Probing the parallel kinetic resolution of 1-phenylethanol using quasi-enantiomeric oxazolidinone adducts

Article abstract of DOI:10.1016/j.tetasy.2007.09.015

The parallel kinetic resolution of racemic 1-phenylethanol using an equimolar combination of quasi-enantiomeric oxazolidinones is discussed. The levels of diastereoselectivity were high leading to separable quasi-enantiomeric esters in good yield.

Full text of DOI:10.1016/j.tetasy.2007.09.015

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2313–2325
Probing the parallel kinetic resolution of 1-phenylethanol
using quasi-enantiomeric oxazolidinone adducts
Elliot Coulbeck and Jason Eames*
Department of Chemistry, University of Hull, Cottingham Road, Kingston upon Hull, HU6 7RX, UK
Received 31 July 2007; accepted 13 September 2007
Abstract—The parallel kinetic resolution of racemic 1-phenylethanol using an equimolar combination of quasi-enantiomeric oxazolidi-
nones is discussed. The levels of diastereoselectivity were high leading to separable quasi-enantiomeric esters in good yield.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
pyridinium chloride (S,S)-2 to give the corresponding
carbonate (S,R)-5 (Scheme 1). The levels of molecular
recognition between these complementary components,
(R)-1 and (S)-3, and (S,S)-2 and (R)-3, were sufficiently
high enough to allow efficient separation of their
enantiomers.10
Over the last decade, the kinetic resolution of secondary
alcohols by enantioselective alkyl and arylcarbonyl trans-
fer, involving stoichiometric and sub-stoichiometric chiral
mediators, has attracted significant attention.1 Within this
area, there have been three distinct approaches; those that
utilise either enzymes,2 chemical resolution3 and/or
thermodynamic separation.4 In an attempt to improve
the levels of stereoselection and chemical yield, a variety
of elegant strategies have been developed.5–9 One particular
strategy that holds promise is the parallel kinetic resolution
of secondary alcohols, which has attracted significant
attention.10 However, the lack of reports within this field
is primarily due to the difficulty in obtaining the required
complementary quasi-enantiomeric components for
efficient parallel kinetic resolution.8,11 Within this area,
Vedejs et al.10,12 have elegantly shown the parallel resolu-
tion of 1-(10-naphthyl) ethanol rac-3 using a pair of doubly
differentiated quasi-enantiomeric pyridinium chlorides
(R)-1 and (S,S)-2 to give two differential carbonates (S)-4
and (S,R)-5 in excellent yield with high levels of stereo-
control (Scheme 1).
As a result of this report,10 we have been interested13,14
over the last few years in the parallel kinetic resolution
of racemic Evans-based oxazolidinones, such as rac-8,
using two quasi-enantiomeric profen active esters (R)-6
and (S)-7, to give two diastereoisomerically pure syn-
adducts (R,S)-9 and (S,R)-10 in good yield with excellent
levels of diastereoselection (Scheme 2). We were origi-
nally interested in these quasi-enantiomeric adducts,
(R,S)-9 and (S,R)-10, as potential alkyl-carbonyl transfer
reagents for the resolution of secondary alcohols. To this
aim, we herein report our study into the use of quasi-
enantiomeric Evans’ oxazolidinones as complementary
diastereoselective alkyl-carbonyl transfer components for
the parallel kinetic resolution of racemic 1-phenylethanol
12.
Within this area, Evans et al.15 has demonstrated the
kinetic resolution of 1-phenylethanol rac-12 using a benz-
oylated oxazolidinone, such as (S)-11 (in the presence of
magnesium dibromide and N-methyl-piperidine), to give
the corresponding 1-phenylethyl benzoate (R)-13 in excel-
lent yield (>90%) with good levels of enantioselectivity
(72% ee) (Scheme 3). The levels of stereocontrol were
improved (to 85% ee) by the use of a more sterically
demanding oxazolidinone (S)-14 (Scheme 3). Recently,
Davies and co-workers16 has extended this methodology
From this study,10 it is evident that the (S)-enantiomer of
1-(10-naphthyl) ethanol 3 was selectivity derivatised by
pyridinium chloride (R)-1 [to give carbonate (S)-4],
whereas the remaining enantiomer (R)-3 was selectively
derivatised using the complementary quasi-enantiomeric
*
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.2007.09.015

2314
E. Coulbeck, J. Eames / Tetrahedron: Asymmetry 18 (2007) 2313–2325
NMe2
O
Me
O
H
Me
OH
t-Bu
OMe
N
Cl3C
O
Cl
Cl3C
O
O
(S)-4; 88% e.e.; 46%
[derived from (S)-3 + (R)-1]
(R)-1
rac-3
NMe2
Et3N, MgBr2
H
O
H
Me
H
t-Bu
OBn
O
O
N
Cl
O
O
(S,R)-5; >95% d.e.; 49%
[derived from (R)-3 + (S,S)-2]
(S,S)-2
Scheme 1. Parallel kinetic resolution of alcohol (rac)-3 using (R)-1 and (S,S)-2.
MeO
O
O
OC6F5
OC6F5
Me
H
H
Me
(S)-7
(R)-6
MeO
O
O
O
O
O
1. n-BuLi
THF, -78oC
HN
O
N
O
N
O
2. (R)-6 and
(S)-7
H
Me
Me
H
Ph
rac-8
Ph
(R,S)-syn-9
syn-9:anti-9 95:5; 65%
Ph
(S,R)-syn-10
syn-10:anti-10 95:5; 61%
Scheme 2. Parallel kinetic resolution of oxazolidinone (rac)-8 using (R)-6 and (S)-7.
OH
Ph
Me
O
O
O
O
O
(rac)-12
(10 equiv.)
(R)-13
85% e.e.
Ph
O
H
Ph
N
O
Ph
N
O
MgBr2OEt2
N-methylpiperidine
CH2Cl2, 25oC
Ph
Me
i-Pr
t-Bu
(S)-11
(S)-14
(R)-13; 72% e.e.
Scheme 3. Kinetic resolution of alcohol (rac)-12 using oxazolidinones (S)-11 and (S)-14.
through the use of a designer oxazolidinone, SuperQuat
(S)-15, to give the required 1-phenylethyl benzoate (R)-13
with a higher level of enantiocontrol (91% ee16 vs 72%
ee15) as shown in Scheme 4, which was shown to be compa-
rable to that derived from the more expensive and less
available oxazolidinone adduct (S)-14 (Scheme 3). Within
both these studies,15,16 the relative enantiomeric recogni-
tion was identical; the (S)-enantiomer of the oxazolidinone
recognised the (R)-enantiomer of 1-phenylethanol 12 (and
vice versa) to give ester (R)-13 (Scheme 4). Yamada has
also probed this particular reaction-type using oxazolidin-
2-thiones.17
OH
Ph
Me
O
O
O
rac-12
(10 equiv.)
Ph
O
H
Ph
N
O
MeMgBr
THF, 0oC
Ph
Me
Me
i-Pr
Me
(S)-15
(R)-13; 91% e.e.
Scheme 4. Kinetic resolution of alcohol (rac)-12 using oxazolidinone (S)-
15.

E. Coulbeck, J. Eames / Tetrahedron: Asymmetry 18 (2007) 2313–2325
2315
2. Results and discussion
phenyl 2-phenylpropionate rac-6 in 61% yield] gave no
level of enantiomer selection for racemic 1-phenylethanol
12 (Scheme 5, entry 3). However, when using the diastereo-
isomeric oxazolidinones rac-syn- and rac-anti-9, these gave
improved levels of diastereocontrol for ester 17 in favour of
the anti-diastereoisomer (Scheme 5: entries 1 and 2). Inter-
estingly, syn-oxazolidinone 9 gave higher levels of enantio-
mer selection for racemic 1-phenylethanol 12 than its
related oxazolidinone anti-9 (68% de vs 24% de) (Scheme
5: entry 1 vs entry 2). Evidently, the stereo-directing phenyl
group at the C(4)-position within the oxazolidinone ring in
rac-syn- and rac-anti-9 appears to be less dominant than
their adjacent 2-phenylpropionyl motif as both these dia-
stereoisomers favoured the formation of anti-ester 17
(Scheme 5). In contrast to Evans15 and Davies,16 it appears
that this enantiomeric recognition process is dependent on
both the structural nature of the parent oxazolidinone and
the carbonyl-transferring motif.
