)-12
syn-16: anti-27
95:5; 66%
92:8; 66%
O
O
O
O
O
O
1. n-BuLi
THF, -78oC
N
O
N
O
HN
Ph
O
HN
O
2.
(R)-14
(S)-19
Me
H
H
Me
EtO2C
Ph
EtO2C
(S)-12
syn-26: anti-15
(S)-20
syn-23: anti-28
98:2; 56%
98:2; 60%
Scheme 11. Mutual kinetic separation of oxazolidinones 12, 13 and 20 with active esters (R)-14 and (S)-19.

2520
E. Boyd et al. / Tetrahedron: Asymmetry 18 (2007) 2515–2530
COCl
H
(S)-36
Me
O
O
N
O
O
H
Me
i-Pr
O
1. n-BuLi
THF, -78 oC
syn-16: anti-16
HN
O
MeO
2. Active esters
(see table)
O
O
i-Pr
N
rac-13
H
Me
i-Pr
syn-27: anti-27
Active ester and/or
acid chloride
Products
Entry
1
(S)-19 then (S)-36 syn-:anti-16; 12:88; 84%
syn-:anti-27; 85:15; 84%
rac-36
rac-19
syn-:anti-16; 30:70; 60%13
2
3
4
syn-:anti-27; 98:2; 58%
syn-:anti-27; 92:8; 59%
(S)-36 then (S)-19 syn-:anti-16 40:60; 55%
Scheme 12. Sequential resolution of oxazolidinone (rac)-13 with acid chloride (S)-36 and active ester (S)-19.
zolidinone combinations (S)-13 and (R)-12, and (S)-20 and
(R)-12, these gave the corresponding oxazolidinone ad-
ducts syn-16 and syn-28, and syn-23 and syn-26, respec-
tively, with similarly high levels of mutual kinetic
separation (Scheme 11).
trophilic active ester (S)-19, as these are known to favour
the (S)-14 and (R)-enantiomers8,9 of 13, respectively
(Scheme 12). The treatment of the lithiated oxazolidinone
rac-13-Li [derived from rac-13 and n-BuLi], followed by
the sequential addition of the active ester (S)-19 and acid
chloride (S)-36, gave the corresponding oxazolidinone ad-
ducts anti-16 and syn-27 in good yield with modest to good
levels of diastereocontrol (Scheme 12, entry 1). The relative
reaction rates and the resulting diastereocontrol were
evidently different; the oxazolidinone anti-16 was formed
with significantly higher diastereoselectivity relative to its
mutual kinetic resolution,14 whereas, its complementary
In an attempt to probe this mutual recognition process, we
next investigated the sequential resolution of racemic oxa-
zolidinone rac-13 using two complementary carbonyl
derivatives which had differing degrees of electrophilicity
and enantiomer selection (Scheme 12). We chose to use
the more electrophilic acid chloride (S)-36 and the less elec-
O
O
O
O
LiOH, H2O2
HN
O
OH
N
O
CH2Cl2, H2O
Me
H
Me
H
i-Pr
i-Pr
(S)-17; 95%
(S)-13; 93%
anti-16
MeO
MeO
O
O
O
O
LiOH, H2O2
HN
O
OH
N
O
CH2Cl2, H2O
Me
H
Me
H
i-Pr
i-Pr
(S)-18; 75%
(R)-13; 90%
syn-27
Scheme 13. Hydrolysis of oxazolidinones adducts syn-16 and syn-27.

E. Boyd et al. / Tetrahedron: Asymmetry 18 (2007) 2515–2530
2521
partner, oxazolidinone syn-27 was formed with lower
4.2. (ꢀ)-Pentafluorophenyl 2-phenylpropionate (R)-14
diastereocontrol (Scheme 12, entries 2 and 3). This is
understandable as the formation of syn-27 and anti-16
must proceed via kinetic resolution of racemic rac-13 and
scalemic oxazolidinone (S)-13 [due to the (R)-enantiomer
being partially removed from rac-13 by the active ester
(S)-19], respectively. By comparison, the addition of acid
chloride (S)-36 to the lithiated oxazolidinone [derived from
n-BuLi addition to oxazolidinone rac-13], followed by the
active ester (S)-19, gave the corresponding adducts anti-
16 and syn-27 in good yield. The levels of diastereocontrol
for the oxazolidinone anti-16 and syn-27 were slightly lower
than their mutual kinetic resolutions (Scheme 12, entry 4 vs
entries 2 and 3). This particular reagent combination was
evidently less diastereoselective, and illustrated that this
outcome was governed more by the less diastereoselective
acid chloride (S)-36 than its complementary active ester
(S)-19 (Scheme 12).
2-Phenylpropionic acid (R)-17 (3.0 g, 20.0 mmol)
24
{½aꢁD ¼ ꢀ71:7 (c 2.0, CHCl3)} was added to a stirred solu-
tion of N,N0-dicyclohexylcarbodiimide (DCC) (4.53 g,
22.0 mmol) in dichloromethane (100 ml). The resulting
solution was stirred for 10 min. A solution of pentafluoro-
phenol (4.90 g, 26.7 mmol) in dichloromethane (20 ml) was
slowly added, and the resulting solution was stirred for
12 h. The resulting precipitate (N,N0-dicyclohexylurea)
was filtered off (using suction filtration). Water (100 ml)
was added and the solution extracted with dichlorometh-
ane (3 · 100 ml) and dried over MgSO4. The combined
organic layers were evaporated under reduced pressure.
The crude residue was purified by flash column chromato-
graphy on silica gel eluting with light petroleum (bp
40–60 ꢁC)/diethyl ether (9:1) to give pentafluorophenyl
2-phenylpropionate (R)-14 (5.37 g, 85%) as a colourless
oil; RF [light petroleum (40–60 ꢁC)/diethyl ether (1:1)]
24
Lithium hydroxide mediated hydrolysis of these oxazo-
lidinone adducts anti-16 and syn-27, gave the corresponding
enantiomerically pure (S)- and (R)-enantiomers of oxazo-
lidinone 13, respectively, in good yields (Scheme 13). The
complementary resolving profens (S)-17 and (S)-18 were
re-isolated in excellent yield with no loss of enantiomeric
purity (Scheme 13). This has been shown to be the case
for a wide variety of structurally related profen-based oxa-
zolidinone adducts and this has been reported elsewhere.14
0.75; ½aꢁD ¼ ꢀ75:0 (c 3.3, CHCl3);
mmax(CHCl3)/
cmꢀ1 1779 (C@O); dH (270 MHz; CDCl3) 7.41–7.29 (5H,
m, 5 · CH; Ph), 4.07 (1H, q, J 7.2, PhCHCH3) and 1.64
(3H, d, 6.9, PhCHCH3); dC (100 MHz; CDCl3) 170.6
1
(OC@O), 141.1 (142.40 and 139.90, 2C, ddt, JC,F
=
2
3
251.3 Hz, JC,F = 12.2 Hz and JC,F = 3.8 Hz, C(2)–F),
1
139.4 (140.70 and 138.18, 1C, dtt, JC,F = 253.2 Hz,
2JC,F = 13.4 Hz and JC,F = 4.2 Hz, C(4)–F), 138.7 (i-C;
3
1
Ph), 137.8 (139.05 and 136.58, 2C, dtdd, JC,F = 249.1 Hz,
2JC,F = 14.5 Hz, JC,F = 5.7 Hz and JC,F = 3.1 Hz, C(3)–
3
4
F), 128.9, 127.8 and 127.5 (3 · CH; Ph), 125.2 (1C, tdt,
4
3
2JC,F = 14.2 Hz, JC,F = 4.2 Hz and JC,F = 2.0 Hz, i-CO;
3. Conclusion
OC6F5), 45.1 (PhCHCH3) and 18.5 (PhCHCH3); dF
3
(378 MHz; CDCl3) ꢀ152.6 (2F, d, JF,F 17.0, Fortho),
In conclusion, we have reported an efficient parallel kinetic
resolution of racemic oxazolidinones using an equimolar
combination of quasi-enantiomeric profens. This method-
ology8,9 is efficient for a variety of structurally related oxa-
zolidinones [e.g., rac-20] and quasi-enantiomeric profens
[e.g., (R)-14 and (S)-19], and is predictable leading to the
separable, diastereoisomerically pure, syn-adducts 23 and
28 in good yield.
3
3
ꢀ157.9 (1F, t, JF,F 21.7, Fpara) and ꢀ162.3 (2F, dd, JF,F
21.7 and 17.0, Fmeta) (Found M+, 316.0514. C15H9F5O2
requires M+, 316.0517).
4.3. (+)-Pentafluorophenyl-2-(6-methoxynaphthalene-2-yl)-
propionate (S)-19
In the same way as the active ester (R)-14, (S)-(+)-6-meth-
oxy-(2-naphthyl)propionic acid (S)-18 (5.0 g, 21.7 mmol)
20
{½aꢁD ¼ þ64:8 (c 3.4, CHCl3)}, DCC (4.93 g, 23.9 mmol)
4. Experimental
4.1. General
and pentafluorophenol (4.0 g, 21.7 mmol) gave pentafluoro-
phenyl-2-(6-methoxynaphthalene-2-yl)propionate (S)-19
(7.24 g, 84%) as a white powder; mp = 78–80 ꢁC; RF [light
20
petroleum (40–60 ꢁC)/diethyl ether (1:1)] 0.65; ½aꢁD
¼
All solvents were distilled before use. All reactions were
carried out under nitrogen using an oven-dried glassware.
Flash column chromatography was carried out using
Merck Kieselgel 60 (230–400 mesh). Thin layer chromato-
graphy (TLC) was carried out on commercially available
pre-coated plates (Merck Kieselgel 60F254 silica). Proton
and carbon NMR spectra were recorded on a Bruker 400
and 270 MHz Fourier transform spectrometers using an
internal deuterium lock. Chemical shifts are quoted in parts
per million downfield from tetramethylsilane. Carbon
NMR spectra were recorded with broad proton decou-
pling. Infrared spectra were recorded on a Shimadzu
8300 FTIR spectrometer. Optical rotation was measured
using an automatic AA-10 Optical Activity Ltd
polarimeter.
þ93:6 (c 5.6, CHCl3); mmax(CHCl3)/cmꢀ1 1781 (C@O); dH
(250 MHz; CDCl3) 7.76–7.13 (6H, m, 6 · CH; Ar), 4.38
(1H, q, J 7.2, CHCH3) 3.91 (3H, s, CH3) and 1.71 (3H,
d, J 7.2, CH3CH); dC (100 MHz; CDCl3) 170.7 (C@O),
157.9 (i-CO; Ar), 141.0 (142.32 and 139.82.67, 2C, ddt,
1JC,F = 249.8 Hz, JC,F = 12.2 Hz and JC,F = 4.6 Hz,
2
3
1
C(2)–F), 139.3 (140.63 and 138.11, 1C, dtt, JC,F
252.1 Hz, JC,F = 13.0 Hz and JC,F = 4.5 Hz, C(4)–F),
=
2
3
1
137.8 (139.04 and 136.54, 2C, dtdd, JC,F = 250.6 Hz,
2JC,F = 13.8 Hz, JC,F = 5.3 and JC,F = 3.0 Hz, C(3)–F) ,
133.9, 133.7 and 128.9 (3 · i-C; Ar), 129.3, 127.5, 126.2,
125.7, 119.3 and 105.6 (6 · CH; Ar), 125.2 (1C, m, i-CO;
OC6F5), 55.3 (OCH3), 45.9 (ArCH) and 18.5 (CHCH3);
3
4
3
dF (378 MHz; CDCl3) ꢀ152.5 (2F, d, JF,F 17.0, Fortho),
3
3
ꢀ157.9 (1F, t, JF,F 21.6, Fpara) and ꢀ162.3 (2F, dd, JF,F

2522
E. Boyd et al. / Tetrahedron: Asymmetry 18 (2007) 2515–2530
21.6 and 17.0, Fmeta) (Found M+, 396.0783; C20H13F5O
requires 396.0779).
