Resolution of pentafluorophenyl 2-phenylpropanoate using combinations of quasi-enantiomeric oxazolidin-2-ones

Article abstract of DOI:10.1016/j.tetasy.2011.02.022

The kinetic, mutual and parallel resolution of a series of structurally related active esters derived from 2-phenylpropanoic acid using a combination of quasi-enantiomeric oxazolidin-2-ones is discussed.

Full text of DOI:10.1016/j.tetasy.2011.02.022

Tetrahedron: Asymmetry 22 (2011) 413–438
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Resolution of pentafluorophenyl 2-phenylpropanoate using combinations
of quasi-enantiomeric oxazolidin-2-ones
Najla Al Shaye a, David M. Benoit b, Sameer Chavda a,c, Elliot Coulbeck a, Marco Dingjan a,c
,
c
Jason Eames a, , Yonas Yohannes
⇑
a Department of Chemistry, University of Hull, Cottingham Road, Kingston upon Hull, HU6 7RX, UK
b Nachwuchsgruppe Theorie im SFB 569, Albert-Einstein-Allee 11, University of Ulm, D-89081 Ulm, Germany
c Department of Chemistry, Queen Mary University of London, Mile End Road, London E1 4NS, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The kinetic, mutual and parallel resolution of a series of structurally related active esters derived from 2-
phenylpropanoic acid using a combination of quasi-enantiomeric oxazolidin-2-ones is discussed.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 11 November 2010
Revised 17 February 2011
Accepted 24 February 2011
Available online 30 March 2011
1. Introduction
and the enantiomers of 2-phenylpropanoyl chloride (RS)-3
(Scheme 1). In an attempt to improve the levels of this molecular
The continuing development of novel synthetic methodologies
for the efficient separation of enantiomers is important.1 A strategy
that has attracted considerable interest over the last decade has
been the parallel separation of enantiomers using two complemen-
tary chiral auxiliaries.2 The synthetic outcomes of this resolution
strategy have been well documented by Davies3 and Vedejs.4 Since
2005, we have been interested in the applicability of this strategy
for the parallel resolution of profens,5 such as 2-phenylpropanoic
acid, using an equimolar combination of quasi-enantiomeric6
Evans oxazolidin-2-ones (Scheme 1).
recognition between the oxazolidin-2-ones (R)-1/(S)-2 and the 2-
phenylpropanoyl chloride (R/S)-3 [=(rac)-3], we chose to investi-
gate the use of active esters8 as surrogate acid chlorides, which
were known to be less electrophilic and more sterically demanding
than 2-phenylpropanoyl chloride (rac)-3. Herein we report our
study into the use of racemic active esters, derived from 2-phenyl-
propanoic acid, as electrophilic acyl equivalents for the parallel ki-
netic resolution of 2-phenylpropanoic acid 6 using an equimolar
combination of quasi-enantiomeric oxazolidin-2-ones, such as
(R)-1 and (S)-2.
We have shown7 that deprotonation of an equimolar mixture of
oxazolidin-2-ones (R)-1 and (S)-2 with n-BuLi in THF at ꢀ78 °C, fol-
lowed by the addition of 2-phenylpropanoyl chloride (rac)-3, gave
after 2 h at ꢀ78 °C, a separable diastereoisomeric mixture of oxaz-
olidin-2-ones syn- and anti-4 (ratio 44:56) and anti- and syn-5
(ratio 50:50) in a combined 48% and 54% yields, respectively
(Scheme 1). From this study,7 it was evident that there was little
molecular recognition between the oxazolidin-2-ones (R)-1/(S)-2
2. Results and discussion
For this study, we were required to synthesise a series of active
esters (rac)-14–18 and anhydrides (rac)-19–21 which contained a
wide variety of traditional pro-leaving groups (Scheme 2). These
active esters, (rac)-14–18, and anhydride (rac)-19 were synthes-
ised in moderate to high yield through DCC coupling of
O
O
O
O
O
1. n-BuLi
O
THF, -78 oC
Ph
Ph
N
O
HN
O
HN
O
N
O
Ph
COCl
CH3
(rac)-3
2.
Me
Me
Ph
Ph
H
(R)-1
(S)-2
syn-:anti-4
44:56; 48%
syn-:anti-5
50:50; 54%
Scheme 1. Parallel resolution of 2-phenylpropanoyl chloride (rac)-3 using a quasi-enantiomeric combination of oxazolidin-2-ones (R)-1 and (S)-2.
⇑
Corresponding author.
E-mail address: j.eames@hull.ac.uk (J. Eames).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.02.022