For our study, we first probed the mutual kinetic resolution
of a series of 2-phenylpropionated oxazolidinones rac-syn-
9, rac-anti-9 and rac-16 with 1-phenylethanol rac-12
(10 equiv) to determine the potential levels of complemen-
tary recognition (Scheme 5). For a comparable study to
Evans’15 and Davies’,16 we chose to add the oxazolidinones
rac-syn-9, rac-anti-9 and rac-16 to a stirred solution of
magnesium 1-phenylethoxide bromide and 1-phenylethanol
(ratio 1:9) in THF at 0 ꢁC (Scheme 5). After stirring for
12 h, this gave the corresponding 1-phenylethyl 2-phenyl-
propionate 17 in moderate yield (41–59%) with good levels
of diastereoselectivity, favouring the formation of the anti-
diastereoisomer in 68%, 24% and 0% de, respectively
(Scheme 5). The levels of stereocontrol were determined
by 1H NMR spectroscopy (400 MHz) by integration of
the corresponding methyl doublets in anti- and syn-17.18
Interestingly, the formation of 1-phenylethyl-2-phenylpro-
pionate 17 must have occurred via exo-cleavage of the
corresponding oxazolidinone and the levels of stereoselec-
tion appear to be governed by the relative stereogenicity
of the oxazolidinone framework (Scheme 5). For the
simplest oxazolidinone rac-16 [formed by addition of
lithiated oxazolidin-2-one to a solution of a pentafluoro-
The formation of the carbonates meso- and rac-18 must
have occurred via endo-cleavage19 of the oxazolidinone ring
(Scheme 5). The levels of stereocontrol and yield were
found to be dependent on the structural nature of the
oxazolidinone adduct. However, in all cases, meso-
carbonate 18 was found to be the major diastereoisomer
(from 14% to 40% de) (Scheme 5). The absence of
O
Ph
H
O
Ph
OH
Me
Ph
Me
Ph
Me
O
Me
O
H
O
Me
O
Ph
H
H
rac-12
Ph
Me
(10 equiv.)
MeMgBr
THF, 0oC
rac-anti-17
rac-syn-17
N
O
H
Ph
O
O
Ph Ph
Me
O
O
Ph
Me
R
rac-syn
Me
H
Me
H
H
H
O
O
meso-18
rac-18
carbonate 18
meso-: rac-
rac-ester-17
anti-:syn-
Oxazolidinone
Entry
D.e
D.e
O
O
Ph
65:35; 14%
68%
30%
84:16; 55%
1
N
O
O
Me
H
Ph
rac-syn-9
O
O
Ph
Me
2
57:43; 4%
N
62:38; 41%
50:50; 59%
24%
0%
14%
40%
H
Ph
rac-anti-9
O
O
3
Ph
Me
70:30; <1%
N
H
O
rac-16
Scheme 5. Mutual kinetic resolution of alcohol (rac)-12 using oxazoldinones (rac)-9 and 16.

2316
E. Coulbeck, J. Eames / Tetrahedron: Asymmetry 18 (2007) 2313–2325
O
Ph
H
O
Ph
OH
Ar
Ar
O
Me
H
O
H
Ph
Me
O
Me
O
R
H
R
H
rac-12
Ar
(10 equiv.)
rac-anti
rac-syn
N
O
MeMgBr
THF, 0oC
R
H
Ph
Me
O
O
Ph Ph
O
O
Ph
Me
Ph
rac-syn
H
Me
Me
H
H
O
O
meso-18
rac-18
Carbonate 18
meso-: rac-
rac-Ester
anti-: syn-
Oxazolidinone
De
De
Entry
1
O
O
4-Me-C6H4
Me
rac-22; 53%
N
O
O
O
64:34; 12%
66%
30%
83:17
H
Ph
rac-syn-19
O
O
4-i-Bu-C6H4
rac-23; 54%
N
63:37; 21%
62:38; 19%
2
70%
76%
26%
24%
85:15
Me
H
Ph
rac-syn-20
O
O
Ph
rac-24; 35%
N
3
88:12
H
Me
Ph
rac-syn-21
Scheme 6. Mutual kinetic resolution of alcohol (rac)-12 using oxazolidinones 19–21.
carbonate formation from Evans’ and Davies’ studies was
presumably due to the promoted exo-cleavage.20 Davies
has also demonstrated that his designer SuperQuat oxazo-
lidinones sterically disfavours endo-cleavage.16,21
With this information in hand, we next investigated the
mutual kinetic resolution of racemic 1-phenylethanol 12
using a series of structurally related syn-diastereoisomeric
oxazolidinones rac-syn-19–21 (Scheme 6). The addition of
O
O
O
Ph
Ph
Ph
N
O
O
H
Me
H
Me
H
Me
Ph
(R,S)-9
OH
Me
(R,R)-anti-17
anti-17:syn-17 87:13; 62%
Ph
rac-12
(20 equiv.)
Ph
O
O
Ph
MeMgBr
THF, 0oC
Me
H
O
Me
meso-18:rac-1823 57:43; 18%
MeO
MeO
O
O
O
Ph
H
N
O
O
Me
Me
H
Me
H
Ph
(S,R)-10
(S,S)-anti-25
anti-25:syn-25 84:16; 66%
Scheme 7. Parallel kinetic resolution of alcohol (rac)-12 using oxazolidinones 9 and 10.

E. Coulbeck, J. Eames / Tetrahedron: Asymmetry 18 (2007) 2313–2325
2317
methyl magnesium bromide (1 equiv) to a stirred solution
of 1-phenylethanol rac-12 (10 equiv), followed by the addi-
tion of oxazolidinones rac-syn-19–21 in THF at 0 ꢁC, gave
a racemic mixture of diastereoisomeric esters rac-anti- and
rac-syn-22–24 and carbonates meso- and rac-18 in moder-
ate to good yields (Scheme 6). For 2-(4-methylphenyl)-
and 2-(4-isobutylphenyl)propionyl oxazolidinones rac-19
and rac-20, these favoured the formation of the esters
rac-anti-22 and rac-anti-23 in 53% and 54% yields, respec-
tively, with near identical levels of diastereoselection (66%
and 70% de) to its closely related parent oxazolidinone rac-
syn-9 (Scheme 6, entries 1 and 2 vs Scheme 5, entry 1).
Whereas the use of a more structurally demanding 2-phe-
nylbutyryl motif in oxazolidinone rac-syn-21 gave a slight
improvement in enantiomer selection favouring formation
of the ester anti-24 with 76% de in lower yield (35%)
(Scheme 6, entry 3).
We next turned our attention to probing the parallel kinetic
resolution of 2-phenylethanol rac-12 using three combina-
tions of enantiomerically pure quasi-enantiomeric oxazo-
lidinones (Schemes 7–9). For this study, we chose to use
a more polar naproxen-derived oxazolidinone (S,R)-syn-
10 as our complementary component due to its known
separability from related profen-derived adducts (as shown
in Scheme 7).13,14,22 We chose to screen three structurally
related parallel kinetic resolutions, by the addition of an
equimolar combination of (R,S)-syn-9 and (S,R)-syn-10,
O
O
O
Ph
O
H
N
O
Me
H
Me
H
Me
Ph
OH
(R,R)-anti-23
anti-23:syn-23 88:12; 56%
(R,S)-20
Ph
Me
rac-12
(20 equiv.)
Ph
O
O
Ph
MeMgBr
THF, 0oC
Me
H
O
Me
meso-18:rac-1823 60:40; 13%
MeO
MeO
O
O
O
Ph
H
N
O
O
Me
Me
H
Me
H
Ph
(S,R)-10
(S,S)-anti-25
anti-25:syn-25 81:19; 49%
Scheme 8. Parallel kinetic resolution of alcohol (rac)-12 using oxazolidinones 10 and 20.23
O
O
O
Ph
Ph
Ph
N
O
O
H
Me
H
H
Me
Ph
Me
OH
Me
(R,R)-anti-24
anti-24:syn-24 89:11; 47%
(R,S)-21
Ph
rac-12
(20 equiv.)
Ph
O
O
Ph
MeMgBr
THF, 0oC
Me
H
O
Me
meso-18:rac-1823 61:39; 20%
MeO
MeO
O
O
O
Ph
H
N
H
O
O
Me
Me
Me
H
Ph
(S,R)-10
(S,S)-anti-25
anti-25:syn-25 81:19; 52%
Scheme 9. Parallel kinetic resolution of alcohol (rac)-12 using oxazolidinones 10 and 21.

2318
E. Coulbeck, J. Eames / Tetrahedron: Asymmetry 18 (2007) 2313–2325
MeO
LiAlH4
THF
H
OH
Ph
(S)-12; 72%
(S,S)-anti-25
OH
Me
Me
H
(S)-26; 74%
LiAlH4
THF
HO
Me
(R)-12; 64%
H
(R,R)-anti-23
OH
Ph
H
Me
(R)-27; 69%
Scheme 10. Synthesis of alcohols (S)-26 and (R)-27, and 1-phenylethanol (S)-and (R)-12.
(R,S)-syn-20 and (S,R)-syn-10, and (R,S)-syn-21 and (S,R)-
syn-10 to a stirred solution of preformed racemic magne-
sium 2-phenylethoxide bromide and 2-phenylethanol
rac-12 (ratio 1:9) in THF at 0 ꢁC (Schemes 7–9).
alkyl-carbonyl transfer reaction and competing carbonate
formation, and this will be reported in due course.
4. Experimental
4.1. General
These parallel resolutions proceeded efficiently giving three
pairs of diastereoisomeric esters, anti- and syn-17 (87:13;
62%) and anti- and syn-25 (84:16; 66%) (in Scheme 7), anti-
and syn-23 (88:12; 56%) and anti- and syn-25 (81:19; 49%)
(in Scheme 8), and anti- and syn-24 (89:11; 47%) and anti-
and syn-25 (81:19; 52%), respectively (Scheme 9), in good
yield, with good to excellent levels of diastereocontrol
(68–78% de). These levels of complementary stereocontrol
were near identical to their corresponding mutual kinetic
resolution. The complementary esters 17, 23 and 24 were
efficiently separated from the more polar naproxen-derived
ester 25, by flash column chromatography on silica gel,
eluting with light petroleum ether (bp 40–60 ꢁC)/diethyl
ether (9:1) (DRF = 0.25) (Schemes 7–9). The remaining
byproduct, oxazolidinone rac-8, was recovered in ꢀ40%
yield.24
All solvents were distilled before use. All reactions were
carried out under nitrogen using oven-dried glassware.