1.22 mmol), ( )-4-phenyl oxazolidin-2-one rac-20 (0.20 g,
1.22 mmol) and (ꢀ)-pentafluorophenyl 2-phenylpropionate
(R)-14 (0.19 g, 0.61 mmol) in THF gave a separable mix-
ture of two diastereoisomeric oxazolidinones syn- and
anti-23 [syn-/anti- 80:20]. The crude mixture was purified
by flash column chromatography on silica gel eluting with
light petroleum (bp 40–60 ꢁC)/diethyl ether (7:3) to give the
oxazolidinone (R,R)-anti-23 (21 mg, 12%) as a white solid;
þ
3
4.4. Kinetic resolution of racemic oxazolidinones using (ꢀ)-
pentafluorophenyl 2-phenylpropionate (R)-14
4.4.1. (4R)-Isopropyl-3-(2R-phenylpropionyl)-oxazolidin-2-
one anti-16 and (4S)-isopropyl-3-(2R-phenylpropionyl)-
oxazolidin-2-one syn-16. n-BuLi (0.61 ml, 2.5 M in hex-
ane, 1.54 mmol) was added to a stirred solution of ( )-4-
isopropyl-oxazolidin-2-one rac-13 (0.20 g, 1.54 mmol) in
THF (5 ml) at ꢀ78 ꢁC. After stirring for 1 h, a solution
of (ꢀ)-pentafluorophenyl 2-phenylpropionate (R)-14
(0.24 g, 0.77 mmol) in THF (1 ml) was added. The resulting
mixture was stirred for 2 h at ꢀ78 ꢁC. The reaction was
quenched with water (10 ml). The organic layer was
extracted with diethyl ether (2 · 10 ml), dried over MgSO4
and evaporated under reduced pressure to give a separable
mixture of two diastereoisomeric oxazolidinones syn- and
anti-16 [syn-/anti- 74:26]. The crude mixture was purified
by flash column chromatography on silica gel eluting with
light petroleum (bp 40–60 ꢁC)/diethyl ether (7:3) to give
the oxazolidinone (R,R)-anti-16 (32 mg, 16%); RF [light
petroleum (bp 40–60 ꢁC)/diethyl ether (1:1)] 0.64;
mp 158–160 ꢁC; RF [light petroleum (bp 40–60 ꢁC)/
20
diethyl ether (1:1)] 0.58; ½aꢁD ¼ ꢀ179:1 (c 3.0, CHCl3);
20
27
{lit.14 ½aꢁD ¼ ꢀ180:5 (c 1.52, CHCl3); lit.17 ½aꢁD ¼ ꢀ163:2
(c 0.1, CHCl3)}; mmax(CHCl3)/cmꢀ1 1780 (C@O) and
1700 (C@O); dH (270 MHz; CDCl3) 7.39–7.26 (10H, m,
10 · CH; 2 · Ph), 5.32 (1H, dd, J 8.8 and 3.2, PhCHN),
5.11 (1H, q, J 7.2, PhCHCH3), 4.55 (1H, t, J 8.8, CHAH-
BO), 4.21 (1H, dd, J 8.8 and 3.2, CHAHBO) and 1.40
(3H, d, J 7.2, PhCHCH3); dC (62.9 MHz; CDCl3) 174.1
(NC@O), 152.9 (OC@O), 140.2 (i-C; PhA), 139.4 (i-C;
PhB), 129.32, 128.71, 128.62, 128.22, 127.31 and 125.82
(10 · CH; PhA and PhB), 69.7 (CH2O), 58.1 (PhCHN),
43.2 (PhCHCH3) anþd 19.4 (PhCHCH3) (Found MH+,
296.1282; C18H18NO3 requires 296.1287); and the oxazo-
lidinone (R,S)-syn-23 (88 mg, 49%) as a white solid;
mp 128–130 ꢁC {for (S,R)-syn-23; mp = 140–142 ꢁC; RF
[light petroleum (bp 40–60 ꢁC)/diethyl ether (1:1)]
0.42; mmax(CHCl3)/cmꢀ1 1778 (C@O) and 1701 (C@O);
20
20
½aꢁD ¼ ꢀ109:6 (c 11.6, CHCl3); {(S,S)-anti-16; ½aꢁD
¼
20
þ128:9 (c 3.5, CHCl3);14 and lit.15 ½aꢁD ¼ þ100:6 (c 1.11,
CHCl3)}, mmax (film) cmꢀ1 1774 (C@O) and 1701 (C@O);
dH (250 MHz; CDCl3) 7.38–7.20 (5H, m, 5 · CH; Ph),
5.15 (1H, q, J 7.0, PhCHCH3), 4.39–4.33 (1H, m, i-
PrCHN), 4.18–4.08 (2H, m, CH2O), 2.50–2.38 (1H, m,
CH(CH3)2), 1.52 (3H, d, J 7.0, PhCHCH3), 0.92 (3H, d,
20
20
½aꢁD ¼ ꢀ83:4 (c 5.0, CHCl3); {lit.14 (S,R)-23; ½aꢁD
¼
27
þ88:5 (c 4.0, CHCl3); lit.17 (S,R)-23 ½aꢁD ¼ þ143:4 (c 0.5,
CHCl3)}; dH (270 MHz; CDCl3) 7.29–7.21 (10H, m,
10 · CH; 2 · Ph), 5.45 (1H, dd J 9.0 and 5.1, PhCHN),
5.09 (1H, q, J 6.9, PhCHCH3), 4.63 (1H, t, J 9.0, CHAH-
BO), 4.08 (1H, dd, J 9.0 and 5.1, CHAHBO) and 1.39
(3H, d, J 6.9, PhCHCH3); dC (62.9 MHz; CDCl3) 173.7
(NC@O), 153.2 (OC@O), 139.9 (i-C; PhA), 138.3 (i-C;
PhB), 128.92, 128.71, 128.52, 128.22, 127.11 and 125.92
(10 · CH; PhA and PhB), 69.6 (CH2O), 57.9 (PhCHN),
43.9 (PhCHCH3) andþ 18.6 (PhCHCH3) (Found MH+,
296.1286; C15H18NO3 requires 296.1287); m/z 295.1
(10%, M+), 132.1 (100, Ph(CH3)C@C@O+), 105.1 (25,
PhCH2þÞ and 77.1 (20, Ph+).
J
7.0, CHA3 CHCHB3 Þ and 0.91 (3H, d,
J
6.9,
CHA3 CHCH3B); dC (62.9 MHz; CDCl3) 174.7 (NC@O),
153.6 (OC@O), 140.4 (i-C; Ph), 128.6, 128.2 and 127.2
(3 · CH; Ph), 63.2 (CH2O), 59.1 (i-PrCHN), 43.1
(PhCHCH3), 28.6 (CH(CH3)2), 19.7 (CH3), 18.1 (CH3)
and 14.8 þ (PhCHCH3) (Found MH+ 262.1434;
C15H20NO requires 262.1443); m/z 262 (30, MH+), 130
3
(48, MꢀC9H8O) and 105 (100, MꢀC7H11NO3); and the
oxazolidinone (R,S)-syn-16 (88 mg, 44%); RF [light
petroleum (bp 40–60 ꢁC)/diethyl ether (1:1)] 0.43;
20
20
½aꢁD ¼ ꢀ19:4 (c 3.0, CHCl3); {lit.14 ½aꢁD ¼ ꢀ19:8 (c 3.3,
4.4.3. (4R)-Benzyl-3-(2R-phenylpropionyl)-oxazolidine-2-one
anti-24 and (4S)-benzyl-3-(2R-phenylpropionyl)-oxazolidine-
2-one syn-24. In the same way as oxazolidinone 16,
n-BuLi (0.45 ml, 2.5 M in hexane, 1.12 mmol), ( )-4-benz-
yl-oxazolidin-2-one rac-21 (0.20 g, 1.12 mmol) and (ꢀ)-
pentafluorophenyl 2-phenylpropionate (R)-14 (0.17 g,
0.56 mmol) in THF gave a separable mixture of two diaste-
reoisomeric oxazolidinones syn- and anti-24 [syn-/anti-
67:33]. The crude mixture was purified by flash column
chromatography on silica gel eluting with light petroleum
(bp 40–60 ꢁC)/diethyl ether (7:3) to give the oxazolidinone
20
CHCl3); lit.16 ½aꢁD ¼ ꢀ19:2 (c 1.15, CHCl3)}; {for (S,R)-
20
16; ½aꢁD ¼ þ18:3 (c 6.0, CHCl3)}; mmax(CHCl3)/cmꢀ1
1774 (C@O) and 1703 (C@O); dH (250 MHz; CDCl3)
7.39–7.19 (5H, m, 5 · CH; Ph), 5.14 (1H, q, J 6.9,
PhCHCH3), 4.49 (1H, m, i-PrCHN), 4.24 (1H, t, J 8.9,
CHAHBO), 4.10 (1H, dd, J 8.9 and 3.5, CHAHBO), 2.24–
2.12 (1H, m, CH(CH3)2), 1.47 (3H, d, J 6.9, PhCHCH3),
0.79 (3H, d, J 7.0, CH3ACHCHB3 Þ and 0.46 (3H, d, J 6.9,
ACH3CHBCH3); dC (62.9 MHz; CDCl3) 174.5 (NC@O),
153.5 (OC@O), 140.5 (i-C; Ph), 128.6, 128.1 and 127.2
(3 · CH; Ph), 62.9 (CH2O), 58.1 (i-PrCHN), 43.3
(PhCHCH3), 27.9 (CH(CH3)2), 18.7 (CH3), 17.8 (CH3)
and 14.1 þ (PhCHCH3) (Found MH+ 262.1432;
C15H20NO3 requires 262.1443); m/z 262 (30%, MH+),
130 (48, MꢀC9H8O) and 105 (100, MꢀC7H11NO3).
(R,R)-anti-24 (40 mg, 23%) as an oil; RF [light petroleum
20
(bp 40–60 ꢁC)/diethyl ether (1:1)] 0.66; ½aꢁD ¼ ꢀ104:0
20
(c 4.0, CHCl3) {lit.14 (S,S)-24; ½aꢁD ¼ þ130:4 (c 1.8,
20
CHCl3); lit.15 ½aꢁD ¼ þ107:1 (c 1.01, CHCl3)};
m
max(CHCl3)/cmꢀ1 1780 (C@O) and 1699 (C@O); dH
(270 MHz; CDCl3) 7.39–7.21 (10H, m, 10 · CH; 2 · Ph),
5.12 (1H, q, J 7.0, PhCHCH3), 4.61–4.54 (1H, m, PhCHN),
4.12–4.10 (2H, m, CH2O), 3.35 (1H, dd, J 13.1 and 3.2,
CHAHBPh), 2.80 (1H, dd, J 13.1 and 9.8, CHAHBPh)
and 1.55 (3H, d, J 7.0, PhCHCH3); dC (100 MHz; CDCl3)
4.4.2. Synthesis of (4R)-4-phenyl-3-(2R-phenylpropionyl)-
oxazolidin-2-one anti-23 and (4S)-4-phenyl-3-(2R-phenyl-
propionyl)-oxazolidin-2-one syn-23. In the same way as
oxazolidinone 16, n-BuLi (0.49 ml, 2.5 M in hexane,

E. Boyd et al. / Tetrahedron: Asymmetry 18 (2007) 2515–2530
2523
174.7 (NC@O), 152.9 (OC@O), 140.3 (i-C; PhA), 135.4
(i-C; PhB), 129.52, 129.02, 128.72, 128.12, 127.41 and
127.31 (10 · CH; PhA and PhB), 65.9 (CH2O), 55.8
(BnCHN), 43.2 (PhCHCH3), 38.0 (CH2Ph) and 19.5
1.51 (3H, d, J 7.1, PhCHCH3) and 0.74 (3H, d, J 6.6,
CH3CHN); dC (62.9 MHz; CDCl3) 174.3 (NC@O), 152.5
(OC@O), 140.3 (i-C; PhA; PhCHCH3), 133.5 (i-C; PhB;
PhCHO), 128.9, 128.8, 128.6, 128.1, 127.1 and 125.7
(6 · CH; PhA and PhB), 78.8 (OCHPh), 54.7 (BnCHN),
43.6 (PhCHCH3), 19.4 (PhCHCH3) and 14.1 (CH3CHN)
(PhCHCH3) (Found MH+ 310.1442. C19H20NO requires
þ
3
310.1443); m/z 310 (80%, MH+), 178 (18, MꢀC9H8O), 132
(Found MH+ 310.1460. C19H20NO requires 310.1443);
þ
(100, MꢀC10H12NO2) and 105 (18, MꢀC11H11NO3); and
the oxazolidinone (R,S)-syn-24 (85 mg, 48%) as a viscous
oil; RF [light petroleum (bp 40–60 ꢁC)/diethyl ether (1:1)]
3
m/z 310 (28%, MH+), 178 (8, MꢀC9H8O) and 105 (100,
MꢀC11H11NO3).
20
20
0.43; ½aꢁD ¼ þ1:46 (c 9.8, CHCl3) [lit.14 ½aꢁD ¼ þ2:8 (c
20
5.5, CHCl3); lit.14,18 ½aꢁD ¼ þ2:2 (c 2.8, CHCl3); lit.15
4.4.5. Synthesis of ethyl (4S,2R)-2-oxa-3-(20-phenylpropion-
yl)-oxazolidin-4-carboxylate anti-15 and ethyl (4R,2R)-
2-oxa-3-(20-phenylpropionyl)-oxazolidin-4-carboxylate syn-
15. In the same way as oxazolidinone 16, n-BuLi
(0.50 ml, 2.5 M in hexane, 1.25 mmol), ( )-ethyl oxazoli-
din-2-one 4-carboxylate rac-12 (0.20 g, 1.25 mmol) and
27
½aꢁD ¼ þ16:1 (c 0.96, CHCl3)]; mmax (CHCl3); cmꢀ1 1775
(C@O) and 1700 (C@O); dH (270 MHz; CDCl3) 7.45–6.94
(10H, m, 10 · CH; PhA and PhB), 5.11 (1H, q, J 6.9,
PhCHCH3), 4.79–4.70 (1H, m, BnCHN), 4.18 (1H, t, J
8.5, CHAHBO), 4.07 (1H, dd J 8.5 and 3.2, CHAHBO),
3.08 (1H, dd J 13.5 and 3.2, CHAHBPh), 2.58 (1H, dd, J
13.5 and 8.8, CHAHBPh) and 1.52 (3H, d, J 6.9,
PhCHCH3); dC (100 MHz; CDCl3) 174.5 (NC@O), 153.0
(OC@O), 140.2 (i-C; PhA), 135.0 (i-C; PhB), 129.42,
128.82, 128.62, 128.32, 127.31 and 127.21 (10 · CH; PhA
and PhB), 65.8 (CH2O), 54.9 (BnCHN), 43.2 (PhCHCH3),
37.4 (CH2) þand 19.2 (PhCHCH3) (Found MH+ 310.1438.