414
N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
O
O
O
O
O
1. n-BuLi
THF, -78 oC
Y
HO
Y
Ph
Ph
Ph
OH
O
HN
O
N
O
2.
DCC, CH2Cl2
Me
Me
(rac)-6
Me
(rac)-14-18
Me
X
Ph
Ph
(rac)-1
Ph
(rac)-syn-4:anti-4
(rac)-
O
2 h
Pro-leaving
group
Yield
87%
Entry
Active ester
Active ester
syn-4:anti-4
X =
Yield
58%6
Entry
1
OH
(rac)-14
1
2
7
8
(rac)-3
Cl
44:56
O2N
O
F
F
(rac)-14
(rac)-15
2
3
87:13
97:3
68%
70%
F
F
OH
F
(rac)-15
O2N
92%
F
F
F
F
O
OH
N
F
O
(rac)-16
(rac)-17
(rac)-18
3
4
5
9
34%
49%
57%
O
N
OH
O
(rac)-16
(rac)-17
4
5
90:10
76:24
35%
42%
N
10
N
N
O
N
O
N
N
11
N
OH
OH
O
O
(rac)-18
6
84:16
40%
N
O
Ph
(rac)-6
(rac)-19
64%
6
O
O
(rac)- and
(meso)-19
(1:1)
Ph
7
8
43:57
54:46
60%
63%
O
O
O
O
O
O
R
OH
Ph
Ph
OH
R
O
Et3N, CH2Cl2
(rac)-20
(rac)-21
Me
Me
O
(rac)-19-21
(rac)-6
O
(rac)-20a
7
12
9
65:35
40%
Cl
O
O
O
Scheme 3. Mutual kinetic resolution of active esters (rac)-14–21 using oxazolidin-
2-one (rac)-1.
(rac)-21a
13
8
Cl
O
active esters (rac)-14–18 and anhydrides (rac)-19–21 in hand, we
next investigated their mutual kinetic resolution using 4-phenyl-
oxazolidin-2-one (rac)-1 (Scheme 3). The treatment of 4-phenylox-
azolidin-2-one (rac)-1 with n-BuLi in THF at ꢀ78 °C, followed by
the addition of active esters (rac)-14–18 and anhydrides (rac)-
19–21 gave, after 2 h at ꢀ78 °C, a separable diastereoisomeric mix-
ture of oxazolidin-2-ones syn- and anti-4 in moderate yield with
poor to excellent levels of diastereocontrol (as determined by
400 MHz 1H NMR spectroscopy)10 (Scheme 3). In virtually all of
the cases studied, the syn-oxazolidin-2-one 4 was the major diaste-
reoisomer. Higher levels of diastereocontrol were obtained using
active esters (rac)-14–16 that contained a substituted phenol
as the pro-leaving group [e.g., (rac)-15 (94% de) > (rac)-16
aSynthesised and used in situ
Scheme 2. Synthesis of active esters (rac)-14–21.
corresponding phenols 7–9, 1-hydroxybenzotriazole 10, N-hydroxy
succinimide 11 and 2-phenylpropanoic acid (rac)-6, with 2-phe-
nylpropanoic acid (rac)-6 as shown in Scheme 2. The remaining
mixed anhydrides (rac)-20 and (rac)-21 were formed in situ by
the addition of 2-phenylpropanoic acid (rac)-6 to a solution of
pivaloyl chloride and adamantyl carbonyl chloride, respectively,
with triethylamine in dichloromethane (Scheme 2).9 With these