Flash column chromatography was carried out using
Merck Kieselgel 60 (230–400 mesh). Thin layer chromatog-
raphy (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 MHz Fourier transform spectrometer using an internal
deuterium lock. Chemical shifts are quoted in parts per
million downfield from tetramethylsilane. Carbon NMR
spectra were recorded with broad proton decoupling.
Infrared spectra were recorded on a Shimadzu 8300 FTIR
spectrometer. Optical rotation was measured using an
automatic AA-10 Optical Activity Ltd polarimeter. For
all the mutual and parallel kinetic resolutions reported,
the yields are based on the amount of oxazolidinone
present.
Access to the (S)-enantiomer of 1-phenylethanol 12 was
achieved by LiAlH4 reduction of ester (S,S)-anti-25, to give
1-phenylethanol (S)-12 and 2-(6-methoxy-2-naphthyl)pro-
panol (S)-26 in 72% and 74% yields, respectively (Scheme
10). LiAlH4 reduction of the complementary ester (R,R)-
anti-23 gave an inseparable mixture of 2-(4-isobutyl-
phenyl)propanol (R)-27 and 1-phenylethanol (R)-12 in
69% and 64% yields.25
4.2. Synthesis of 3-(2-phenylpropionyl)-oxazolidin-2-one
rac-16
n-BuLi (0.96 ml, 2.5 M in hexanes, 2.40 mmol) was added
to
a
stirred solution of oxazolidin-2-one (0.19 g,
2.18 mmol) in THF (10 ml) at ꢁ78 ꢁC. After stirring for
1 h, a solution of pentafluorophenyl 2-phenylpropionate
rac-6 (0.69 g, 2.18 mmol) in THF (10 ml) was added. The
resulting mixture was stirred for 2 h at ꢁ78 ꢁC. The reac-
tion was quenched with water (25 ml). The organic layer
was extracted with dichloromethane (3 · 25 ml), washed
with brine (25 ml), dried over MgSO4 and evaporated
under reduced pressure. The residue was purified by flash
column chromatography on silica gel eluting with light
petroleum ether–diethyl ether (9:1), to give 3-(2-phenylpro-
pionyl)-oxazolidin-2-one rac-16 (0.29 g, 61%) as a colour-
less liquid; RF [light petroleum (bp 40–60 ꢁC)–diethyl
3. Conclusion
In conclusion, we have reported a diastereoselective parallel
kinetic resolution approach for the resolution of 2-phenyl-
ethanol rac-12, using an equimolar combination of quasi-
enantiomeric oxazolidinones [e.g., (R,S)-9 and (S,R)-10].
The levels of diastereocontrol were found to be excellent
and predictably favoured the formation of the correspond-
ing anti-diastereoisomeric ester (R,S)-17. We are currently
exploring the scope and limitation of this diastereoselective

E. Coulbeck, J. Eames / Tetrahedron: Asymmetry 18 (2007) 2313–2325
2319
ether (1:1)] 0.14; mmax (CHCl3) cmꢁ1 1772 (NC@O) and
1700 (OC@O); dH (400 MHz; CDCl3) 7.37 (2H, dt, J 7.1
and 1.5, 2 · CH; Ph), 7.31 (2H, br ddd, J 7.1, 1.5 and
1.0, 2 · CH; Ph), 7.27–7.22 (1H, br tt, J 7.1 and 1.5, CH;
Ph), 5.11 (1H, q, J 7.0, CHCH3), 4.42–4.25 (2H, m,
CH2O), 4.11–4.02 (1H, ABq, CHAHBN), 3.97–3.89 (1H,
ABq, CHAHBN) and 1.50 (3H, d, J 7.0, CH3); dC
(100 MHz; CDCl3) 174.4 (NC@O), 152.9 (OC@O), 140.2
(i-C; Ph), 128.42, 129.02 and 127.01 (5 · CH; Ph), 61.6
(CH2O), 42.7 (CH2N), 42.6 (CHCH3) and 19.2 (CH3)
(Found M+, 219.0888; C12H13NO3 requires 219.0890);
m/z 219 (3%, M+), 132 (10, PhCH3C@C@O+), 105 (55,
PhCH3CH+), 104 ð50; PhCHCHþÞ, 77 ð95; C6HþÞ and 43
45.6 (PhCH), 22.0 (PhCHCH3O) and 18.3 (PhCHCH3)
(Found
MNHþ4 ,
272.1648;
C17H22NO2
requires
272.1645); m/z 254 (5%, M+), 105 ð100; PhCHCH3þÞ and
77 ð10; C6Hþ5 Þ.
4.3.3. Di-(1-phenylethyl)-carbonate meso-18.26 Oil; RF
[light petroleum (bp 40–60 ꢁC)–diethyl ether (1:1)] 0.75;
mmax (CHCl3); cmꢁ1 1751 (C@O); dH (400 MHz; CDCl3)
7.39–7.23 (10H, m, 10 · CH; PhA and PhB), 5.69 (2H, q,
J
6.8, 2 · PhCHCH3) and 1.59 (6H, d,
J
6.8,
2 · PhCHCH3); dC (100 MHz; CDCl3) 153.9 (C@O),
141.2 (2 · i-C; 2 · Ph), 128.5 (4 · CH; 2 · Ph), 128.1
(2 · CH; 2 · Ph), 126.1 (4 · CH; 2 · Ph), 76.4
(2 · PhCHCH3) and 22.4 (2 · PhCHCH3) (Found
MNHþ4 , 288.1593; C17H22NO4 requires 288.1594); m/z
269 (1%, M+ꢁH), 165 (15, M+ꢁPhCHCH3), 121 (30,
PhCHCH3O+), 105 ð100; PhCHCHþÞ and 77 ð40; C6HþÞ.
2
5
(100, NHCO+).
4.3. 1-Phenylethyl-2-phenylpropionate rac-anti-17 [derived
from the mutual kinetic resolution of 1-phenylethanol rac-12
and 3-(2-phenylpropionyl)-oxazolidin-2-one rac-16]
3
5
4.3.4. Di-(1-phenylethyl)-carbonate rac-18.27 Oil; RF
[light petroleum (bp 40–60 ꢁC)–diethyl ether (1:1)]
0.75; mmax (CHCl3); cmꢁ1 1742 (C@O); dH (400 MHz;
CDCl3) 7.38–7.26 (10H, m, 10 · CH; PhA and PhB), 5.66
(2H, q, J 6.8, 2 · PhCHCH3) and 1.53 (6H, d, J 6.8,
2 · PhCHCH3); dC (100 MHz; CDCl3) 153.8 (C@O),
141.1 (2 · i-C; 2 · Ph), 128.5 (4 · CH; 2 · Ph), 128.0
(2 · CH; 2 · Ph), 126.0 (4 · CH; 2 · Ph), 76.3
(2 · PhCHCH3) and 22.2 (2 · PhCHCH3) (Found
MNHþ4 , 288.1593; C17H22NO4 requires 288.1594); m/z
269 (1%, M–H+), 165 (10, M+ꢁPhCHCH3), 121 (25,
PhCHCH3O+), 105 ð100; PhCHCHþÞ and 77 ð75; C6HþÞ.
Methyl magnesium bromide (0.37 ml, 3 M in diethyl ether,
1.00 mmol) was added to a stirred solution of 1-phenyl-
ethanol rac-12 (1.23 g, 10.00 mmol) in THF (6 ml) at
0 ꢁC. After stirring for 10 min, a solution of oxazolidinone
adduct rac-16 (0.22 g, 1.00 mmol) in THF (6 ml) was
added. The resulting solution was stirred for 12 h at room
temperature. The reaction was quenched with saturated
aqueous NH4Cl (10 ml). The organic layer was extracted
with dichloromethane (3 · 25 ml), washed with water
(25 ml), dried (over MgSO4) and evaporated under reduced
pressure. The residue was purified by flash column chroma-
tography on silica gel eluting with light petroleum ether–
diethyl ether (9:1) to give an inseparable mixture25 of two
pairs of diastereoisomeric 1-phenylethyl 2-phenylpro-
pionates rac-anti- and rac-syn-17 (0.15 g, 59%; syn-:anti-
50:50), and di-(1-phenylethyl) carbonates meso- and rac-
18 (ꢀ2 mg, 0.7%; meso-:rac- 70:30) as an oil.