C19H20NO3 requires 310.1443); m/z 310 (80%, MH+),
178 (15, MꢀC9H8O), 132 (100, MꢀC10H12NO2) and 105
(15, MꢀC11H11NO3).
(ꢀ)-pentafluorophenyl
2-phenylpropionate
(R)-14
(0.197 g, 0.62 mmol) in THF gave a separable mixture of
two diastereoisomeric oxazolidinones syn- and anti-15
[syn-/anti- 78:22]. The crude mixture was purified by flash
column chromatography on silica gel eluting with light
petroleum (bp 40–60 ꢁC)/diethyl ether (7:3) to give the oxa-
zolidinone (4S,2R)-anti-15(23 mg, 13%) as an oil; RF [light
petroleum (bp 40–60 ꢁC)/diethyl ether (1:1)] 0.42;
20
20
½aꢁD ¼ ꢀ129:5 (c 2.2, CHCl3); [lit.14 ½aꢁD ¼ ꢀ135:8 (c 4.5,
CHCl3)]; mmax(CHCl3)/cmꢀ1 1794 (C@O), 1747 (C@O)
and 1705 (C@O); dH (270 MHz; CDCl3) 7.33–7.20 (5H,
m, 5 · CH; Ph), 5.10 (1H, q, J 7.0, PhCHCH3), 4.77 (1H,
dd, J 9.4 and 3.7, EtO2CCHN), 4.38 (1H, t, J 9.4, CHAH-
BO), 4.31–4.21 (3H, m, CHAHBO and CH2CH3), 1.50 (3H,
d, J 7.0, PhCHCH3) and 1.30 (3H, t, J 7.2, CH3CH2); dC
(62.9 MHz; CDCl3) 174.5 (NC@O), 168.7 (CC@O), 152.1
(OC@O), 140.0 (i-C; Ph), 128.7, 128.3 and 127.4 (3 · CH;
Ph), 64.3 (CH2O), 62.6 (CH2O), 55.9 (EtO2CCHN), 43.0
(PhCHCH3), 19.3 (PhCHCH3) and 14.1 (CH3CH2) (Found
4.4.4. (4R,5S)-4-Methyl-5-phenyl-3-(2R-phenylpropionyl)-
oxazolidin-2-one anti-25 and (4S,5R)-4-methyl-5-phenyl-3-
(2R-phenylpropionyl)-oxazolidin-2-one syn-25. In the
same way as oxazolidinone 16, n-BuLi (0.54 ml, 2.5 M in
hexane, 1.13 mmol), ( )-4-methyl-5-phenyl oxazolidin-2-
one rac-22 (0.20 g, 1.13 mmol) and (ꢀ)-pentafluorophenyl
2-phenylpropionate (R)-14 (0.17 g, 0.56 mmol) in THF
gave a separable mixture of two diastereoisomeric oxazo-
lidinones syn- and anti-24 [syn-/anti- 74:26]. The crude mix-
ture was purified by flash column chromatography on silica
gel eluting with light petroleum (bp 40–60 ꢁC)/diethyl ether
(7:3) to give the oxazolidinone (4R,5S,2R)-anti-25 (33 mg,
MH+, 292.1195; C15H18NO requires 292.1185) and the
þ
5
oxazolidinone (4R,2R)-syn-15 (84 mg, 46%) as a white
powder; mp 97–99 ꢁC; RF [light petroleum (bp 40–60 ꢁC)/
20
diethyl ether (1:1)] 0.30; ½aꢁD ¼ ꢀ24:8 (c 5.3, CHCl3)
20
19%) as a white solid; mp 89–92 ꢁC; RF [light petroleum
[lit.14 (4S,2S)-syn-15 ½aꢁD ¼ þ17:2 (c 2.2, CHCl3)];
20
(bp 40–60 ꢁC)/diethyl ether (1:1)] 0.76; ½aꢁD ¼ ꢀ39:2 (c
m
max(CHCl3)/cmꢀ1 1793 (C@O), 1747 (C@O) and 1705
20
4.0, CHCl3); {for (4S5R,2S)-anti-25; ½aꢁD ¼ þ35:1 (c 3.6,
20
(C@O); dH (270 MHz; CDCl3) 7.40–7.20 (5H, m, 5 · CH;
Ph), 5.03 (1H, q, J 7.0, PhCHCH3), 4.94 (1H, dd, J 9.3
and 4.9, EtO2CCHN), 4.52 (1H, t, J 9.3, CHAHBO), 4.23
(1H, dd, J 9.3 and 4.9, CHAHBO), 4.11 (2H, q, J 7.2,
CH2CH3), 1.48 (3H, d, J 7.0, PhCHCH3) and 1.11 (3H,
t, J 7.2, CH3CH2); dC (62.9 MHz; CDCl3) 174.3 (NC@O),
168.1 (CC@O), 152.0 (OC@O), 139.8 (i-C; Ph), 128.5, 128.2
and 127.2 (3 · CH; Ph), 64.3 (CH2O), 62.4 (CH2O), 55.7
(EtO2CCHN), 43.2 (PhCHCH3), 19.4 (PhCHCH3) and
CHCl3)} {lit.14 ½aꢁD ¼ ꢀ42:7 (c 3, CHCl3)}; mmax(CHCl3)/
cmꢀ1 1778 (C@O) and 1697 (C@O); dH (250 MHz; CDCl3)
7.44–7.24 (10H, m, 10 · CH; 2 · Ph), 5.49 (1H, d, J 7.1,
OCHPh), 5.14 (1H, q, J 7.1, PhCHCH3), 4.68 (1H, m,
CH3CHN), 1.51 (3H, d, J 7.1, PhCHCH3) and 0.94 (3H,
d, J 6.6, CH3CHN); dC (62.9 MHz; CDCl3) 174.5 (NC@O),
152.6 (OC@O), 140.5 (i-C; PhA; PhCHCH3), 133.3 (i-C;
PhB; PhCHO), 129.2, 129.1, 128.7, 128.2, 127.3 and 125.6
(6 · CH; PhA and PhB), 78.7 (OCHPh), 55.5 (CH3CHN),
43.4 (PhCHCH3), 19.3 (PhCHCH3) and 14.6 (CH3CHN)
13.9 (CH3CH2) (Found MH+, 292.1195; C15H18NO
þ
5
requires 292.1185).
(Found MH+ 310.1430. C19H20NO requires 310.1443);
þ
3
m/z 310 (31%, MH+), 178 (9, MꢀC9H8O) and 105 (100,
4.5. Kinetic resolution of racemic oxazolidinones using (+)-
pentafluorophenyl 6-methoxy-(2-naphthyl)propionate (S)-19
MꢀC11H11NO3); and the oxazolidinone (4S5R,2R)-syn-
25 (95 mg, 55%) as a white solid; mp 112–114 ꢁC; RF
[light petroleum (bp 40–60 ꢁC)/diethyl ether (1:1)] 0.63;
4.5.1. Synthesis of (4S,2S)-3-[2-(6-methoxynaphth-2-yl)-prop-
ionyl]-4-phenyl-oxazolidin-2-one anti-28 and (4R,2S)-3-[2-
(6-methoxynaphth-2-yl)-propionyl]-4-phenyl-oxazolidin-2-
one syn-28. In the same way as oxazolidinone 16, n-BuLi
(0.49 ml, 2.5 M in hexane, 1.22 mmol), ( )-4-phenyl-oxaz-
olidin-2-one rac-20 (0.20 g, 1.22 mmol) and (+)-pentafluoro-
20
20
½aꢁD ¼ ꢀ106:9 (c 3.2, CHCl3); [lit.14 (4R5S,2S)-25; ½aꢁD
¼
þ105:9 (c 2.6, CHCl3)]; mmax(CHCl3)/cmꢀ1 1774 (C@O)
and 1701 (C@O); dH (250 MHz; CDCl3) 7.40–7.17 (10H,
m, 10 · CH; PhA and PhB), 5.64 (1H, d, J 7.2, OCHPh),
5.08 (1H, q, J 7.1, PhCHCH3), 4.82 (1H, m, BnCHN),

2524
E. Boyd et al. / Tetrahedron: Asymmetry 18 (2007) 2515–2530
phenyl 2-(6-methoxynaphth-2-yl)propionate (S)-19 (0.24 g,
0.61 mmol) in THF gave a separable mixture of two diaste-
reoisomeric oxazolidinones anti- and syn-28 [anti-/syn-
21:79]. The crude mixture was purified by flash column
chromatography on silica gel eluting with light petroleum
(bp 40–60 ꢁC)/diethyl ether (7:3) to give the oxazolidi-
none (S,S)-anti-28 (32 mg, 14%) as a white solid; RF [light
and 3.2, CHN), 4.10 (1H, dd, J 9.1 and 3.2, CHAHBO),
4.05 (1H, t, J 9.1, CHAHBO), 3.88 (3H, s, CH3O), 2.50–
2.39 (1H, m, CH(CH3)2), 1.57 (3H, d, J 7.2, ArCHCH3)
and 0.90 (6H, ꢂd, J 6.9, 2 · CH3, CH3CHCH3); dC
(100 MHz; CDCl3) 174.7 (NC@O), 157.6 (OC@O), 153.7
(i-CO; Ar), 135.4, 133.8 and 128.8 (3 · i-CC; Ar), 129.3,
127.0, 126.8, 126.6, 118.8 and 105.5 (6 · CH; Ar), 63.0
(CH2O), 59.0 (i-PrCHN), 55.2 (OCH3), 42.8 (ArCHCH3),
28.5 (CH(CH3)2), 19.6 (CH3; i-Pr), 17.9 (CH3; i-Pr), and
14.6 (ArCHCH3) (Found MH+, 342.1707; C20H24NO4
requires 342.1700); and the oxazolidinone (R,S)-syn-
petroleum (bp 40–60 ꢁC)/diethyl ether (1:1)] 0.45;
20
½aꢁD ¼ þ218:4 (c 2.0, CHCl3); mp 120–121 ꢁC; mmax(CHCl3)/
cmꢀ1 1782 (NC@O) and 1705 (OC@O); dH (270 MHz;
CDCl3) 7.75 (1H, s, CH; Ar), 7.69 (2H, dd, J 8.6 and 2.5,
2 · CH; Ar and Ph), 7.49–7.30 (6H, m, 6 · CH; Ar and
Ph), 7.15–7.10 (2H, m, 2 · CH, Ar and Ph), 5.31 (1H, dd,
J 8.6 and 3.2, PhCHN), and 5.27 (1H, q, J 6.9, ArCHCH3),
4.47 (1H, t, J 8.6, CHAHBO), 4.17 (1H, dd, J 8.6 and 3.2,
CHAHBO), 3.90 (3H, s, CH3O) and 1.48 (3H, d, J 6.9,
CH3CH); dC (100.6 MHz; CDCl3) 174.1 (NC@O), 157.6
(OC@O), 153.2 (i-CO; Ar), 139.3, 135.3, 133.7 and 128.8
(4 · i-C; Ar and Ph), 129.2, 127.1, 126.8, 126.7, 118.9 and
105.5 (6 · CH; Ar), 128.8,2 128.61 and 125.72 (5 · CH;
Ph), 69.6 (CH2O), 58.0 (PhCHN), 55.2 (CH3O), 43.0
(ArCHCH3) and 19.3 (ArCHCH3) (Found MH+,
376.1545; C23H22NO4 requires 376.1543); and the oxazol-
idinone (R,S)-syn-28 (0.121 g, 53%) as a white solid; mp
27 (0.15 g, 56%) as an oil; RF [light petroleum (bp
22
40–60 ꢁC)/diethyl ether (1:1) 0.34; ½aꢁD ¼ þ59:6 (c 3.3,
CHCl3); mmax(CHCl3)/cmꢀ1 1778 (NC@O) and 1701
(OC@O); dH (270 MHz; CDCl3) 7.72 (1H, s, CH; Ar),
7.67 (2H, br d, J 8.4, 2 · CH; Ar), 7.45 (1H, dd, J 8.4
and 1.6, CH; Ar), 7.13–7.09 (2H, m, 2 · CH; Ar), 5.26
(1H, q, J 6.9, ArCHCH3), 4.52–4.46 (1H, dt, J 8.9 and
3.3, CHN), 4.21 (1H, t, J 8.9, CHAHBO), 4.06 (1H, dd,
J 8.9 and 3.3, CHAHBO), 3.88 (3H, s, CH3O), 2.25–2.13
(1H, m, CH(CH3)2), 1.53 (3H, d, J 6.9, ArCHCH3), 0.75
(3H, d, J 6.9, CH3ACHCHB3 Þ and 0.38 (3H, d, J 6.9,
CHA3 CHCH3B); dC (100 MHz; CDCl3) 174.6 (NC@O),
157.6 (OC@O), 153.3 (i-CO; Ar), 135.7, 133.7 and 128.9
(3 · i-CC; Ar), 129.4, 127.0, 126.7, 126.6, 118.8 and 105.5
(6 · CH; Ar), 62.9 (CH2O), 58.1 (i-PrCHN), 55.3
(OCH3), 43.2 (ArCHCH3), 27.9 (CH(CH3)2), 18.7 (CH3;
i-Pr), 17.7 (CH3; i-Pr) and 14.0 (ArCHCH3) (Found
MH+, 342.1701; C20H24NO4 requires 342.1700).