N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
415
(80% de) > 14 (74% de)] (Scheme 3: entries 2–4). In comparison, ac-
tive esters, (rac)-17 and (rac)-18, which contained 1-hydroxyben-
zotriazole (BtOH) 10 and N-hydroxy succinimide 11 as their pro-
leaving group gave moderate to good levels of diastereoselectivity
(Scheme 2: entries 3-5, and Scheme 3: entries 4–6). For the
remaining the mixed anhydrides (rac)-19–21, these gave consider-
ably lower levels of mutual recognition and diastereoselection
than the phenol-derived active esters (rac)-14–16 even though
they had similar pro-leaving ability (Scheme 3: entries 7–9 vs
entries 2–4).
With this information in hand, we next synthesised a wide
range of structurally related active esters, (rac)-53–83, which
contained a variety of mono-, di- and tri-substituted phenols 22–
52 as pro-leaving groups in an attempt to study and improve the
overall level of diastereoselectivity (Scheme 4).11 The required
active esters (rac)-52–83 were synthesised in good yield by the
addition of the corresponding phenol, 22–52, to a solution of DCC
and 2-phenylpropanoic acid (rac)-6 in dichloromethane (Scheme 4).
We next chose to screen these active esters, (rac)-53–83, using
our benchmark lithitated oxazolidin-2-one (rac)-1-Li. The treat-
ment of the oxazolidin-2-one (rac)-1 with n-BuLi at ꢀ78 °C, fol-
lowed by the addition of active esters (rac)-53–83 in THF gave,
after 2 h the corresponding oxazolidin-2-one syn- and anti-4 with
poor to excellent levels of diastereoselectivity (10% de?96% de)
(Scheme 5). Under these reaction conditions, the more electro-
philic active esters (rac)-53–63, 65–68, 70–72, (rac)-74 and
(rac)-81, that contained electron-withdrawing phenolic groups,
gave the oxazolidin-2-one syn-4 in moderate to high yield and with
excellent levels of diastereoselectivity (66% de?96% de) (Scheme 5:
entries 1–11, 13–16, 18–21, 23 and 30), whereas, the less electro-
philic active esters, (rac)-64, (rac)-75 and (rac)-79, which contained
either a sterically demanding phenolic group or an electron-
donating group gave the corresponding oxazolidin-2-one syn-4 in
20% yield (with 38% de), in 8% yield (with 22% de) and 17% yield
(with 26% de), respectively (Scheme 5: entries 12, 24 and 28).
For the remaining active esters, (rac)-69, (rac)-73, (rac)-76–78,
(rac)-80 and (rac)-82–83, that contained electron-donating pheno-
lic pro-leaving groups only gave the recovered starting materials as
they were not electrophilic enough to allow nucleophilic addition
of the lithiated oxazolidin-2-one (rac)-1-Li under these reaction
conditions (Scheme 5: entries 17, 22, 25–27, 29 and 31–32).
However, these addition reactions were found to proceed by
allowing the reaction mixture to warm up from ꢀ78 °C to room
temperature, and stirring the resulting solution for 12 h. These
reactions gave the required oxazolidin-2-one 4 in moderate yield
(25%?34%) but with a reversal of diastereoselection; the anti-dia-
stereoisomeric adduct 4 was preferentially formed in moderate to
good levels of diastereoselectivity (20% de?66% de). For the active
ester (rac)-75, the formation of the syn-diastereoisomer 4 was pre-
ferred at low temperature (22% de; 8%), whereas, the anti-diaste-
reoisomer was preferred at high temperature and longer reaction
times (38% de; 21%) (Scheme 6: entry 4 vs Scheme 5: entry 24).
X
X
O
O
HO
DCC, CH2Cl2
Ph
Ph
OH
O
Me
(rac)-6
Me
12 h
(rac)-15 and 53-83
Yield
Yield
Phenol
Active ester
Entry
Entry
Phenol
Active ester
1
2
2-FC6H4OH 22
(rac)-53
(rac)-54
83%
87%
C6H5OH
C6F5OH
38
8
(rac)-69
(rac)-15
76%
17
18
2-ClC6H4OH
2-BrC6H4OH
3-FC6H4OH
92%
30%
92%
23
24
25
26
(rac)-55
(rac)-56
80%
72%
C6Cl5OH
C6H5SH
(rac)-70
(rac)-71
3
4
5
39
40
19
20
3-ClC6H4OH
(rac)-57
(rac)-58
(rac)-59
C6F5SH
61%
84%
91%
41
42
43
(rac)-72
(rac)-73
(rac)-74
84%
80%
69%
21
22
23
4-MeC6H4OH
6
7
4-FC6H4OH 27
4-ClC6H4OH 28
4-BrC6H4OH 29
4-MeC6H4SH
2-EtC6H4OH
3-EtC6H4OH
44
45
(rac)-75
(rac)-76
8
9
(rac)-60
(rac)-61
87%
65%
53%
65%
24
25
2,3-Cl2C6H3OH
2,4-Cl2C6H3OH 31
2,5-Cl2C6H3OH
2,6-Cl2C6H3OH 33
30
10
11
(rac)-62
(rac)-63
92%
87%
4-EtC6H4OH
46
47
(rac)-77
(rac)-78
57%
56%
26
27
4-i-PrC6H4OH
32
12
13
14
(rac)-64
(rac)-65
(rac)-66
84%
67%
52%
2-MeOC6H4OH
4-MeOC6H4OH
4-PhC6H4OH
(rac)-79
(rac)-80
(rac)-81
48
49
50
70%
62%
64%
28
29
30
3,4-Cl2C6H3OH
3,5-Cl2C6H3OH
34
35
2,4,5-Cl3C6H3OH
(rac)-67
(rac)-68
2,6-Me2C6H3OH
15
16
36
86%
64%
31
32
51
52
(rac)-82
(rac)-83
43%
49%
2,4,6-Cl3C6H3OH 37
2,6-Me2(4-NO2)C6H2OH
Scheme 4. Synthesis of active esters (rac)-15 and (rac)-53–83.