3
5
4.4. Mutual kinetic resolution of 1-phenylethanol rac-12 with
3-(2-phenylpropionyl)-4-phenyl-oxazolidin-2-one rac-anti-9
In the same way as above, methyl magnesium bromide
(0.26 ml, 3 M in diethyl ether, 0.78 mmol), 1-phenylethanol
rac-12 (0.95 g, 7.79 mmol) and 3-(2-phenylpropionyl)-4-
phenyl-oxazolidin-2-one rac-anti-9 (0.23 g, 0.78 mmol) in
THF (10 ml), gave after purification by flash column chro-
matography on silica gel eluting with light petroleum
ether–diethyl ether (9:1!7:3) an inseparable mixture25 of
two pairs of diastereoisomeric 1-phenylethyl-2-phenylpro-
pionates rac-anti- and rac-syn-17 (81 mg, 41%; anti-:syn-
62:38) and di-(1-phenylethyl) carbonates meso- and rac-18
(9 mg, 4%; meso-:rac- 57:43), which were spectroscopically
identical to that previously obtained.
Characterisation data for:
4.3.1. 1-Phenylethyl-2-phenylpropionate rac-anti-17. Oil;
RF [light petroleum (bp 40–60 ꢁC)–diethyl ether (1:1)]
0.80; mmax (CHCl3)/cmꢁ1 1730 (C@O); dH (400 MHz;
CDCl3) 7.30–7.14 (8H, m, 8 · CH; 2 · Ph), 7.05–7.00
(2H, m, 2 · CH; 2 · Ph), 5.78 (1H, q, J 6.6, PhCHCH3O),
3.68 (1H, q, J 7.2, PhCHCH3), 1.43 (3H, d, J 7.2,
PhCHCH3) and 1.42 (3H, d, J 6.6, PhCHCH3O); dC
(100 MHz; CDCl3) 173.5 (C@O), 141.6 (i-C; PhA), 140.4
(i-C; PhB), 128.5,2 128.3,2 127.6.,2 127.5,1 127.01 and
125.62 (10 · CH; PhA and PhB), 72.4 (PhCHO), 45.7
(PhCH), 22.3 (PhCHCH3O) and 18.3 (PhCHCH3) (Found
MNHþ4 , 272.1647; C17H22NO2 requires 272.1645); m/z 254
(10%, M+) and 105 ð100; PhCHCHþ3 Þ.
4.5. Mutual kinetic resolution of 1-phenylethanol rac-12 with
3-(2-phenylpropionyl)-4-phenyl-oxazolidin-2-one rac-syn-9
In the same way as above, methyl magnesium bromide
(0.23 ml, 3 M in diethyl ether, 0.68 mmol), 1-phenylethanol
rac-12 (0.83 g, 6.77 mmol) and 3-(2-phenylpropionyl)-4-
phenyl-oxazolidin-2-one rac-syn-9 (0.2 g, 0.68 mmol) in
THF (10 ml), gave after purification by flash column chro-
matography on silica gel eluting with light petroleum
ether–diethyl ether (9:1!7:3) an inseparable mixture25 of
two pairs of diastereoisomeric 1-phenylethyl-2-phenylpro-
pionates rac-anti- and rac-syn-17 (95 mg, 55%; anti-:syn-
84:16) and di-(1-phenylethyl) carbonates meso- and rac-18
(25 mg, 14%; meso-:rac- 65:35), which were spectroscopi-
cally identical to that previously obtained.
4.3.2. 1-Phenylethyl-2-phenylpropionate rac-syn-17. Oil;
RF [light petroleum (bp 40–60 ꢁC)–diethyl ether (1:1)]
0.78; mmax (CHCl3)/cmꢁ1 1723 (C@O); dH (400 MHz;
CDCl3) 7.28–7.13 (10H, m, 10 · CH; PhA and PhB), 5.78
(1H, q, J 6.6, PhCHCH3O), 3.66 (1H, q, J 7.2, PhCHCH3),
1.41 (3H, d, J 7.2, PhCHCH3) and 1.35 (3H, d, J 6.6,
PhCHCH3O); dC (100 MHz; CDCl3) 173.7 (C@O), 141.6
(i-C; PhA), 140.5 (i-C; PhB), 128.5,2 128.4,2 127.8,1 127.5,2
127.01 and 126.02 (10 · CH; PhA and PhB), 72.5 (PhCHO),

2320
E. Coulbeck, J. Eames / Tetrahedron: Asymmetry 18 (2007) 2313–2325
4.6. Mutual kinetic resolution of 1-phenylethanol rac-12 with
4-phenyl-[3-(4-methylphenyl)-2-propyl]-oxazolidin-2-one
rac-syn-19
mixture25 of two pairs of diastereoisomeric 1-phenylethyl-
2-(4-isopropylphenyl)-propionates rac-anti- and rac-syn-23
(0.21 g, 54%; anti-:syn- 85:15) and di-(1-phenylethyl)-
carbonate meso- and rac-18 (88 mg, 21%; meso-:rac-
63:37).
In the same way as above, methyl magnesium bromide
(0.52 ml, 3 M in diethyl ether, 1.55 mmol), 1-phenylethanol
rac-12 (1.90 g, 15.52 mmol) and 4-phenyl-[3-(4-methyl-
phenyl)-2-propyl]-oxazolidin-2-one rac-syn-19 (0.48 g,
1.55 mmol) in THF (10 ml), gave after purification by flash
column chromatography on silica gel eluting with light
petroleum ether–diethyl ether (9:1) an inseparable mix-
ture25 of two pairs of diastereoisomeric 1-phenylethyl-2-
(4-methylphenyl)propionates rac-anti- and rac-syn-22
(0.21 g, 53%; anti-:syn- 83:17) and di-(1-phenylethyl)car-
bonate meso- and rac-18 (49 mg, 12%; meso-:rac- 64:36).
Characterisation data for:
4.7.1. 1-Phenylethyl-2-(4-isopropylphenyl)propionate rac-
anti-23. Oil; RF [light petroleum (bp 40–60 ꢁC)–diethyl
ether (1:1)] 0.85; mmax (CHCl3)/cmꢁ1 1723 (C@O);
dH (400 MHz; CDCl3) 7.21–7.17 (3H, m, 3 · CH; Ph),
7.11 (2H, br d, J 8.1, 2 · CH; Ar), 7.08–7.05 (2H, m,
Ph), 7.05 (2H, br d, J 8.1, 2 · CH; Ar), 5.78 (1H, q, J
6.6, PhCHCH3O), 3.65 (1H, q, J 7.2, ArCHCH3), 2.37
(2H, d, J 7.1, CH2Ar), 1.77 (1H, triple septet (appears
as a nonet), J 7.1 and 6.6, CH(CH3)2), 1.42 (3H, d, J
6.6, PhCHCH3O), 1.41 (3H, d, J 7.1, ArCHCH3) and
0.82 (6H, d, J 6.6, CH(CH3)2); dC (100 MHz; CDCl3)
173.7 (C@O), 141.7 (i-C; Ar), 140.4 (i-C; Ph), 137.6 (i-
CCH2; Ar), 129.2,2 and 125.62 (4 · CH; Ar), 128.2,2
127.5,1 and 127.32 (5 · CH; Ph), 72.3 (PhCHCH3O), 45.3
(ArCHCH3), 45.0 (CH2Ar) 30.2 (CH(CH3)2), 22.33 (3 C,
CH(CH3)2 and PhCHCH3O) and 18.2 (ArCHCH3)
Characterisation data for:
4.6.1. 1-Phenylethyl-2-(4-methylphenyl)propionate rac-anti-
22. Oil; RF [light petroleum (bp 40–60 ꢁC)–diethyl ether
(1:1)] 0.79; mmax (CHCl3)/cmꢁ1 1730 (C@O); dH
(400 MHz; CDCl3) 7.20–7.12 (3H, m, 3 · CH; Ph), 7.08–
7.00 (6H, m, 3 · CH; Ar and Ph), 5.78 (1H, q, J 6.6,
PhCHCH3O), 3.64 (1H, q, J 7.2, ArCHCH3), 2.25 (3H, s,
CH3; Ar), 1.41 (3H, d, J 6.6, PhCHCH3O) and 1.40 (3H,
d, J 7.2, ArCHCH3); dC (100 MHz; CDCl3) 173.7 (C@O),
141.7 (i-C; Ar), 137.4 (i-C; Ph), 136.6 (i-CCH3; Ar),
129.2,2 and 125.72 (4 · CH; Ar), 128.3,2 127.5,1 and
127.42 (5 · CH; Ph), 72.4 (PhCHCH3O), 45.3 (ArCHCH3),
22.3 (PhCHCH3O), 21.0 (CH3; Ar) and 18.4 (ArCHCH3)
(Found
MNHþ4 ,
328.2273;
C21H30NO2
requires
328.2271); m/z 310 (5%, M+), 161 ð100; ArCHCH3þÞ and
105 ð80; PhCHCHþ3 Þ.