156–158 ꢁC; RF [light petroleum (bp 40–60 ꢁC)/diethyl
27
ether (1:1)] 0.33; ½aꢁD ¼ þ194:3 (c 1.6, CHCl3); {lit.9
+166.2, c 1.49, CHCl3}; mmax(CHCl3)/cmꢀ1 1780 (NC@O),
and 1699 (OC@O); dH (270 MHz; CDCl3) 7.60 (1H, d, J
8.4, CH; Ar), 7.51 (1H, d, J 8.4, CH; Ar), 7.33 (1H, s, CH;
Ar), 7.29–7.09 (6H, m, 6 · CH; Ar and Ph), 6.90 (2H, d, J
7.1; 2 · CH Ar or Ph), 5.46 (1H, dd, J 8.9 and 5.2, PhCHN),
5.20 (1H, q, J 6.9, ArCHCH3), 4.60 (1H, t, J 8.9, CHAHBO),
4.03 (1H, dd, J 8.9 and 5.2, CHAHBO), 3.92 (3H, s, CH3O)
and 1.44 (3H, d, J 6.9, ArCHCH3); dC (100 MHz; CDCl3)
173.6 (NC@O), 157.6 (OC@O), 153.0 (i-CO; Ar), 138.2,
135.1, 133.6 and 128.8 (4 · i-C; Ar and Ph), 129.4, 127.0,
126.4, 126.3, 118.7 and 105.5 (6 · CH; Ar), 128.82, 127.21
and 125.92 (5 · CH; Ph), 69.5 (CH2O), 57.8 (PhCHN),
55.3 (CH3O), 43.8 (ArCHCH3) and 18.7 (ArCHCH3)
(Found MH+, 376.1553; C23H22NO4 requires 376.1543).
4.5.3. Synthesis of (4S,2S)-4-benzyl-3-[2-(6-methoxynaphth-
2-yl)-propionyl]-oxazolidin-2-one anti-29 and (4R,2S)-4-
benzyl-3-[2-(6-methoxynaphth-2-yl)-propionyl]-oxazolidin-2-
one syn-29. In the same way as oxazolidinone 16, n-BuLi
(0.44 ml, 2.5 M in hexane, 1.12 mmol), ( )-4-benzyl-
oxazolidin-2-one rac-21 (0.20 g, 1.12 mmol) and (+)-penta-
fluorophenyl 2-(6-methoxynaphth-2-yl)propionate (S)-19
(0.22 g, 0.56 mmol) in THF gave a separable mixture of
two diastereoisomeric oxazolidinones syn- and anti-29
[syn-/anti- 73:27]. The crude mixture was purified by flash
column chromatography on silica gel eluting with light
petroleum (bp 40–60 ꢁC)/diethyl ether (7:3) to give the oxa-
zolidinone (S,S)-anti-29 (45 mg, 21%) as a white solid; mp
4.5.2. Synthesis of (4S,2S)-4-isopropyl-3-[2-(6-methoxy-
and
naphth-2-yl)propionyl]-oxazolidin-2-one
anti-27
(4R,2S)-4-isopropyl-3-[2-(6-methoxynaphth-2-yl)propionyl]-
oxazolidin-2-one syn-27. In the same way as oxazolidi-
none 16, n-BuLi (0.62 ml, 2.5 M in hexane, 1.55 mmol),
77–79 ꢁC; RF [light petroleum (bp 40–60 ꢁC)/diethyl
30
ether (1:1)] 0.42; ½aꢁD ¼ þ135:6 (c 0.73, CHCl3);
m
max(CHCl3)/cmꢀ1 1780 (C@O) and 1697 (C@O); dH
( )-4-isopropyl-oxazolidin-2-one
rac-27
(0.20 g,
(270 MHz; CDCl3) 7.74 (1H, s, CH; Ar), 7.69 (2H, d, J
8.5, 2 · CH; Ar), 7.48 (1H, dd, J 8.4 and 1.7, CH; Ar),
7.37–7.09 (7H, m, 7 · CH, Ar and Ph), 5.26 (1H, q, J
7.2, ArCHCH3), 4.62–4.54 (1H, m, BnCHN), 4.08 (1H,
dd, J 9.1 and 2.4, CHAHBO), 3.97 (1H, t, J 9.1, CHAHBO),
3.89 (3H, s, CH3O), 3.36 (1H, dd, J 13.1 and 3.2,
CHAHBPh), 2.82 (1H, dd, J 13.1 and 3.2, CHAHBPh)
and 1.62 (3H, d, J 6.9, ArCHCH3); dC (100 MHz; CDCl3)
174.7 (NC@O), 157.6 (OC@O), 152.9 (i-CO; Ar), 135.3,
135.4, 133.8 and 129.8 (4 · i-C; Ar and Ph), 129.3, 127.1,
126.7, 126.6, 118.9 and 105.5 (6 · CH; Ar), 128.9,2 128.82
and 127.31 (5 · CH; Ph), 65.8 (CH2O), 55.8 (BnNCH),
55.2 (CH3O), 42.9 (ArCHCH3), 37.9 (CH2Ph) and 19.4
(ArCHCH3) (Found MH+, 390.1702; C24H24NO4 requires
390.1700) and the oxazolidinone syn-(S,R)-29 (0.126 g,
58%) as a white solid; mp 61–63 ꢁC; RF [light petroleum
1.55 mmol) and (+)-pentafluorophenyl
2-(6-meth-
oxynaphth-2-yl)propionate (S)-19 (0.30 g, 0.77 mmol) in
THF gave a separable mixture of two diastereoisomeric
oxazolidinones syn- and anti-27 [syn-/anti- 82:18]. The
crude mixture was purified by flash column chromatogra-
phy on silica gel eluting with light petroleum (bp 40–
60 ꢁC)/diethyl ether (7:3) to give the oxazolidinone (S,S)-
anti-27 (34 mg, 13%) as a white solid; mp 120–121 ꢁC; RF
[light petroleum (bp 40–60 ꢁC)/diethyl ether (1:1)]
20
20
0.51; ½aꢁD ¼ þ167:5 (c 1.4, CHCl3); f½aꢁD ¼ þ156:4 (c
0.62, CHCl3)};19 max(CHCl3)/cmꢀ1 1778 (NC@O) and
m
1701 (OC@O); dH (270 MHz; CDCl3) 7.70 (1H, s, CH;
Ar), 7.68 (2H, dd, J 8.4 and 2.7, 2 · CH; Ar), 7.46 (1H,
dd, J 8.7 and 1.6, CH; Ar), 7.14–7.09 (2H, m, 2 · CH;
Ar), 5.28 (1H, q, J 6.9, ArCH), 4.36–4.31 (1H, dt, J 9.1

E. Boyd et al. / Tetrahedron: Asymmetry 18 (2007) 2515–2530
2525
23
(bp 40–60 ꢁC)/diethyl ether (1:1)] 0.35; ½aꢁD ¼ þ29:2 (c 1.2,
(i-CO; Ar), 135.4, 133.6, 133.3 and 128.9 (4 · i-C; Ar and
Ph), 129.3, 127.1, 126.7, 126.7, 118.8 and 105.5 (6 · CH;
Ar), 128.71, 128.52 and 125.62 (5 · CH; Ph), 78.7 (PhCHO),
55.3 (OCH3), 54.6 (CH3CHN), 43.5 (ArCHCH3), 19.3
(ArCHCH3) and 14.1 (CH3CHN) (Found MH+,
390.1699; C24H24NO4 requires 390.1700).
30
CHCl3); {½aꢁD ¼ þ22:8 (c 0.91, CHCl3)};18,19
mmax(CHCl3)/
cmꢀ1 1778 (C@O) and 1699 (C@O); dH (270 MHz; CDCl3)
7.82 (1H, s, CH; Ar), 7.73 (2H, d, J 8.4, 2 · CH; Ar and/or
Ph), 7.54 (1H, dd, J 8.4 and 1.5, CH; Ar), 7.17–7.02 (5H,
m, 5 · CH; Ar and Ph), 6.88 (2H, d, J 7.1, 2 · CH; Ar
and/or Ph), 5.26 (1H, q, J 6.9, ArCHCH3), 4.79–4.71
(1H, m, BnCHN), 4.16 (1H, t, J 8.9, CHAHBO), 4.04
(1H, dd, J 8.9 and 3.1, CHAHBO), 3.91 (3H, s, CH3O),
3.06 (1H, dd, J 13.6 and 3.5, CHAHBPh), 2.55 (1H, dd, J
13.6 and 8.7, CHAHBPh) and 1.60 (3H, d, J 6.9, CH3CH);
dC (100 MHz; CDCl3) 174.5 (NC@O), 157.7 (OC@O),
152.9 (i-CO; Ar), 135.2, 134.8, 133.7 and 129.7 (4 · i-C;
Ar and Ph), 129.3, 127.2, 126.6, 125.9, 118.9 and 105.5
(6 · CH; Ar), 128.92, 128.72 and 128.51 (5 · CH; Ph),
65.8 (CH2O), 55.2 (CH3O), 54.8 (BnCHN), 43.0
(ArCHCH3), 37.3 (CH2Ph) and 19.0 (ArCHCH3) (Found
MH+, 390.1706; C24H24NO4 requires 390.1700).
4.5.5. Synthesis of ethyl (4R,2S)-3-[2-(6-methoxynaphth-
2-yl)-propionyl]-2-oxazolidine-4-carboxylate anti-26 and
ethyl (4S,2S)-3-[2-(6-methoxynaphth-2-yl)]-2-oxazolidinone-
4-carboxylate syn-26. In the same way as oxazolidinone
16, n-BuLi (0.50 ml, 2.5 M in hexane, 1.25 mmol), ( )-
ethyl-oxazolidin-2-one 4-carboxylate rac-12 (0.20 g,
1.25 mmol)
and
(+)-pentafluorophenyl
2-(6-meth-
oxynaphth-2-yl)propionate (S)-19 (0.24 g, 0.62 mmol) in
THF gave a separable mixture of two diastereoisomeric
oxazolidinones syn- and anti-26 [syn-/anti- 79:21]. The
crude mixture was purified by flash column chromatogra-
phy on silica gel eluting with light petroleum (bp 40–
60 ꢁC)/diethyl ether (7:3) to give the oxazolidinone (S,R)-
4.5.4. Synthesis of (4S,5R,2S)-3-[2-(6-methoxynaphth-2-yl)-
propionyl]-4-methyl-5-phenyl-oxazolidin-2-one anti-30 and
(4R,5S,2S)-3-[2-(6-methoxynaphth-2-yl)]-4-methyl-5-phenyl-
oxazolidin-2-one syn-30. In the same way as oxazolidi-
none 16, n-BuLi (0.45 ml, 2.5 M in hexane, 1.12 mmol),
( )-4-methyl-5-phenyl-oxazolidin-2-one rac-22 (0.20 g,
anti-26 (39 mg, 17%) as an oil; RF [light petroleum (bp
23
40–60 ꢁC)/diethyl ether (1:1)] 0.28; ½aꢁD ¼ þ146:8 (c 0.92,
CHCl3); mmax(CHCl3)/cmꢀ1 1791 (C@O), 1751 (C@O)
and 1705 (C@O); dH (270 MHz; CDCl3) 7.72 (1H, s, CH;
Ar), 7.67 (2H, dd, J 8.4 and 2.6, 2 · CH; Ar), 7.46 (1H,
dd, J 8.6 and 1.9, CH; Ar), 7.11 (1H, dd, J 8.4 and 2.6,
CH; Ar), 7.07 (1H, s, CH; Ar), 5.24 (1H, q, J 6.9,
ArCHCH3), 4.76 (1H, dd, J 9.1 and 3.7, EtO2CCHN),
4.37–4.20 (4H, m, 2 · CH2O), 3.88 (3H, s, CH3O), 1.58
(3H, d, J 6.9, CH3CH) and 1.31 (3H, t, J 6.9, CH3CH2);
dC (100 MHz; CDCl3) 174.5 (NC@O), 168.6 (CC@O),
157.7 (OC@O), 152.0 (i-CO; Ar), 135.0, 133.8 and 128.8
(3 · i-C; Ar), 129.3, 127.1, 126.8, 126.7, 119.0 and 105.5
(6 · CH; Ar and Ph), 64.2 (CH2O), 62.5 (CH2O), 55.8
(CHN), 55.3 (CH3O), 42.8 (ArCHCH3), 19.1 (ArCHCH3)
and 14.0 (CH3CH2) (Found MH+, 372.1445, C20H22NO6
requires 372.1442); and the oxazolidinone (S,S)-syn-26
(0.14 g, 61%) as a white solid; mp 155–157 ꢁC; RF [light
1.12 mmol)
and
(+)-pentafluorophenyl
2-(6-meth-
oxynaphth-2-yl)propionate (S)-19 (0.22 g, 0.56 mmol) in
THF gave a separable mixture of two diastereoisomeric
oxazolidinones syn- and anti-30 [syn-/anti- 67:33]. The
crude mixture was purified by flash column chromatogra-
phy on silica gel eluting with light petroleum (bp 40–
60 ꢁC)/diethyl ether (7:3) to give the oxazolidinone
(4S,5R,2S)-anti-30 (37 mg, 17%) as a white solid; mp
140–142 ꢁC; RF [light petroleum (bp 40–60 ꢁC)/diethyl
23
ether (1:1)] 0.65; ½aꢁD ¼ þ88:9 (c 1.2, CHCl3);
m
max(CHCl3)/cmꢀ1 1776 (C@O) and 1697 (C@O); dH
(270 MHz; CDCl3) 7.76 (1H, s, CH; Ar), 7.71 (2H, dd, J
8.7 and 2.5, 2 · CH; Ar), 7.49 (1H, dd, J 8.4 and 1.7,
CH; Ar), 7.40–7.22 (5H, m, 5 · CH; Ar and Ph), 7.25–
7.11 (2H, m, 2 · CH; Ar and Ph), 5.43 (1H, d, J 7.1,
PhCHO), 5.27 (1H, q, J 6.9, ArCHCH3), 4.71–4.61 (1H,
m, CH3CHN), 3.90 (3H, s, CH3O), 1.57 (3H, d, J 6.9,
petroleum (bp 40–60 ꢁC)/diethyl ether (1:1)] 0.18;
25
½aꢁD ¼ þ55:7 (c 3.0, CHCl3); mmax(CHCl3)/cmꢀ1 1789
(C@O), 1745 (C@O) and 1705 (C@O); dH (270 MHz;
CDCl3) 7.74 (1H, s, CH; Ar), 7.67 (2H, dd, J 8.4 and 2.6,
2 · CH; Ar), 7.44 (1H, dd J 8.6 and 1.8, CH; Ar), 7.13
(1H, dd, J 8.4 and 2.6, 2 · CH; Ar), 7.09 (1H, s, CH;
Ar), 5.16 (1H, q, J 6.9, ArCHCH3), 4.94 (1H, dd, J 9.7
and 4.9, EtO2CCHN), 4.49 (1H, t, J 9.7, CHAHBCH),
4.20 (1H, dd, J 9.7 and 4.9, CHAHBCH), 4.07 (2H, q, J
7.2, CH2CH3), 3.88 (3H, s, CH3O), 1.55 (3H, d, J 7.2,
CH3CH) and 1.03 (3H, t, J 7.2, CH3CH2); dC (100 MHz;
CDCl3) 174.3 (NC@O), 167.9 (CC@O), 157.6 (OC@O),
151.9 (i-CO; Ar), 134.8, 133.7, 128.9 (3 · i-C; Ar), 129.1,
127.1, 126.9, 126.8, 118.7 and 105.6 (6 · CH; Ar), 64.1
(CH2O), 63.6 (CH2O), 55.6 (CHN), 55.2 (CH3O), 43.1
(ArCHCH3), 19.2 (ArCHCH3) and 13.7 (CH3CH2) (Found
MNH4þ, 389.1703; C20H25N2O6 requires 389.1707).