4.7.2. 1-Phenylethyl-2-(4-isopropylphenyl)propionate rac-
syn-23. Oil; RF [light petroleum (bp 40–60 ꢁC)–diethyl
ether (1:1)] 0.84; mmax (CHCl3)/cmꢁ1 1723 (C@O); dH
(400 MHz; CDCl3) 7.27–7.19 (5H, m, 5 · CH; Ph), 7.14
(2H, dt, J 8.1 and 1.8, 2 · CH; Ar), 7.02 (2H, dt, J 8.1
and 1.8, 2 · CH; Ar), 5.78 (1H, q, J 6.6, PhCHCH3O),
3.64 (1H, q, J 7.2, ArCHCH3), 2.38 (2H, d, J 7.1, CH2Ar),
1.78 (1H, triple septet (appears as a nonet), J 7.1 and 6.6,
CH(CH3)2), 1.40 (3H, d, J 7.2, ArCHCH3), 1.34 (3H, d,
J 6.6, PhCHCH3O) and 0.83 (6H, d, J 6.6, CH(CH3)2);
dC (100 MHz; CDCl3) 174.0 (C@O), 141.7 (i-C; Ar),
140.4 (i-C; Ph), 137.6 (i-CCH2; Ar), 129.2,2 and 125.92
(4 · CH; Ar), 128.4,2 127.7,1 and 127.22 (5 · CH; Ph),
72.4 (PhCHCH3O), 45.2 (ArCHCH3), 45.0 (CH2Ar) 30.2
(CH(CH3)2), 22.32 (CH(CH3)2), 22.0 (PhCHCH3O) and
18.3 (ArCHCH3) (Found MNHþ4 , 328.2271; C21H30NO2
requires 328.2271); m/z 310 (5%, M+), 161
ð100; ArCHCHþ3 Þ and 105 ð100; PhCHCHþ3 Þ.
(Found
MNHþ4 ,
286.1804;
C18H24NO2
requires
286.1802); m/z 268 (5%, M+), 119 ð100; ArCHCH3þÞ and
105 ð60; PhCHCHþ3 Þ.
4.6.2. 1-Phenylethyl-2-(4-methylphenyl)propionate rac-syn-
22. Oil; RF [light petroleum (bp 40–60 ꢁC)–diethyl ether
(1:1)] 0.79; mmax (CHCl3)/cmꢁ1 1723 (C@O); dH
(400 MHz; CDCl3) 7.38–7.27 (5H, m, 5 · CH; Ph), 7.22
(2H, br d, J 8.2, 2 · CH; Ar), 7.15 (2H, br d, J 8.2,
2 · CH; Ar), 5.87 (1H, q, J 6.6, PhCHCH3O), 3.72 (1H,
q, J 7.1, ArCHCH3), 2.34 (3H, s, CH3; Ar), 1.48 (3H,
d,
J
7.1, ArCHCH3) and 1.44 (3H, d,
J
6.6,
PhCHCH3O); dC (100 MHz; CDCl3) 173.9 (C@O),
141.7 (i-C; Ar), 137.5 (i-C; Ph), 136.6 (i-CCH3; Ar),
129.2,2 and 126.02 (4 · CH; Ar), 128.4,2 127.8,1 and
127.32 (5 · CH; Ph), 72.4 (PhCHCH3O), 45.2
(ArCHCH3), 22.0 (PhCHCH3O), 21.0 (CH3; Ar) and
18.5 (ArCHCH3) (Found MNHþ4 , 286.1801; C18H24NO2
requires 286.1802); m/z 268 (7%, M+), 119
ð100; ArCHCHþ3 Þ and 105 ð70; PhCHCHþ3 Þ.
4.8. Mutual kinetic resolution of 1-phenylethanol rac-12 with
4-phenyl-3-(2-phenylbutyryl)-oxazolidin-2-one rac-syn-21
4.7. Mutual kinetic resolution of 1-phenylethanol rac-12 with
4-phenyl-3-[2-(4-isopropyl)phenylpropionyl]-oxazolidin-2-
one rac-syn-20
In the same way as above, methyl magnesium bromide
(0.34 ml, 3 M in diethyl ether, 1.03 mmol), rac-1-phenyl-
ethanol 12 (1.26 g, 10.31 mmol) and 4-phenyl-3-(2-phenyl-
butyryl)-oxazolidin-2-one rac-syn-21 (0.32 g, 1.03 mmol)
in THF (10 ml), gave after purification by flash column
chromatography on silica gel eluting with light petroleum
ether–diethyl ether (9:1!7:3) an inseparable mixture25 of
two pairs of diastereoisomeric 1-phenylethyl-2-phenylbuty-
rates rac-anti- and rac-syn-24 (98 mg, 35%; anti-:syn- 88:12)
and di-(1-phenylethyl)carbonate meso- and rac-18 (53 mg,
19%; meso-:rac- 62:38).
In the same way as above, methyl magnesium bromide
(0.52 ml, 3 M in diethyl ether, 1.52 mmol), 1-phenylethanol
rac-12 (1.91 g, 15.65 mmol) and 4-phenyl-[3-(4-isopropyl-
phenyl)-2-propyl]-oxazolidin-2-one rac-syn-20 (0.55 g,
1.52 mmol) in THF (10 ml), gave after purification by flash
column chromatography on silica gel eluting with light
petroleum ether–diethyl ether (9:1) an inseparable

E. Coulbeck, J. Eames / Tetrahedron: Asymmetry 18 (2007) 2313–2325
2321
Characterisation data for:
Characterisation data for:29
4.8.1. 1-Phenylethyl-2-phenylbutyrate28 rac-anti-24. Oil;
RF [light petroleum (bp 40–60 ꢁC)–diethyl ether (1:1)]
0.79; mmax (CHCl3)/cmꢁ1 1723 (C@O); dH (400 MHz;
CDCl3) 7.30–7.14 (8H, m, 8 · CH; PhA and PhB), 7.05–
7.00 (2H, m, 2 · CH; PhA or PhB), 5.88 (1H, q, J 6.6,
PhCHCH3O), 3.51 (1H, t, J 7.6, PhCHCH2CH3), 2.13
(1H, ddq, J 13.7, 7.6 and 7.5, CHAHBCH3), 1.82 (1H,
ddq, J 13.7, 7.6 and 7.5, CHAHBCH3), 1.51 (3H, d, J 6.6,
PhCHCH3O) and 0.90 (3H, t, J 7.5, CH3CH2); dC
(100 MHz; CDCl3) 172.8 (C@O), 141.5 (i-C; PhCHCH3O),
138.8 (i-C; PhCHCH3), 128.3,2 128.1,2 127.9,2 127.4,1
126.91 and 125.92 (10 · CH; PhA and PhB), 72.2
(PhCHCH3O), 53.5 (PhCHCH3), 26.4 (CH3CH2), 22.2
(PhCHCH3O) and 12.0 (CH3CH2) (Found MNHþ4 ,
286.1805; C18H24NO2 requires 286.1802); m/z 268
4.9.1. 1-Phenylethyl-2-phenylpropionate30 (R,R)-anti-17.
Transparent solid; mp 81–83 ꢁC; RF [light petroleum
20
(bp 40–60 ꢁC)–diethyl ether (1:1)] 0.80; ½aꢂD ¼ þ10:5 (c
20
3.0, CHCl3) {lit.;30 ½aꢂD ¼ þ9:9 (c 0.87, CHCl3)}; mmax
(CHCl3)/cmꢁ1 1730 (C@O); dH (400 MHz; CDCl3) 7.30–
7.14 (8H, m, 8 · CH; PhA and PhB), 7.05–7.00 (2H, m,
2 · CH; PhA or PhB), 5.78 (1H, q, J 6.6, PhCHCH3O),
3.68 (1H, q, J 7.2, PhCHCH3), 1.43 (3H, d, J 7.2,
PhCHCH3) and 1.42 (3H, d, J 6.6, PhCHCH3O); dC
(100 MHz; CDCl3) 173.5 (C@O), 141.6 (i-C; PhCHCH3O),
140.4 (i-C; PhCHCH3), 128.5,2 128.3,2 127.6.,2 127.5,1
127.0,1 and 125.6,2 (10 · CH; PhA and PhB), 72.4
(PhCHCH3O), 45.7 (PhCHCH3), 22.3 (PhCHCH3O) and
18.3 (PhCHCH3) (Found MNHþ4 , 272.1648; C17H22NO2
requires 272.1645); m/z 254 (10%, M+) and 105
ð100; PhCHCHþ3 Þ.
(5%, M+), 119 ð30; PhCHCH2CHþÞ and 105 ð100;
3
PhCHCHþ3 Þ.