ArCHCH3) and 0.94 (3H,
J 6.4, CH3CHN); dC
(100 MHz; CDCl3) 174.5 (NC@O), 157.5 (OC@O), 152.6
(i-CO; Ar), 135.6, 133.7, 133.2 and 129.0 (4 · i-C; Ar and
Ph), 129.3, 127.1, 126.7, 126.6, 118.9 and 105.5 (6 · CH;
Ar), 128.81, 128.72 and 125.62 (5 · CH; Ph), 78.6 (PhCHO),
55.4 (CH3CHN), 55.3 (OCH3), 43.2 (ArCHCH3), 19.2
(ArCHCH3) and 14.5 (CH3CHN); (Found MH+,
390.1704; C24H24NO4 requires 390.1700) and the oxazolid-
inone (4R,5S,2S)-syn-30 (74 mg, 34%) as a white solid; mp
147–149 ꢁC; RF [light petroleum (bp 40–60 ꢁC)/diethyl
23
ether (1:1)] 0.55; ½aꢁD ¼ þ142:9 (c 1.4, CHCl3);
m
max(CHCl3)/cmꢀ1 1782 (C@O) and 1701 (C@O); dH
(270 MHz; CDCl3) 7.74 (1H, s, CH; Ar), 7.70 (2H, br d,
J 8.4, 2 · CH; Ar and/or Ph), 7.47 (1H, dd, J 8.4 and
1.5, CH; Ar), 7.30–7.27 (3H, m, 3 · CH; Ar and Ph),
7.15–7.11 (4H, m, 4 · CH; Ar and Ph), 5.62 (1H, d, J
7.4, PhCHO), 5.20 (1H, q, J 6.9, ArCHCH3), 4.88–4.78
(1H, m, CH3CHN), 3.90 (3H, s, CH3O), 1.57 (3H, d, J
6.9, ArCHCH3) and 0.71 (3H, d, J 6.4, CH3CHN); dC
(100 MHz; CDCl3) 174.3 (NC@O), 157.6 (OC@O), 152.5
4.5.6. Parallel kinetic resolution of racemic ethyl-oxazolidin-
2-one 4-carboxylate rac-12 using a combination of quasi-
enantiomeric oxazolidinones (R)-14 and (S)-19. In the
same way as oxazolidinone 16, n-BuLi (0.50 ml, 2.5 M in
hexane, 0.125 mmol), ( )-ethyl-oxazolidin-2-one 4-carbox-
ylate rac-12 (0.20 g, 0.125 mmol), (ꢀ)-pentafluorophenyl 2-

2526
E. Boyd et al. / Tetrahedron: Asymmetry 18 (2007) 2515–2530
phenylpropionate (R)-14 (0.20 g, 0.625 mmol) and (+)-
pentafluorophenyl 2-(6-methoxynaphth-2-yl)propionate
hexane, 1.12 mmol), ( )-4-methyl-5-phenyl-oxazolidin-2-
one rac-22 (0.20 g, 1.22 mmol), (ꢀ)-pentafluorophenyl
2-phenylpropionate (R)-14 (0.17 g, 0.56 mmol) and (+)-penta-
fluorophenyl 2-(6-methoxynaphth-2-yl)propionate (S)-19
(0.22 g, 0.56 mmol) in THF gave a separable pair of diaste-
reoisomeric oxazolidinones syn- and anti-25 [syn-/
anti- 82:18] and syn- and anti-30 [syn-/anti- 85:15]. The crude
mixture was purified by flash column chromatography on
silica gel eluting with light petroleum (bp 40–60 ꢁC)/diethyl
ether (7:3) to give the oxazolidinones anti-25 (0.13 mg, 8%),
an inseparable mixture (ꢂ77 mg) of syn-25 (ꢂ62 mg, 36%)
and anti-30 (ꢂ15 mg, 7%), and syn-30 (91 mg, 42%).
(S)-19 (0.25 g, 0.625 mmol) in THF gave a separable pair
of diastereoisomeric oxazolidinones syn- and anti-15
[syn-/anti- 95:5] and syn- and anti-26 [syn-/anti- 95:5]. The
crude mixture was purified by flash column chromato-
graphy on silica gel eluting with light petroleum (bp
40–60 ꢁC)/diethyl ether (7:3) to give oxazolidinones syn-
15 (0.10 g, 55%) and syn-26 (0.139 g, 59%).
4.5.7. Parallel kinetic resolution of racemic 4-isopropyl-
oxazolidin-2-one rac-13 using a combination of quasi-enan-
tiomeric oxazolidinones (R)-14 and (S)-19. In the same
way as oxazolidinone 16, n-BuLi (0.62 ml, 2.5 M in hexane,
4.5.11. Pentafluorophenyl 2-(4-isobutylphenyl)propionate
acid
1.54 mmol),
( )-4-isopropyl-oxazolidin-2-one
rac-13
(R)-32. 2-(4-Isopropylphenyl)propionic
(R)-31
20
(0.20 g, 1.54 mmol), (ꢀ)-pentafluorophenyl 2-phenylpropi-
onate (R)-14 (0.24 g, 0.77 mmol) and (+)-pentafluorophen-
yl 2-(6-methoxynaphth-2-yl)propionate (S)-19 (0.31 g,
0.77 mmol) in THF gave a separable pair of diastereoiso-
meric oxazolidinones syn- and anti-16 [syn-/anti- 95:5]
and syn- and anti-27 [syn-/anti- 95:5]. The crude mixture
was purified by flash column chromatography on silica
gel eluting with light petroleum (bp 40–60 ꢁC)/diethyl ether
(7:3) to give oxazolidinones syn-16 (0.115 g, 57%) and syn-
27 (0.155 g, 59%).
(0.50 g, 2.42 mmol) {½aꢁD ¼ ꢀ54:3 (c 2.0, EtOH)} was
added to a stirred solution of N,N0-dicyclohexylcarbodiim-
ide (DCC) (0.50 g, 2.67 mmol) in dichloromethane (10 ml).
The resulting solution was stirred for 10 min. A solution of
pentafluorophenol (0.45 g, 0.25 ml, 2.42 mmol) in dichloro-
methane (5 ml) was slowly added, and the resulting solution
was stirred for 12 h. The resulting precipitate (N,N0-dicyclo-
hexylurea) was filtered off (using suction filtration). Water
(10 ml) was added and the solution was extracted with
dichloromethane (3 · 20 ml) and dried over MgSO4. The
combined organic layers were evaporated under reduced
pressure. The crude residue was purified by flash column
chromatography on silica gel eluting with light petroleum
(bp 40–60 ꢁC)/diethyl ether (9:1) to give pentafluorophenyl
2-(4-isopropylphenyl)propionate (R)-32 (0.74 g, 82%) as a
4.5.8. Parallel kinetic resolution of racemic 4-phenyl-oxaz-
olidin-2-one rac-20 using a combination of quasi-enantio-
meric oxazolidinones (R)-14 and (S)-19. In the same way as
oxazolidinone 16, n-BuLi (0.48 ml, 2.5 M in hexane,
0.122 mmol), ( )-4-phenyl-oxazolidin-2-one rac-20 (0.20 g,
0.122 mmol), (ꢀ)-pentafluorophenyl 2-phenylpropionate
(R)-14 (0.19 g, 0.61 mmol) and (+)-pentafluorophenyl 2-(6-
methoxynaphth-2-yl)propionate (S)-19 (0.24 g, 0.61 mmol)
in THF gave a separable pair of diastereoisomeric oxazolid-
inones syn- and anti-23 [syn-/anti- 95:5] and syn- and anti-28
[syn-/anti- 95:5]. The crude mixture was purified by flash
column chromatography on silica gel eluting with light
petroleum (bp 40–60 ꢁC)/diethyl ether (7:3) to give oxazolid-
inones syn-23 (0.180 g, 65%) and syn-28 (0.139 g, 61%).
liquid; RF [light petroleum (bp 40–60 ꢁC)/diethyl ether
25
(9:1)] 0.63; ½aꢁD ¼ ꢀ91:4 (c 5.0, CHCl3); {for (S)-32;
25
½aꢁD ¼ þ91:7 (c 29.6, CHCl3)}; mmax(CHCl3)/cmꢀ1 1782
(C@O); dH (270 MHz; CDCl3) 7.26 (2H, dt, J 8.2 and 2.2,
2 · CH; Ar), 7.14 (2H, dt, J 8.2 and 2.2, 2 · CH; Ar), 4.04
(1H, q, J 7.2, ArCHCH3), 2.46 (2H, d, J 7.2, CH2Ar),
1.92–1.80 (1H, m, CH(CH3)2), 1.62 (3H, d, J 7.2,
ArCHCH3), 0.99 (3H, d, J 6.7, (CH3)ACH(CH3)B) and
0.88 (3H, d, J 6.7, (CH3)BCH(CH3)A); dC (100 MHz;
CDCl3) 170.3 (OC@O), 140.8 (i-C; Ar), 141.2 (142.92 and
1
2
139.42, 2C, ddt, JC,F = 251.3 Hz, JC,F = 11.9 Hz and
4.5.9. Parallel kinetic resolution of racemic 4-benzyl-oxaz-
olidin-2-one rac-21 using a combination of quasi-enantio-
meric oxazolidinones (R)-14 and (S)-19. In the same way
as oxazolidinone 16, n-BuLi (0.45 ml, 2.5 M in hexane,
1.12 mmol), ( )-4-benzyl-oxazolidin-2-one rac-21 (0.20 g,
1.12 mmol), (ꢀ)-pentafluorophenyl 2-phenylpropionate
(R)-14 (0.17 g, 0.56 mmol) and (+)-pentafluorophenyl 2-
3JC,F = 4.2 Hz, C(2)–F), 138.9 (140.18 and 137.66, 1C,
dtt, JC,F = 253.2 Hz, JC,F = 13.8 Hz and JC,F = 3.8 Hz,
1
2
3
1
C(4)–F), 137.3 (138.61 and 136.08, 2C, dtdd, JC,F
=
2
3
4
254.7 Hz, JC,F = 14.5 Hz, JC,F = 5.3 and JC,F = 3.0 Hz,
C(3)–F), 135.5 (i-C; Ar), 129.1 and 126.7 (2 · CH; Ar),
2
4
124.7 (1C, tdt, JC,F = 14.2 Hz, JC,F = 4.6 Hz and
3JC,F = 2.3 Hz, i-CO; OC6F5), 44.5 (CH2Ar), 44.4
(ArCHCH3), 29.7 (CHCH2), 21.9 (CH(CH3)2) and 18.0
(6-methoxynaphth-2-yl)propionate
(S)-19
(0.22 g,
3
0.56 mmol) in THF gave a separable pair of diastereoiso-
meric oxazolidinones syn- and anti-24 [syn-/anti- 78:28]
and syn- and anti-29 [syn-/anti- 70:30]. The crude mixture
was purified by flash column chromatography on silica
gel eluting with light petroleum (bp 40–60 ꢁC)/diethyl ether
(7:3) to give the oxazolidinones anti-24 (22 mg, 13%), a par-
tially separable mixture (ꢂ86 mg) of syn-24 (ꢂ58 mg, 34%)
and anti-29 (ꢂ28 mg, 13%), and syn-29 (63 mg, 29%).