4.9.2. 1-Phenylethyl-2-phenylpropionate (R,S)-syn-17. Oil;
4.8.2. 1-Phenylethyl-2-phenylbutyrate rac-syn-24. Oil; RF
[light petroleum (bp 40–60 ꢁC)–diethyl ether (1:1)] 0.75;
mmax (CHCl3)/cmꢁ1 1723 (C@O); dH (400 MHz; CDCl3)
7.38–7.23 (10H, m, 10 · CH; PhA and PhB), 5.88 (1H, q,
J 6.6, PhCHCH3O), 3.51 (1H, t, J 7.5, PhCHCH2CH3),
2.11 (1H, ddq, J 13.5, 7.5 and 7.5, CHAHBCH3), 1.80
(1H, ddq, J 13.5, 7.5 and 7.5, CHAHBCH3), 1.44 (3H, d,
J 6.6, PhCHCH3O) and 0.87 (3H, t, J 7.5, CH3CH2); dC
(100 MHz; CDCl3) 173.3 (C@O), 141.7 (i-C; PhCHCH3O),
139.1 (i-C; PhCHCH3), 128.5,2 128.4,2 127.9,2 127.7,1
127.11 and 126.02 (10 · CH; PhA and PhB), 72.5
(PhCHCH3O), 53.6 (PhCHCH2CH3), 26.6 (CH3CH2),
21.9 (PhCHCH3O) and 12.1 (CH3CH2) (Found MNHþ4 ,
286.1805; C18H24NO2 requires 286.1802); m/z 268
RF [light petroleum (bp 40–60 ꢁC)–diethyl ether (1:1)]
20
0.78; ½aꢂD ¼ ꢁ60:4 (c 1.9, CHCl3); mmax (CHCl3)/cmꢁ1
1723 (C@O); dH (400 MHz; CDCl3) 7.28–7.13 (10H, m,
10 · CH; PhA and PhB), 5.78 (1H, q, J 6.6, PhCHCH3O),
3.66 (1H, q, J 7.2, PhCHCH3), 1.41 (3H, d, J 7.2,
PhCHCH3) and 1.35 (3H, d, J 6.6, PhCHCH3O); dC
(100 MHz; CDCl3) 173.7 (C@O), 141.6 (i-C; PhA), 140.5
(i-C; PhB), 128.5,2 128.4,2 127.8,1 127.5,2 127.01 and
126.02 (10 · CH; PhA and PhB), 72.5 (PhCHCH3O), 45.6
(PhCHCH3), 22.0 (PhCHCH3O) and 18.3 (PhCHCH3)
(Found
MNHþ4 ,
272.1647;
C17H22NO2
requires
272.1645); m/z 254 (5%, M+), 105 ð100; PhCHCH3þÞ and
77 (10, Ph+).
(5%, M+), 119 ð50; PhCHCH2CHþÞ and 105 ð100;
4.9.3. 1-Phenylethyl-2-(6-methoxy-naphthalene-2-yl)propio-
nate (S,S)-anti-25. White solid; mp 94–96 ꢁC; RF [light
3
PhCHCHþ3 Þ.
petroleum (bp 40–60 ꢁC)–diethyl ether (1:1)] 0.62;
20
4.9. Parallel kinetic resolution of 1-phenylethanol rac-12
using 3-(2-phenylpropionyl)-4-phenyl-oxazolidin-2-one
(R,S)-syn-9 and 3-[2-(6-methoxy-naphthalen-2-yl)-propio-
nyl]-4-phenyl-oxazolidin-2-one (S,R)-syn-10
½aꢂD ¼ þ26:6 (c 3.2, CHCl3); mmax (CHCl3)/cmꢁ1 1723
(C@O); dH (400 MHz; CDCl3) 7.66 (1H, d, J 8.4, CH;
Ar), 7.63 (1H, d, J 8.4, CH; Ar), 7.55 (1H, br s, CH; Ar),
7.33 (1H, dd, J 8.3 and 1.8, CH; Ar), 7.19–7.08 (7 H, m,
7 · CH; Ar and Ph), 5.86 (1H, q, J 6.6, PhCHCH3O),
3.90 (3H, s, OCH3; Ar), 3.88 (1H, q, J 7.2, ArCHCH3),
1.56 (3H, d, J 7.2, ArCHCH3) and 1.50 (3H, d, J 6.6,
PhCHCH3O); dC (100 MHz; CDCl3) 173.7 (C@O), 147.5
(i-CO; Ar), 141.6 (i-C; Ph), 135.6 (i-C; Ar), 133.6 and
128.9 (2 · i-C; Ar), 129.3,1 127.0,1 126.4,1 126.0,1 118.81
and 105.51 (6 · CH; Ar), 128.2,2 127.51 and 125.72
(5 · CH; Ph), 72.5 (PhCHCH3O), 55.3 (OCH3), 45.6
(ArCHCH3), 22.3 (PhCHCH3O) and 18.4 (ArCHCH3)
Methyl magnesium bromide (1.65 ml, 3 M in diethyl ether,
4.94 mmol) was added to a stirred solution of 1-phenyleth-
anol rac-12 (6.04 g, 49.35 mmol) in THF (20 ml) at 0 ꢁC.
After stirring for 10 min, a mixed solution of 3-(2-phenyl-
propionyl)-4-phenyl-oxazolidin-2-one (R,S)-syn-9 (0.73 g,
2.47 mmol) and 3-[2-(6-methoxy-naphthalen-2-yl)-propio-
nyl]-4-phenyl-oxazolidin-2-one
(S,R)-syn-10
(0.93 g,
2.47 mmol) in THF (40 ml) was added. The resulting mix-
ture was stirred overnight at room temperature. The reac-
tion was quenched with saturated aqueous NH4Cl
(30 ml). The organic layer was extracted with dichloro-
methane (3 · 50 ml), washed with water (50 ml), dried
(over MgSO4) and evaporated under reduced pressure.
The residue was purified by flash column chromatography
on silica gel eluting with light petroleum (bp 40–60 ꢁC)–
diethyl ether (9:1–0:1) to give two pairs of inseparable dia-
stereoisomers25 (R,R)-anti- and (S,S)-syn-17 (0.39 g, 62%)
(ratio: anti-:syn- 87:13) and meso- and rac-18 (0.24 g,
18%) (ratio: syn-:anti- 57:43), and (S,S)-anti- and (R,R)-
syn-25 (0.55 g, 66%) (ratio: anti-:syn- 84:16).
(Found
MNHþ4 ,
352.1907;
C22H26NO3
requires
352.1907); m/z 334 (20%, M+), 185 ð100; ArCHCH3þÞ and
105 ð60; PhCHCHþ3 Þ.
4.9.4. 1-Phenylethyl-2-(6-methoxy-naphthalene-2-yl)propio-
nate (S,R)-syn-25. White solid; mp 73–75 ꢁC; RF [light
petroleum (bp 40–60 ꢁC)–diethyl ether (1:1)] 0.61;
20
½aꢂD ¼ þ8:75 (c 1.64, CHCl3); mmax (CHCl3)/cmꢁ1 1730
(C@O); dH (400 MHz; CDCl3) 7.68 (2H, dd, J 8.4 and
2.0, 2 · CH; Ar), 7.66 (1H, br s, CH; Ar), 7.40 (1H, dd, J
8.4 and 1.8, CH; Ar), 7.33–7.25 (5H, 5 · CH; Ph), 7.12
(1H, dd, J 8.4 and 1.8, CH; Ar), 7.10 (1H, br s, CH; Ar),

2322
E. Coulbeck, J. Eames / Tetrahedron: Asymmetry 18 (2007) 2313–2325
5.85 (1H, q, J 6.6, PhCHCH3O), 3.90 (3H, s, OCH3; Ar),
3.85 (1H, q, J 7.2, ArCHCH3), 1.54 (3H, d, J 7.2,
ArCHCH3) and 1.40 (3H, d, J 6.6, PhCHCH3O); dC
(100 MHz; CDCl3) 173.9 (C@O), 157.6 (i-CO; Ar), 141.6
(i-C; Ph), 135.7 (i-C; Ar), 133.6 and 128.9 (2 · i-C; Ar),
129.3, 127.0, 126.3, 125.9, 118.9 and 105.5 (6 · CH; Ar
and Ph), 128.4,2 127.8,1 and 126.02 (5 · CH; Ph), 72.6
(PhCHCH3O), 55.3 (OCH3), 45.6 (ArCHCH3), 22.0
(PhCHCH3O) and 18.5 (ArCHCH3) (Found MNHþ4 ,
352.1905; C22H26NO3 requires 352.1907); m/z 334 (20%,
M+), 185 ð100; ArCHCH3þÞ and 105 ð50; PhCHCHþ3 Þ.
(CH(CH3)2), 22.33 (3 C, CH(CH3)2 and OCHCH3) and
18.2 (ArCHCH3) (Found MNHþ4 , 328.2273; C21H30N1O2
requires 328.2271); m/z 310 (5%, M+), 161
ð100; ArCHCHþ3 Þ and 105 ð80; PhCHCHþ3 Þ.
4.10.2. 1-Phenylethyl-2-(4-isopropylphenyl)propionate (S,R)-
anti-23. Oil; RF [light petroleum (bp 40–60 ꢁC)–diethyl
20
ether (1:1)] 0.84; ½aꢂD ¼ þ29:4 (c 0.65, CHCl3); mmax
(CHCl3)/cmꢁ1 1723 (C@O); dH (400 MHz; CDCl3) 7.27–
7.19 (5H, m, 5 · CH; Ph), 7.14 (2H, dt, J 8.1 and 1.8,
2 · CH; Ar), 7.02 (2H, dt, J 8.1 and 1.8, 2 · CH; Ar),
5.78 (1H, q, J 6.6, PhCHCH3O), 3.64 (1H, q, J 7.2,
ArCHCH3), 2.38 (2H, d, J 7.1, CH2Ar), 1.78 [1H, triple
septet, J 7.1 and 6.6, CH(CH3)2], 1.40 (3H, d, J 7.2,
ArCHCH3), 1.34 (3H, d, J 6.6, ArCHCH3O) and 0.83
(6H, d, J 6.6, CH(CH3)2); dC (100 MHz; CDCl3) 174.0
(C@O), 141.7 (i-C; PhCHCH3O), 140.4 (i-C; ArCHCH3),
137.6 (i-CCH2; Ar), 129.2,2 and 125.92 (4 · CH; Ar),
128.4,2 127.7,1 and 127.22 (5 · CH; Ph), 72.4
(PhCHCH3O), 45.2 (ArCHCH3), 45.0 (CH2Ar) 30.2
[CH(CH3)2], 22.32 (CH(CH3)2), 22.0 (PhCHCH3O) and
18.3 (ArCHCH3) (Found MNHþ4 , 328.2271; C21H30N1O2
requires 328.2271); m/z 310 (5%, M+), 161
ð80; ArCHCHþ3 Þ and 105 ð100; PhCHCHþ3 Þ.