(ArCHCH3); dF (378 MHz; CDCl3) ꢀ152.6 (2F, d, JF,F
3
18.5, Fortho), ꢀ158.1 (1F, t, JF,F 20.8, Fpara) and ꢀ162.4
(2F, dd, JF,F 20.8 and 18.5, Fmeta) (Found M+, 372.1144;
3
C19H17F5O2 requires 372.1143).
4.5.12. Parallel kinetic resolution of racemic ethyl-oxazoli-
din-2-one 4-carboxylate rac-12 using a combination of quasi-
enantiomeric oxazolidinones (R)-32 and (S)-19. In the
same way as oxazolidinone 16, n-BuLi (0.50 ml, 2.5 M in
hexane, 1.25 mmol), ( )-ethyl-oxazolidin-2-one 4-carbox-
ylate rac-12 (0.20 g, 1.25 mmol), (ꢀ)-pentafluorophenyl 2-
(4-isobutylphenyl)propionate (R)-32 (0.23 g, 0.625 mmol)
and (+)-pentafluorophenyl 2-(6-methoxynaphth-2-yl)pro-
4.5.10. Parallel kinetic resolution of racemic 4-methyl-5-
phenyl-oxazolidin-2-one rac-22 using a combination of quasi-
enantiomeric oxazolidinones (R)-14 and (S)-19. In the
same way as oxazolidinone 16, n-BuLi (0.45 ml, 2.5 M in

E. Boyd et al. / Tetrahedron: Asymmetry 18 (2007) 2515–2530
2527
pionate (S)-19 (0.25 g, 0.625 mmol) in THF gave a separa-
ble pair of diastereoisomeric oxazolidinones syn- and anti-
26 [syn-/anti- 96:4] and syn- and anti-33 [syn-/anti- 96:4].
The crude mixture was purified by flash column chromato-
graphy on silica gel eluting with light petroleum (bp
40–60 ꢁC)/diethyl ether (7:3) to give the oxazolidinones
syn-26 (0.106 g, 46%) and syn-33 (0.89 mg, 41%).
Characterisation data for: 3-[2-(4-Isobutylphenyl)-pro-
pionyl]-4-isopropyl-oxazolidin-2-one (4R,2R)-anti-34: Oil;
RF [light petroleum (bp 40–60 ꢁC)/diethyl ether (1:1)]
20
0.77; ½aꢁD ¼ ꢀ87:5 (c 12.0, CHCl3); [(4S,2S)-anti-34;
20
½aꢁD ¼ þ117:3 (c 1.3, CHCl3)]; mmax(CHCl3)/cmꢀ1 1776
(C@O) and 1692 (C@O); dH (250 MHz; CDCl3) 7.23 (2H,
d, J 8.2, 2 · CH; Ar), 7.07 (2H, d, J 8.2, 2 · CH; Ar),
5.11 (1H, q, J 7.2, ArCHCH3), 4.37–4.32 (1H, dt, J 7.2
and 3.8, i-PrCHN), 4.15–4.07 (2H, m, CH2O), 2.46–2.39
(2H, m, CH2), 1.87–1.77 (1H, m, CH(CH3)2), 1.49 (3H,
d, J 7.2, ArCHCH3) and 0.92–8.86 (12H, m, 2 ·
CH(CH3)2); dC (100.6 MHz; CDCl3) 174.9 (NC@O),
153.6 (OC@O), 140.6 (i-C; Ar), 137.5 (i-C; Ar), 129.3 and
127.8 (2 · CH; Ar), 63.1 (CH2O), 59.0 (i-PrCHN), 45.1
(CH(CH3)2), 42.6 (ArCHCH3), 30.2 (CH2), 28.6
(CH(CH3)2), 22.7 (CHA3 CHCH3B; i-BuC6H4–), 22.4
(CHACHCHB; i-BuC6H4–), 19.7 (CHACHCHB; oxazolidi-
Characterisation data for: Ethyl 3-[2-(4-isobutylphenyl)-
propionyl]-2-oxo-oxazolidine-4-carboxylate (4S,2R)-anti-
33: Oil; RF [light petroleum (bp 40–60 ꢁC)/diethyl
25
ether (1:1)] 0.53; ½aꢁD ¼ ꢀ125:4 (c 1.2, CHCl3);
m
max(CHCl3)/cmꢀ1 1791 (C@O), 1751 (C@O) and 1701
(C@O); dH (270 MHz; CDCl3) 7.23 (2H, d, J 8.0, 2 · CH;
Ar), 7.10 (2H, d, J 8.0, 2 · CH; Ar), 5.09 (1H, q, J 6.9,
ArCHCH3), 4.78 (1H, dd, J 9.4 and 3.7, EtO2CCHN),
4.41 (1H, t, J 9.0, CHAHBO), 4.33–4.23 (3H, m, 3 · CH,
CHAHBO and CH2CH3), 2.42 (2H, d, J 7.2, CH2), 1.87–
1.77 (1H, m, CH(CH3)2), 1.49 (3H, d, J 6.9, ArCHCH3),
1.30 (3H, t, J 7.2, CH3CH2) and 0.88 (6H, d, J 6.7,
CHA3 CHCH3BÞ; dC (100.6 MHz; CDCl3) 174.7 (NC@O),
168.6 (CC@O), 152.0 (OC@O), 140.8 (i-C; Ar), 137.1 (i-C;
Ar), 129.4 and 127.9 (2 · CH; Ar), 64.2 (CH2O), 62.5
(CH2O; ester), 55.9 (EtO2CCHN), 45.1 (CH(CH3)2), 42.5
(ArCHCH3), 30.2 (CH2), 22.4 (CHA3 CHCH3B), 19þ.2
3
3
3
3
none), 18.0 (CHA3 CHCH3B; oxazolidinone) and 14.7
(ArCHCH3) (Found MH+, 318.20062; C19H28NO3
requires 318.2064). 3-[2-(4-Isobutylphenyl)-propionyl]-4-
isopropyl-oxazolidin-2-one (4S,2R)-syn-34: Oil; RF [light
petroleum (bp 40–60 ꢁC)/diethyl ether (1:1) 0.55;
22
22
½aꢁD ¼ ꢀ33:0 (c 1.2, CHCl3) {for (4R,2S)-syn-34 ½aꢁD
¼
þ34:2 (c 2.0, CHCl3)}; mmax(CHCl3)/cmꢀ1 1778 (C@O)
and 1699 (C@O); dH (400 MHz; CDCl3) 7.23 (2H, d, J
8.2, 2 · CH; Ar), 7.03 (2H, d, J 8.2, 2 · CH; Ar), 5.11
(1H, q, J 6.9, ArCHCH3), 4.50–4.44 (1H, dt, J 8.80 and
3.48, i-PrCHN), 4.21 (1H, t, J 8.6, CHAHBO), 4.07 (1H,
dd, J 8.6 and 3.5, CHAHBO), 2.40 (2H, d, J 7.2, CH2),
2.19–2.07 (1H, m, CH(CH3)2), 1.87–1.75 (1H, m,
CH(CH3)2), 1.44 (3H, d, J 6.9, ArCHCH3), 0.85 (3H, d,
J 6.7, CH3; CHA3 CHCH3BÞ, 0.84 (3H, d, J 6.7, CH3;
CH3ACHCH3BÞ, 0.76 (3H, d, J 6.9, CH3ACHCH3BÞ and 0.38
(3H, d, J 6.9, CHA3 CHCH3BÞ; dC (100.6 MHz; CDCl3)
174.8 (NC@O), 153.5 (OC@O), 140.6 (i-C; Ar), 137.6
(i-C; Ar), 129.3 and 127.8 (2 · CH; Ar), 62.8 (CH2O),
58.0 (i-PrCHN), 45.0 (CH(CH3)2), 42.9 (ArCHCH3),
30.2 (CH2), 27.8 (CH(CH3)2; oxazolidinone), 22.7
(CHA3 CHCHB3 ; i-BuC6H4–), 22.3 (CH3ACHCHB3 ; i-
BuC6H4–), 18.5 (CH3ACHCHB3 ; oxazolidinone), 17.7
(CHA3 CHCH3B; oxazolidinone) and 14.0 (ArCHCH3)
(Found M, 317.1979; C29H27NO3 requires 317.1985).
(ArCHCH3) and 14.0 (CH3CH2) (Found MNH4
,
365.2069; C19H29N2O5 requires 365.2171). Ethyl 3-[2-(4-
isobutylphenyl)-propionyl]-2-oxo-oxazolidine-4-carboxylate
(4R,2R)-syn-33: Oil; RF [light petroleum (bp 40–
25
60 ꢁC)/diethyl ether (1:1)] 0.35; ½aꢁD ¼ ꢀ25:5 (c 5.0, CHCl3);
25
{for (4S,2S)-33; ½aꢁD ¼ þ29:8 (c 0.95, CHCl3)};18
m
max(CHCl3)/cmꢀ1 1791 (C@O), 1747 (C@O) and 1699
(C@O); dH (270 MHz; CDCl3) 7.23 (2H, d, J 8.1, 2 · CH;
Ar), 7.10 (2H, d, J 8.1, 2 · CH; Ar), 5.01 (1H, q, J 6.9,
ArCHCH3), 4.93 (1H, dd, J 9.4 and 4.7, EtO2CCHN),
4.51 (1H, t, J 9.4, CHAHBO), 4.24 (1H, dd, J 9.4 and 4.7,
CHAHBO), 4.10 (2H, q, J 7.2, CH2CH3), 2.42 (2H, d, J
7.2, CH2), 1.87–1.77 (1H, m, CH(CH3)2), 1.46 (3H, d, J
6.9, ArCHCH3), 1.10 (3H, t, J 7.2, CH3CH2) and 0.88
(6H, d, J 6.7, CHA3 CHCH3BÞ; dC (100.6 MHz; CDCl3)
174.5 (NC@O), 168.0 (OC@O), 152.0 (i-C; Ar), 140.5 (i-C;
Ar), 136.9 (i-C; Ph), 129.2 and 127.9 (2 · CH; Ar), 64.2
(CH2O), 62.3 (CH2O; ester), 55.7 (EtO2CCHN), 45.1
(CH(CH3)2), 42.7 (ArCHCH3), 30.1 (CH2), 22.4
ðCHACHCHBÞ, 19.3 (ArCHCH3) and 13.8 (CH3CH2)
4.5.14. Parallel kinetic resolution of racemic 4-phenyl-
oxazolidin-2-one rac-20 using a combination of quasi-enan-
tiomeric oxazolidinones (R)-32 and (S)-19. In the same
way as oxazolidinone 16, n-BuLi (0.48 ml, 2.5 M in hexane,
1.22 mmol), ( )-4-phenyl-oxazolidin-2-one rac-20 (0.20 g,
1.22 mmol), (ꢀ)-pentafluorophenyl 2-(4-isobutylphenyl)-
propionate (R)-32 (0.22 g, 0.61 mmol) and (+)-pentafluoro-
phenyl 2-(6-methoxynaphth-2-yl)propionate (S)-19 (0.24 g,
0.61 mmol) in THF gave a separable pair of diastereoiso-
meric oxazolidinones syn- and anti-28 [syn-/anti- 95:5]
and syn- and anti-35 [syn-/anti- 97:3]. The crude mixture
was purified by flash column chromatography on silica
gel eluting with light petroleum (bp 40–60 ꢁC)/diethyl ether
(7:3) to give the oxazolidinones syn-28 (0.11 g, 48%) and
syn-35 (0.11 g, 54%).
3
3
(Found MNH4þ, 365.2073; C19H29N2O5 requires 365.2071).
4.5.13. Parallel kinetic resolution of racemic 4-isopropyl-
oxazolidin-2-one rac-13 using a combination of quasi-enan-
tiomeric oxazolidinones (R)-32 and (S)-19. In the same
way as oxazolidinone 16, n-BuLi (0.61 ml, 2.5 M in hexane,
1.54 mmol),
( )-4-isopropyl-oxazolidin-2-one
rac-13
(0.20 g, 1.54 mmol), (ꢀ)-pentafluorophenyl 2-(4-isobutyl-
phenyl)propionate (R)-32 (0.28 g, 0.77 mmol) and (+)-pen-
tafluorophenyl 2-(6-methoxynaphth-2-yl)propionate (S)-19
(0.30 g, 0.77 mmol) in THF gave a separable pair of
diastereoisomeric oxazolidinones syn- and anti-27 [syn-/
anti- 95:5] and syn- and anti-34 [syn-/anti- 95:5]. The crude
mixture was purified by flash column chromatography on
silica gel eluting with light petroleum (bp 40–60 ꢁC)/diethyl
ether (7:3) to give the oxazolidinones syn-27 (0.19 g, 74%)
and syn-34 (0.17 g, 70%).
Characterisation data for: 3-[2-(4-Isobutylphenyl)propion-
yl]-4-phenyl-oxazolidin-2-one
(4R,2R)-anti-35:
White
solid; mp 155–158 ꢁC; RF [light petroleum (bp 40–60 ꢁC)/

2528
E. Boyd et al. / Tetrahedron: Asymmetry 18 (2007) 2515–2530
25
diethyl ether (1:1)] 0.62; ½aꢁD ¼ ꢀ151:3 (c 1.3, CHCl3)
oxazolidin-2-one 4-carboxylate (S)-12 (60 mg, 0.37 mmol),
(ꢀ)-pentafluorophenyl 2-phenylpropionate (R)-14 (0.12 g,
0.376 mmol) and (+)-pentafluorophenyl 2-(6-meth-
oxynaphth-2-yl)propionate (S)-19 (0.149 g, 0.376 mmol)
in THF gave a separable mixture of oxazolidinones syn-
16 and anti-27 [syn-/anti- 92:8], and syn-26 and anti-15
[syn-/anti- 95:5]. The crude mixture was purified by flash
column chromatography on silica gel eluting with light
petroleum (bp 40–60 ꢁC)/diethyl ether (7:3) to give the oxa-
zolidinones syn-16 (96 mg, 65%) and syn-26 (93 mg, 66%).
25
{for (S,S)-anti-35; ½aꢁD ¼ þ144:5 (c 7.2, CHCl3)};
m
max(CHCl3)/cmꢀ1 1780 (C@O) and 1701 (C@O); dH
(270 MHz; CDCl3) 7.28–7.15 (3H, m, 3 · CH; Ph and/or
Ar ), 7.00 (4H, m, 4 · CH, Ph and Ar), 6.90 (2H, dt, J
7.9 and 1.9, 2 · CH; Ar), 5.44 (1H, dd J 9.2 and 5.2,
PhCHN), 5.09 (1H, q, J 6.9; ArCHCH3), 4.63 (1H, t, J
9.0, CHAHBO), 4.06 (1H, dd, J 9.0 and 5.2, CHAHBO),
2.43 (2H, d, J 7.4, CH2), 1.89–1.79 (1H, m, CH(CH3)2),
1.38 (3H, d, J 6.9, ArCHCH3) and 0.90 (6H, d, J 6.7,
2 · CH3, CHA3 CHCH3B); dC (100.6 MHz; CDCl3) 174.3
(NC@O), 153.3 (OC@O), 140.7 (i-C; Ar), 139.4 (i-C; Ar),
137.4 (i-C; Ph), 129.3 and 127.0 (2 · CH; Ar), 129.2,
128.7 and 125.8 (3 · CH; Ph), 69.7 (CH2O), 58.1 (PhCHN),
45.1 (CH(CH3)2), 42.7 (ArCHCH3), 30.2 (CH2), 22.4 (2C,
s, CHACHCHBÞ and 19.4 (ArCHCH3) (Found MH+,
4.5.17. Mutual kinetic separation of 4-phenyl-oxazolidin-2-
one (S)-20 and ethyl-oxazolidin-2-one 4-carboxylate (S)-12
using a combination of quasi-enantiomeric oxazolidinones
(R)-14 and (S)-19. In the same way as oxazolidinone 16,
n-BuLi (0.32 ml, 2.5 M in hexane, 0.79 mmol), 4-phenyl-
oxazolidin-2-one (S)-20 (64 mg, 0.395 mmol), ethyl-
oxazolidin-2-one 4-carboxylate (S)-12 (62 mg, 0.395
mmol), (ꢀ)-pentafluorophenyl 2-phenylpropionate (R)-14
(0.125 g, 0.395 mmol) and (+)-pentafluorophenyl 2-(6-
methoxynaphth-2-yl)propionate (S)-19 (0.156 g, 0.395
mmol) in THF gave a separable mixture of oxazolidinones
syn-23 and anti-28 [syn-/anti- 98:2], and syn-26 and anti-15
[syn-/anti- 98:2]. The crude mixture was purified by flash
column chromatography on silica gel eluting with light
petroleum (bp 40–60 ꢁC)/diethyl ether (7:3) to give the oxa-
zolidinones syn-23 (70 mg, 60%) and syn-26 (82 mg, 56%).
3
3
352.1909; C22H26NO3 requires 352.1907). 3-[20-(4-Isobut-
ylphenyl)propionyl]-4-phenyl-oxazolidin-2-one
(4S,2R)-
syn-35: White solid; mp 86–88 ꢁC; RF [light petroleum
25
(bp 40–60 ꢁC)/diethyl ether (1:1)] 0.41; ½aꢁD ¼ ꢀ114:6 (c
25
4.2, CHCl3); {lit.9 ½aꢁD ¼ ꢀ99:1 (c 0.4, CHCl3)};
25
[(4R,2S)-35; ½aꢁD ¼ þ123:8 (c 1.0, CHCl3)]; mmax(CHCl3)/
cmꢀ1 1779 (C@O) and 1705 (C@O); dH (270 MHz; CDCl3)
7.28–7.15 (3H, m, 3 · CH; Ph and/or Ar ), 7.00 (4H, m,
4 · CH, Ph and Ar), 6.90 (2H, dt, J 7.9 and 1.9, 2 · CH;
Ar), 5.44 (1H, dd J 9.2 and 5.2, CHN), 5.09 (1H, q, J
6.9; ArCH), 4.63 (1H, t, J 9.0, CHAHBO), 4.06 (1H, dd,
J 9.0 and 5.2, CHAHBO), 2.43 (2H, d, J 7.4, CH2), 1.89–
1.79 (1H, m, CH(CH3)2), 1.38 (3H, d, J 6.9, CH3CH)
and 0.90 (6H, d, J 6.7, 2 · CH3, CHA3 CHCH3BÞ; dC
(100.6 MHz; CDCl3) 174.3 (NC@O), 153.3 (OC@O),
140.7 (i-C; Ar), 139.4 (i-C; Ar), 137.4 (i-C; Ph), 129.3 and
127.0 (2 · CH; Ar), 129.2, 128.7 and 125.8 (3 · CH; Ph),
69.7 (CH2O), 58.1 (CHN), 45.1 (CH(CH3)2), 42.7 (ArCH),
30.2 (CH2), 22.4 (2C, s, CHA3 CHCH3BÞ and 19.4 (CH3CH2)
(Found MH+, 352.1909; C22H26NO3 requires 352.1907);
m/z 351.1 (10% M+), 188.1 (Ar(CH3)C@C@O+), 161.1
4.5.18. Synthesis of (+)-2-phenylpropionyl chloride (S)-
36. Oxalyl chloride (0.93 g, 7.33 mmol) was added to a
stirred solution of (S)-2-phenylpropionic acid (1.0 g,
20
6.66 mmol) {½aꢁD ¼ þ72:0 (c 1.4, CHCl3)} in dry toluene
(10 ml) at room temperature. The resulting solution was
stirred for 12 h. The organic solvent was removed under
reduced pressure to give 2-phenylpropionyl chloride (S)-
25
36 (0.95 g, 85%) as an oil; ½aꢁD ¼ þ73:2 (c 4.0, CHCl3)
25
{lit.20 (S)-36; ½aꢁD ¼ þ74:2 (c 2.8, CHCl3); lit.21 (R)-36;
(10, Ar+CHCH3), 145.1 (145, ArCH þÞ and 77.1 (10, Ph+).
25
2
½aꢁD ¼ ꢀ72:6, CHCl3}; 1782 (C@O), dH (270 MHz, CDCl3)
7.36–7.28 (5H, m, 5 · CH; Ar), 4.11 (1H, q, J 7.1,
PhCHCH3) and 1.59 (3H, d, J 7.1, PhCHCH3); dC
(100 MHz, CDCl3) 175.9 (C@O), 140.2 (i-C; Ph), 129.9,
129.3 and 129.2 (3 · CH; Ph), 57.9 (PhCHCH3) and 18.6
(PhCHCH3) (Found M(35Cl), 168.0337; C9H9ClO requires
168.0336).
4.5.15. Mutual kinetic separation of 4-isopropyl-oxazolidin-
2-one (S)-13 and 4-phenyl-oxazolidin-2-one (R)-20 using a
combination of quasi-enantiomeric oxazolidinones (R)-14
and (S)-19. In the same way as oxazolidinone 16,
n-BuLi (1.23 ml, 2.5 M in hexane, 3.08 mmol), 4-isoprop-
yl-oxazolidin-2-one (S)-13(0.20 g, 1.54 mmol), 4-phenyl-
oxazolidin-2-one (R)-20 (0.25 g, 1.54 mmol), (ꢀ)-pentaflu-
orophenyl 2-phenylpropionate (R)-14 (0.48 g, 1.54 mmol)
and (+)-pentafluorophenyl 2-(6-methoxynaphth-2-yl)pro-
pionate (S)-19 (0.61 g, 1.54 mmol) in THF gave a separable
mixture of oxazolidinones syn-16 and anti-27 [syn-/anti-
95:5], and syn-28 and anti-23 [syn-/anti- 95:5]. The crude
mixture was purified by flash column chromatography on
silica gel eluting with light petroleum (bp 40–60 ꢁC)/diethyl
ether (7:3) to give oxazolidinones syn-16 (0.40 g, 67%) and
syn-28 (0.57 g, 67%).
4.5.19. Sequential kinetic resolution of 4-isopropyl-oxazo-
lidin-2-one rac-13 using pentafluorophenyl 2-(6-methoxy-
naphth-2-yl)propionate (S)-19 and then 2-phenylpropionyl
chloride (S)-36. In the same way as oxazolidinone 16,
n-BuLi (0.62 ml, 2.5 M in hexane, 1.55 mmol), 4-isoprop-
yl-oxazolidin-2-one rac-13 (0.20 g, 1.55 mmol) and (+)-
pentafluorophenyl
2-(6-methoxynaphth-2-yl)propionate
(S)-19 (0.31 g, 0.77 mmol) in THF, and after 1 h followed
by 2-phenylpropionyl chloride (S)-36 (0.13 g, 0.77 mmol),
gave a separable mixture of oxazolidinones syn-16 and
anti-16 [syn-/anti- 12:88], and syn-27 and anti-27 [syn-/anti-
85:15]. The crude mixture was purified by flash column
chromatography on silica gel eluting with light petroleum
(bp 40–60 ꢁC)/diethyl ether (7:3) to give the oxazolidinones
anti- and syn-16 (0.17 g, 84%) and anti- and syn-27 (0.22 g,
84%).
4.5.16. Mutual kinetic separation of 4-isopropyl-oxazolidin-
2-one (S)-13 and ethyl-oxazolidin-2-one 4-carboxylate (S)-
12 using a combination of quasi-enantiomeric oxazolidinones
(R)-14 and (S)-19. In the same way as oxazolidinone 16,
n-BuLi (0.30 ml, 2.5 M in hexane, 0.752 mmol), 4-isoprop-
yl-oxazolidin-2-one (S)-13 (48 mg, 0.376 mmol), ethyl-

E. Boyd et al. / Tetrahedron: Asymmetry 18 (2007) 2515–2530
2529
4.5.20. Sequential kinetic resolution of 4-isopropyl-oxazoli-
din-2-one rac-13 using 2-phenylpropionyl chloride (S)-36 and
then pentafluorophenyl 2-(6-methoxynaphth-2-yl)propionate
(S)-19. In the same way as oxazolidinone 16, n-BuLi
(0.62 ml, 2.5 M in hexane, 1.55 mmol), 4-isopropyl-oxaz-
olidin-2-one rac-13 (0.20 g, 1.55 mmol) and 2-phenylpropi-
onyl chloride (S)-36 (0.13 g, 0.77 mmol) in THF, and after
1 h followed by (+)-pentafluorophenyl 2-(6-meth-
oxynaphth-2-yl)propionate (S)-19 (0.31 g, 0.77 mmol),
gave a separable mixture of oxazolidinones syn-16 and
anti-16 [syn-/anti- 40:60], and syn-27 and anti-27 [syn-/anti-
92:8]. The crude mixture was purified by flash column chro-
matography on silica gel eluting with light petroleum (bp
40–60 ꢁC)/diethyl ether (7:3) to give the oxazolidinones
anti- and syn-16 (0.11 g, 55%), and anti- and syn-27
(0.15 g, 59%).