4.9.5.
Di-(1-phenylethyl)-carbonate
(R,R)-18. White
needle-like crystals; mp 48–50 ꢁC; RF [light petroleum (bp
20
40–60 ꢁC)–diethyl ether (1:1)] 0.75; ½aꢂD ¼ þ116:6 (c
0.8, CHCl3); mmax (CHCl3); cmꢁ1 1742.5 (C@O); dH
(400 MHz; CDCl3) 7.38–7.26 (10H, m, 10 · CH; PhA and
PhB), 5.66 (2H, q, J 6.8, 2 · PhCHCH3) and 1.53 (6H, d,
J 6.8, 2 PhCHCH3); dC (100 MHz; CDCl3) 153.8 (C@O),
141.1 (2 · i-C; Ph), 128.54, 128.02, 126.04 (10 · CH;
2 · Ph), 76.3 (2 · PhCHCH3) and 22.2 (2 · PhCHCH3)
(Found
MNHþ4 ,
288.1596;
C17H22NO4
requires
288.1594); m/z 269 (1%, M+ꢁH), 165 (10,
M+ꢁPhCHCH3), 121 (25, PhCH3C@OH+), 105
½100; PhCHCHþ3 Þ and 77 (75, Ph+).
4.11. Parallel kinetic resolution of rac-1-phenylethanol 12
using 3-(2-phenylbutyryl)-4-phenyl-oxazolidin-2-one (R,S)-
syn-21 and 3-[2-(6-methoxy-naphthalen-2-yl)-propionyl]-4-
phenyl-oxazolidin-2-one (S,R)-syn-10
4.10. Parallel kinetic resolution of 1-phenylethanol rac-12
using 3-[2-(4-isopropylphenyl)propionyl]-4-phenyl-oxazol-
idin-2-one (R,S)-syn-20 and 3-[2-(6-methoxy-naphthalen-
2-yl)-propionyl]-4-phenyl-oxazolidin-2-one (S,R)-syn-10
In the same way as above, methyl magnesium bromide
(0.23 ml, 3 M in diethyl ether, 0.69 mmol), 1-phenylethanol
rac-12 (0.75 g, 6.14 mmol), 3-(2-phenylbutyryl)-4-phenyl-
oxazolidin-2-one (R,S)-syn-21 (0.11 g, 0.35 mmol) and
3-[2-(6-methoxy-naphthalen-2-yl)-propionyl]-4-phenyl-oxaz-
olidin-2-one (S,R)-syn-10 (0.13 g, 0.35 mmol) in THF
(10 ml), gave after purification by flash column chromato-
graphy on silica gel eluting with light petroleum
ether–diethyl ether (9:1!0:1), two pairs of inseparable dia-
stereoisomers25 (R,R)-anti- and (S,S)-syn-24 (44 mg, 47%)
(ratio: anti-:syn- 89:11) and meso- and rac-18 (36 mg,
20%) (ratio: syn-:anti- 61:39), and (S,S)-anti- and (R,R)-
syn-25 (60 mg, 52%) (ratio: anti-:syn- 81:19).
In the same way as above, methyl magnesium bromide
(0.59 ml, 3 M in diethyl ether, 1.76 mmol), 1-phenylethanol
rac-12 (2.15 g, 17.59 mmol), 3-[2-(4-isopropylphenyl)propi-
onyl]-4-phenyl-oxazolidin-2-one
0.88 mmol) and 3-[2-(6-methoxy-naphthalen-2-yl)-propion-
yl]-4-phenyl-oxazolidin-2-one (S,R)-syn-10 (0.331 g,
(R,S)-syn-20
(0.309,
0.88 mmol) in THF (10 ml), gave after purification by flash
column chromatography on silica gel eluting with light
petroleum ether–diethyl ether (9:1!7:3) two pairs of insep-
arable diastereoisomers25 (R,R)-anti- and (R,S)-syn-23
(154 mg, 56%) (ratio: anti-:syn- 88:12) and meso- and rac-
18 (60 mg, 13%) (ratio: anti-:syn- 60:40), and (S,S)-anti
and (S,R)-syn-25 (137 mg, 49%) (ratio; anti-:syn- 81:19).
Characterisation data for:29
Characterisation data for:29
4.10.1. 1-Phenylethyl-2-(4-isopropylphenyl)propionate (R,R)-
anti-23. Oil RF [light petroleum (bp 40–60 ꢁC)–diethyl
4.11.1. 1-Phenylethyl-2-phenylbutyrate30–32 (S,S)-anti-
24. Oil; RF [light petroleum (bp 40–60 ꢁC)–diethyl ether
20
20
ether (1:1)] 0.85; ½aꢂD ¼ ꢁ14:2 (c 11.4, CHCl3); mmax
(1:1)] 0.79; ½aꢂD ¼ ꢁ12:9 (c 6.2, CHCl3); mmax
(CHCl3)/cmꢁ1 1723 (C@O); dH (400 MHz; CDCl3) 7.21–
7.17 (3H, m, 3 · CH; Ph), 7.11 (2H, br d, J 8.1, 2 · CH;
Ar), 7.08–7.05 (2H, m, 2 · CH; Ph), 7.05 (2H, br d, J 8.1,
2 · CH; Ar), 5.78 (1H, q, J 6.6, PhCHO), 3.65 (1H, q, J
7.2, ArCH), 2.37 (2H, d, J 7.1, CH2Ar), 1.77 (1H, triple
septet, J 7.1 and 6.6, CH(CH3)2), 1.42 (3H, d, J 6.6,
PhCHCH3O), 1.41 (3H, d, J 7.1, ArCH3CH) and 0.82
(6H, d, J 6.6, CH(CH3)2); dC (100 MHz; CDCl3) 173.7
(C@O), 141.7 (i-C; PhCHCH3O), 140.4 (i-C; ArCHCH3),
137.6 (i-CCH2; Ar), 129.2,2 and 125.62 (4 · CH; Ar),
128.2,2 127.5,1 and 127.32 (5 · CH; Ph), 72.3
(PhCH3CHO), 45.3 (ArCHCH3), 45.0 (CH2Ar), 30.2
(CHCl3)/cmꢁ1 1723 (C@O); dH (400 MHz; CDCl3) 7.30–
7.14 (8H, m, 8 · CH; 2 · Ph), 7.05–7.00 (2H, m, 2 · CH;
2 · Ph), 5.88 (1H, q, J 6.6, PhCHCH3O), 3.51 (1H, t, J
7.6, PhCHCH3), 2.13 (1H, ddq, J 13.7, 7.6 and 7.5,
CHAHBCH3), 1.82 (1H, ddq, J 13.7, 7.6 and 7.5,
CHAHBCH3), 1.51 (3H, d, J 6.6, PhCHCH3O) and 0.90
(3H, t, J 7.5, CH3CH2); dC (100 MHz; CDCl3) 172.8
(C@O), 141.5 (i-C; PhA), 138.8 (i-C; PhB), 128.3,2 128.1,2
127.9,2 127.4,1 126.91 and 125.92 (10 · CH; PhA and
PhB), 72.2 (PhCHCH3O), 53.5 (PhCHCH3), 26.4
(CH3CH2), 22.2 (PhCHCH3O) and 12.0 (CH3CH2) (Found
MNHþ4 , 286.1805; C18H24NO2 requires 286.1802); m/z 268

E. Coulbeck, J. Eames / Tetrahedron: Asymmetry 18 (2007) 2313–2325
2323
(5%,
M+),
119
ð30; PhCHCH2CHþÞ
and
105
under reduced pressure. The residue was purified by col-
umn chromatography eluting with light petroleum ether
(bp 40–60 ꢁC)–diethyl ether (7:3!1:1) to give an insepara-
ble mixture (ꢀ0.169 g) of 1-phenylethanol (R)-12 (63 mg,
3
ð100; PhCHCHþ3 Þ.
4.11.2. 1-Phenylethyl-2-phenylbutyrate31 (R,S)-syn-24.
Oil; RF [light petroleum (bp 40–60 ꢁC)–diethyl ether
64%)
and
2-(4-isopropylphenyl)propanol
(R)-27
20
(1:1)] 0.75; ½aꢂD ¼ þ56:4 (c 1.95, CHCl3); mmax (CHCl3)/
(0.106 mg, 69%). The relative amount of (R)-12 and (R)-
cmꢁ1 1723 (C@O); dH (400 MHz; CDCl3) 7.38–7.23
(10H, m, 10 · CH; PhA and PhB), 5.88 (1H, q, J 6.6,
PhCHCH3O), 3.51 (1H, t, J 7.5, PhCHCH3), 2.11 (1H,
ddq, J 13.5, 7.5 and 7.5, CHAHBCH3), 1.80 (1H, ddq, J
13.5, 7.5 and 7.5, CHAHBCH3), 1.44 (3H, d, J 6.6,
PhCHCH3O) and 0.87 (3H, t, J 7.5, CH3CH2); dC
(100 MHz; CDCl3) 173.3 (C@O), 141.7 (i-C; PhA), 139.1
(i-C; PhB), 128.5,2 128.4,2 127.9,2 127.7,1 127.11 and
126.02 (10 · CH; PhA and PhB), 72.5 (PhCHCH3O), 53.6
(PhCHCH3), 26.6 (CH3CH2), 21.9 (PhCHCH3O) and
12.1 (CH3CH2) (Found MNHþ4 , 286.1805; C18H24NO2
requires 286.1802); m/z 268 (5%, M+), 119
ð50; PhCHCH2CHþÞ and 105 ð100; PhCHCHþÞ.
27 was determined by H NMR spectroscopy.
1
Characterisation data for 2-(4-isopropylphenyl)propanol
(R)-27 [derived from NaBH4 reduction of (4R,2R)-4-
isopropyl-3-[2-(4-isopropylphenyl)propionyl]-oxazolidin-2-
one35]; colourless oil; RF [light petroleum (bp 40–60 ꢁC)–
20
diethyl ether (1:1)] 0.44; ½aꢂD ¼ þ18:5 (c 1.6, CHCl3);
20
{lit.36 (S)-27; 89% ee; ½aꢂD ¼ ꢁ13:0 (c 1.0, CHCl3)}; mmax
(CHCl3)/cmꢁ1 3019 (OH); dH (400 MHz; CDCl3) 7.16
(2H, dd, J 8.3 and 2.0, 2 · CH; Ar), 7.12 (2H, dd, J 8.3
and 2.0, 2 · CH; Ar), 3.71 (1H, dd, J 6.9 and 1.0, CHAHB-
OH), 3.69 (1H, br d, J 6.9, CHAHBOH), 2.94 (1H, ddq
(appears as a sextet, J 6.9), ArCHCH3), 2.46 (2H, d, J
7.2, CH2Ar), 1.86 (1H, m, (appears as a nonet, J 6.6),
(CH3)2CH), 1.57 (1H, s, OH), 1.28 (3H, d, J 6.9,
ArCHCH3) and 0.91 (2 · 3 H, d, J 6.6, (CH3)2CH); dC
(100 MHz; CDCl3) 140.7 (i-C; Ar), 140.1 (i-C; Ar), 129.42
and 127.22 (4 · CH; Ar), 68.8 (CH2OH), 45.0 (ArCHCH3),
42.0 (CH2Ar), 30.2 (CH3CHCH3), 22.42 (CH3CHCH3) and
17.6 (ArCHCH3).
3
3
4.12. LiAlH4 reduction of ester (S,S)-anti-25
LiAlH4 (52 mg, 1.37 mmol) was added to a stirred solution
of ester (S,S)-anti-25 (0.229 g, 0.69 mmol) in THF (5 ml) at
0 ꢁC. The resulting solution was stirred for 4 h. Water
(25 ml) was added, and the resulting solution extracted
with dichloromethane (3 · 25 ml). The combined organic
layers were dried over MgSO4, filtered, and evaporated un-
der reduced pressure. The residue was purified by column
chromatography eluting with light petroleum ether (bp
40–60 ꢁC)–diethyl ether (7:3!1:1) to give 1-phenylethanol
Acknowledgements
We are grateful to the EPSRC for a studentship (to E.C.)
and the EPSRC National Mass Spectrometry Service
(Swansea) for accurate mass determinations.
(S)-12 (60 mg, 72%) as an oil; RF [light petroleum ether
20
(bp 40–60 ꢁC)–diethyl ether (1:1)] 0.33; ½aꢂD ¼ ꢁ43:0 (c
20
11.4, CHCl3) {lit.33 ½aꢂD ¼ ꢁ45:5 (c 5.0, methanol); mmax
(CHCl3)/cmꢁ1 3019 (OH); dH (400 MHz; CDCl3) 7.38–
7.24 (5H, m, 5 · CH; Ph), 4.88 (1H, qd, J 6.4 and 1.9,
CH3CH), 2.04 (1H, d, J 1.9, OH) and 1.49 (3H, d, J 6.4,
CH3CH); dC (100 MHz; CDCl3) 145.8 (i-C; Ph), 128.52,
127.41 and 125.32 (5 · CH; Ph), 70.3 (CH3CH) and 25.1
(CH3CH); and 2-(6-methoxy-2-naphthyl)propanol (S)-26
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CHCl3); lit.34 ½aꢂD ¼ ꢁ17:5 (c 1.0, CHCl3); mmax (CHCl3)/
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8.4, CH; Ar), 7.62 (1H, d, J 8.4, CH; Ar), 7.53 (1H, br s,
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133.5 and 129.0 (3 · i-C; Ar), 129.1, 127.2, 126.2, 125.9,
118.9 and 105.6 (6 · CH; Ar), 68.6 (CH3O), 55.3 (CH2OH),
42.3 (CH3CH) and 17.6 (CH3CH).
4.13. LiAlH4 reduction of ester (R,R)-anti-23
LiAlH4 (61 mg, 1.61 mmol) was added to a stirred solution
of ester (R,R)-anti-23 (0.25 g, 0.81 mmol) in THF (5 ml) at
0 ꢁC. The resulting solution was stirred for 4 h. Water
(25 ml) was added, and the resulting solution was extracted
with dichloromethane (3 · 25 ml). The combined organic
layers were dried over MgSO4, filtered, and evaporated
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A. C.; Long, M. J.; Morrison, R. M.; Roberts, P. M.; Savory,
E. D.; Smith, A. D.; Sweet, M. J.; Withey, J. M. Org. Biomol.
Chem. 2005, 3, 2762–2775.
19. For a representative account of carbonate formation by endo-
cleavage, see: Kanomata, N.; Maruyama, S.; Tomono, K.;
Anada, S. Tetrahedron Lett. 2003, 44, 3599–3603.
20. Increasing the sterically demanding nature of the oxazol-
idinone ring at the C(4)-position has been shown to increase
the relative rate of benzoyl transfer; for additional informa-
tion, see Ref. 15. From our study, increasing the sterically
demanding nature of the oxazolidinone [at C(4) position] and
the phenylacetyl transfer group [at the C(2) position] appears
to disfavour exo-cleavage (and promote competitive endo-
cleavage).
21. For additional studies, see: (a) Davies, S. G.; Sanganee, H. J.
Tetrahedron: Asymmetry 1995, 6, 671–674; (b) Bull, S. D.;
Davies, S. G.; Jones, S.; Polywka, M. E. C.; Prasad, R. S.;
Sanganee, H. J. Synlett 1998, 519–521; (c) Bull, S. D.; Davies,
S. G.; Key, M.-S.; Nicholson, R. L.; Savory, E. D. Chem.
Commun. 2000, 1721–1722.
22. For active esters; RF (light petroleum ether (40–60 ꢁC)–
diethyl ether 9:1) = 0.69 [for (R)-6] and 0.50 [for (S)-7]. For
oxazolidinone adducts; RF (light petroleum ether (40–60 ꢁC)–
diethyl ether 7:3) = 0.36 [for (R,S)-20], 0.33 [for (R,S)-9] and
0.24 [for (S,R)-10].
23. For a perfect PKR, the enantiomeric excesses of the
chiral carbonates were assumed to be zero due to equal
and opposite complementary reactions occurring with two
quasi-enantiomeric oxazolidinone adducts; this is also the
case for an MKR. However, a kinetic resolution between
oxazolidinone (S,R)-10 and 1-phenylethanol rac-12 gave
the corresponding diastereoisomeric esters (S,S)-anti-
and (S,R)-syn-25 in 38% yield (ratio anti-:syn- 90:10) with
80% de and the carbonates meso- and (R,R)-18 in 26%
yield (ratio meso-:(R,R)- 65:35) with 30% de and ꢀ6% ee
(for (R,R)-18). The specific rotation for this stereo-
20
isomeric mixture [meso-:(R,R)- 65:35] was ½aꢂD ¼ þ2:4.
20
The specific rotation of (R,R)-18); ½aꢂD ¼ þ116:6 (c 0.8,
CHCl3).
24. The oxazolidinone rac-8 can be recycled through a PKR
using the active esters (R)-6 and (S)-7 (see Scheme 2). For
additional information, see Refs. 14,35.
25. The relative proportions of the products were determined by
1H NMR spectroscopy (400 MHz). The yields were based on
the (relative) amount isolated.
26. Pozo, M.; Gotor, V. Tetrahedron: Asymmetry 1995, 11, 2797–
2802.
27. Mucciante, V.; Rossi, L.; Feroci, M.; Sotgiu, G. Synth.
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14. Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.;
Motevalli, M.; Northen, J.; Yohannes, Y. Synlett 2006, 101–
105.
29. Synthesised by addition of enantiomerically pure 1-pheny-
ethanol 12 to the corresponding enantiomerically penta-
fluorophenyl active ester [e.g., (S)-7] (derived from the
corresponding carboxylic acid).
30. Yang, H.; Henke, E.; Bornscheuer, U. T. Tetrahedron:
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