8.4 and 2.7, 2 · CH; Ar), 7.46 (1H, dd, J 8.7 and 1.6,
CH; Ar), 7.14–7.09 (2H, m, 2 · CH; Ar), 5.28 (1H, q, J
6.9, ArCHCH3), 4.36–4.31 (1H, dt, J 9.1 and 3.2, i-
PrCHN), 4.10 (1H, dd, J 9.1 and 3.2, CHAHBO), 4.05
(1H, t, J 9.1, CHAHBO), 3.88 (3H, s, CH3O), 2.50–2.39
(1H, m, CH(CH3)2), 1.57 (3H, d, J 7.2, ArCHCH3), 0.86
(3H, d, J 7.2, CH3ACHCHB3 Þ and 0.85 (3H, d, J 7.2,
CHA3 CHCH3BÞ; dC (100 MHz; CDCl3) 174.7 (NC@O),
157.6 (OC@O), 153.7 (i-CO; Ar), 135.4, 133.8 and 128.8
(3 · i-CC; Ar), 129.3, 127.0, 126.8, 126.6, 118.8 and 105.5
(6 · CH; Ar), 63.0 (CH2O), 59.0 (i-PrCHN), 55.2
(OCH3), 42.8 (ArCHCH3), 28.5 (CH(CH3)2), 19.6 (CHA;
3
i-Pr), 17.9 (CHB; i-Pr), and 14.6 (ArCHCH3) (Found
3
MH+, 342.1707; C20H24NO4 requires 342.1700); and syn-
27 (0.29 g, 48%) as a white solid; mp 92–94 ꢁC; RF [light
petroleum (bp 40–60 ꢁC)/diethyl ether (1:1)] 0.34;
m
max(CHCl3)/cmꢀ1 1778 (NC@O) and 1701 (OC@O); dH
4.5.21. Pentafluorophenyl 2-(6-methoxynaphth-2-yl)propio-
nate rac-19. In the same way as active ester (R)-32, race-
mic 2-(6-methoxynaphth-2-yl)propionic acid (2.13 g,
9.25 mmol), pentafluorophenol (1.7 g, 9.25 mmol) and
DCC (2.1 g, 10.18 mmol) in CH2Cl2 (30 ml) gave after
purification by flash column chromatography on silica gel
eluting with light petroleum (bp 40–60 ꢁC)/diethyl ether
(9:1), the pentafluorophenyl 2-(6-methoxynaphth-2-yl)pro-
pionate rac-19 as a white solid; RF [light petroleum (bp 40–
60 ꢁC)/diethyl ether (1:1)] 0.65; mp 51–53 ꢁC; mmax(CHCl3)/
cmꢀ1 1781 (C@O); dH (400 MHz; CDCl3) 7.78 (1H, d, J
8.5, CH; Ar), 7.76 (1H, d, J 1.8, CH; Ar), 7.75 (1H, d, J
8.8, CH; Ar), 7.46 (1H, dd, J 8.5 and 1.8, CH; Ar), 7.19
(1H, dd, J 8.8 and 2.6, CH; Ar) 7.15 (1H, d, J 2.6, CH;
Ar), 4.38 (1H, q, J 7.2, ArCHCH3) 3.91 (3H, s, OCH3)
and 1.71 (3H, d, J 7.2, ArCHCH3); dC (100 MHz; CDCl3)
170.7 (C@O), 157.9 (i-CO; Ar), 141.0 (142.32 and
(270 MHz; CDCl3) 7.69 (3H, m, 3 · CH; Ar), 7.45 (1H,
dd, J 8.4 and 1.6, 1 · CH; Ar), 7.13–7.09 (2H, m,
2 · CH; Ar), 5.26 (1H, q, J 6.9, ArCHCH3), 4.52–4.46
(1H, dt, J 8.9 and 3.2, i-PrCHN), 4.21 (1H, t, J 8.9, CHAH-
BO), 4.06 (1H, dd, J 8.9 and 3.2, CHAHBO), 3.88 (3H, s,
CH3O), 2.25–2.13 (1H, m, CH(CH3)2), 1.53 (3H, d, J 6.9,
ArCHCH3), 0.75 (3H, d, J 6.9, CHA3 CHCH3BÞ and 0.38
(3H, d, J 6.9, CH3ACHCH3BÞ; dC (100 MHz; CDCl3) 174.6
(NC@O), 157.6 (OC@O), 153.5 (i-CO; Ar), 135.7, 133.7
and 128.9 (3 · i-CC; Ar), 129.4, 127.0, 126.7, 126.6, 118.8
and 105.5 (6 · CH; Ar), 62.9 (CH2O), 58.1 (i-PrCHN),
55.3 (OCH3), 43.2 (ArCHCH3), 27.9 (CH(CH3)2), 18.7
(CHA; i-Pr), 17.7 (CHB; i-Pr) and 14.0 (ArCHCH3) (Found
3
3
MH+, 342.1701; C20H24NO4 requires 342.1700).
4.5.23. Hydrolysis of oxazolidione adducts anti-16 (+)-2-
phenylpropionic acid (S)-17. Lithium hydroxide monohy-
drate (16 mg, 0.38 mmol) was slowly added to a stirred
solution of oxazolidinone (S,S)-anti-16 (0.10 g, 0.38 mmol)
and hydrogen peroxide (13 mg, 0.38 mmol, 30%/w) in
THF/water (1:1; 5 ml). The reaction mixture was stirred
at room temperature for 12 h. The reaction was quenched
with water (10 ml) and extracted with dichloromethane
(3 · 10 ml). The combined organic layers were dried over
MgSO4 and evaporated under reduced pressure to give
the recovered oxazolidinone (S)-13 (46 mg, 95%) as a white
1
2
139.8, 2C, ddt, JC,F = 249.8 Hz, JC,F = 12.2 Hz and
3JC,F = 4.6 Hz, C(2)–F), 139.3 (140.63 and 138.11, 1C,
1
2
3
dtt, JC,F = 252.1 Hz, JC,F = 13.0 Hz and JC,F = 4.5 Hz,
1
C(4)–F), 137.8 (139.04 and 136.54, 2C, dtdd, JC,F
=
2
3
4
250.6 Hz, JC,F = 13.8 Hz, JC,F = 5.3 and JC,F = 3.0 Hz,
C(3)–F) , 133.9, 133.7 and 128.9 (3 · i-C; Ar), 129.3,
127.5, 126.2, 125.7, 119.3 and 105.6 (6 · CH; Ar), 125.2
(1C, m, i-CO; OC6F5), 55.3 (OCH3), 45.9 (ArCHCH3)
and 18.5 (ArCHCH3); dF (378 MHz; CDCl3) ꢀ152.5 (2F,
20
20
3
3
d, JF,F 17.0, Fortho), ꢀ157.9 (1F, t, JF,F 21.6, Fpara) and
solid ½aꢁD ¼ þ13:7 (c 3.8, CHCl3), {lit.22 ½aꢁD ¼ þ13:3 (c
ꢀ162.3 (2F, dd, JF,F 21.6 and 17.0, Fmeta) (Found M+,
6.8, CHCl3)}; and (+)-2-phenylpropionic acid (S)-17
3
þ
396.0783; C20H13F5O3 requires 396.0779).
(53 mg, 93%) as an oil; RF [light petroleum (bp 40–60
20
ꢁC)/diethyl ether (1:9)] 0.5; ½aꢁD ¼ þ71:5 (c 2.0, CHCl3),
20
4.5.22. Mutual kinetic resolution of 4-isopropyl-oxazolidin-
2-one rac-13 using pentafluorophenyl 2-(6-methoxynaphth-2-
yl)propionate rac-19. In the same way as oxazolidinone
16, n-BuLi (0.72 ml, 2.5 M in hexane, 1.79 mmol), 4-isoprop-
yl-oxazolidin-2-one rac-13 (0.21 g, 1.63 mmol) and penta-
fluorophenyl 2-(6-methoxynaphth-2-yl)propionate rac-19
(0.64 g, 1.63 mmol) in THF gave a separable mixture of
oxazolidinones rac-syn-27 and rac-anti-27 [syn-/anti-
>98:2]. The crude mixture was purified by flash column
chromatography on silica gel eluting with light petroleum
(bp 40–60 ꢁC)/diethyl ether (7:3) to give the oxazolidinones
anti-27 (60 mg, 10%) as a white solid; mp 122–124 ꢁC; RF
[light petroleum (bp 40–60 ꢁC)/diethyl ether (1:1)] 0.51;
{lit.23 ½aꢁD ¼ þ72:0}; mmax(CHCl3)/cmꢀ1 1706 (C@O); dH
(270 MHz; CDCl3) 7.45–6.98 (5H, m, 5 · CH; Ph), 3.75
(1H, q, J 7.2, PhCH) and 1.5 (3H, d, J 7.2, CH3CH); dC
(67.9 MHz; CDCl3) 181.4 (C@O), 139.9 (i-C; Ph), 128.9,
127.8 and 127.6 (3 · CH; Ph), 45.6 (PhCH) and 18.3
(CH3) (Found MH+ 151.0753. C9H11NO
requires
þ
2
151.0759); m/z 151 (30%, MH) and 105 (100, MꢀCH2O2).
4.5.24. Hydrolysis of oxazolidione adducts syn-27 (+)-2-(6-
methoxynaphth-2-yl)propionic
acid
(S)-18. Lithium
hydroxide monohydrate (29 mg, 0.70 mmol) was slowly
added to a stirred solution of oxazolidinone syn-27
(0.12 g, 0.35 mmol) and hydrogen peroxide (24 mg,
0.2 ml, 0.70 mmol, 30%/w) in THF/water (3:1; 4 ml). The
reaction mixture was stirred at room temperature for
m
max(CHCl3)/cmꢀ1 1778 (NC@O) and 1701 (OC@O); dH
(270 MHz; CDCl3) 7.70 (1H, s, CH; Ar), 7.68 (2H, dd, J

2530
E. Boyd et al. / Tetrahedron: Asymmetry 18 (2007) 2515–2530
5. Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119, 2584–2585.
6. (a) Boyd, E.; Chavda, S.; Coulbeck, E.; Coumbarides, G. S.;
Dingjan, M.; Eames, J.; Flinn, A.; Krishnamurthy, A. K.;
Namutebi, M.; Northen, J.; Yohannes, Y. Tetrahedron:
Asymmetry 2006, 17, 3406–3422; (b) Boyd, E.; Chavda, S.;
Eames, J.; Yohannes, Y. Tetrahedron: Asymmetry 2007, 18,
476–482; (c) Coumbarides, G. S.; Dingjan, M.; Eames, J.;
Flinn, A.; Northen, J. Chirality 2007, 19, 321–328; (d)
Chavda, S.; Coumbarides, G. S.; Dingjan, M.; Eames, J.;
Flinn, A.; Northen, J. Chirality 2007, 19, 313–320, For
additional information see Refs. 8, 9 and 14.
7. For a comprehensive study into this particular active ester,
see Refs. 8, 9. For further information, see: Yohannes, Y.
PhD Thesis, University of London, 2004.
8. Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.;
Northen, J.; Yohannes, Y. Tetrahedron Lett. 2005, 46, 2897–
2902.
12 h. The reaction was quenched with water (10 ml) and ex-
tracted with dichloromethane (3 · 10 ml). The combined
organic layers were dried over MgSO4 and evaporated un-
der reduced pressure to give the recovered oxazolidinone
(R)-13 (41 mg, 90%) as a white solid; RF [diethyl ether]
20
20
0.35; ½aꢁD ¼ ꢀ14:0 (c 2.4, CHCl3), {lit.24 ½aꢁD ¼ ꢀ15:5 (c
7.0, CHCl3)}; and (+)-2-(6-methoxynaphth-2-yl)propionic
acid (S)-18 (60 mg, 74%) as a white solid; RF [diethyl ether]
20
0.56; mp 151–153 ꢁC; ½aꢁD ¼ þ65:0 (c 1.0, CHCl3), {lit.25
21
½aꢁD ¼ þ65:3 (c 1.0, CHCl3); authentic sample from Al-
20
drich Chemical Company; ½aꢁD ¼ þ64:8 (c 3.4, CHCl3);
mp 152–154 ꢁC}; mmax(CHCl3)/cmꢀ1 1710 (C@O); dH
(400 MHz; CDCl3) 7.73–7.68 (3H, m, 3 · CH; Ph), 7.41
(1H, dd, J 8.4 and 1.8, CH; Ar), 7.16–7.10 (2H, m,
2 · CH; Ph), 3.91 (3H, s, CH3O), 3.88 (1H, q, J 7.0,
ArCHCH3) and 1.59 (3H, d, J 7.0, ArCHCH3); dC
(100 MHz; CDCl3) 180.2 (C@O), 157.9 (i-CO; Ar), 134.8,
133.8 and 128.9 (3 · i-C; Ar), 129.3, 127.2, 126.2, 126.1,
119.0 and 105.6 (6 · CH; Ar), 55.3 (CH3O), 45.2
(ArCHCH3) and 18.1 (ArCHCH3); m/z 230 (60%, M+)
and 185 (100, ArCHCH3þ).
9. For our preliminary communication, see: Coumbarides, G.
S.; Dingjan, M.; Eames, J.; Flinn, A.; Motevalli, M.;
Northen, J.; Yohannes, Y. Synlett 2006, 101–105.
10. (a) Evans, D. A.; Ennis, M. D.; Mathrp, D. J. J. Am. Chem.
Soc. 1982, 104, 1737–1739; (b) Evans, D. A. Aldrichim. Acta
1982, 15, 23–32.
11. The yields were based on the amount of each active ester
used.
12. The 4-isobutyl group in (R)-32 makes this active ester less
polar relative to the parent 2-phenylpropionate (R)-14; RF
(light petroleum ether/diethyl ether 9:1) = 0.81 [for (R)-32],
0.69 [for (R)-14] and 0.50 [for (S)-19].
13. The levels of mutual stereocontrol are quoted with respect to
each parent oxazolidinone. This can potentially be inter-
preted as quasi-diastereoselectivity.
14. (a) Chavda, S.; Coulbeck, E.; Coumbarides, G. S.; Dingjan,
M.; Eames, J.; Ghilagaber, S.; Yohannes, Y. Tetrahedron:
Asymmetry 2006, 17, 3386–3399; (b) Coumbarides, G. S.;
Eames, J.; Flinn, A.; Northen, J.; Yohannes, Y. Tetrahedron
Lett. 2005, 46, 849–853.
Acknowledgements
We are grateful to the EPSRC (to E.C. and Y.Y.), Onyx
Scientific Limited (to M.D.), Queen Mary, University of
London and Syngenta (to S.C.) for studentships, The Roy-
al Society, The University of London Central Research
Fund and The University of Hull for their financial support
(to J.E.), and the EPSRC National Mass Spectrometry Ser-
vice (Swansea) for accurate mass determinations.
15. Fukuzawa, S.-I.; Chion, Y.; Yokoyama, T. Tetrahedron:
Asymmetry 2002, 13, 1645–1649.
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