416
N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
O
1. n-BuLi
THF, -78 o
O
O
C
Ph
HN
O
N
O
2.
Me
Me
2 h
X
(rac)-
Ph
Ph
(rac)-1
Ph
syn-4:anti-4
O
Active ester
X =
Active ester
X =
syn-4:anti-4
syn-4:anti-4
Yield
Entry
Entry
Yield
2-FC6H4O-
2-ClC6H4O-
C6H5O-
C6F5O-
(rac)-53
(rac)-69
(rac)-15
0%
95:5
98:2
1
2
39%
36%
17
18
(rac)-54
(rac)-55
(rac)-56
(rac)-57
(rac)-58
(rac)-59
97:3
83:17
95:5
95:5
70%
2-BrC6H4O-
3-FC6H4O-
3-ClC6H4O-
4-FC6H4O-
4-ClC6H4O-
C6Cl5O-
C6H5S-
(rac)-70
(rac)-71
(rac)-72
(rac)-73
(rac)-74
96:4
98:2
98:2
95:5
95:5
3
4
5
6
7
30%
56%
19
20
21
22
23
20%
21%
37%
0%
C6F5S-
67%
39%
39%
34%
4-MeC6H4O-
4-MeC6H4S-
95:5
29%
4-BrC6H4O-
2,3-Cl2C6H3O-
2,4-Cl2C6H3O-
(rac)-60
(rac)-61
(rac)-62
2-EtC6H4O-
3-EtC6H4O-
4-EtC6H4O-
(rac)-75
(rac)-76
(rac)-77
8
9
95:5
98:2
98:2
24
25
26
61:39
8%
0%
0%
45%
49%
10
2,5-Cl2C6H3O-
2,6-Cl2C6H3O-
3,4-Cl2C6H3O-
3,5-Cl2C6H3O-
2,4,5-Cl3C6H3O-
2,4,6-Cl3C6H3O-
(rac)-63
(rac)-64
4-i-PrC6H4O-
(rac)-78
0%
11
42%
27
93:7
2-MeOC6H4O-
4-MeOC6H4O-
4-PhC6H4O-
(rac)-79
(rac)-80
(rac)-81
63:37
90:10
17%
0%
12
13
14
69:31
98:2
20%
29%
32%
28
29
30
(rac)-65
(rac)-66
86:14
56%
2,6-Me2C6H3O-
(rac)-82
(rac)-83
(rac)-67
(rac)-68
41%
20%
31
32
15
16
87:13
55:45
0%
0%
2,6-Me2(4-NO2)C6H2OH
Scheme 5. Mutual kinetic resolution of active esters (rac)-15 and (rac)-53–83 using oxazolidin-2-one (rac)-1.
In comparison, using the more reactive pentafluorophenyl 2-
more noteworthy differences in pro-leaving ability was between
thiophenol (PhSH; pKa 6.50) and phenol (PhOH; pKa 9.95); the for-
mer leads to high levels of diastereoselection [giving (rac)-syn-4 in
21% yield with >90% de], whereas, the latter was shown to be unre-
active under these reaction conditions (Table 1: entry 3 vs entry 7,
and Scheme 5: entry 20 vs entry 17).13
phenylpropanoate (rac)-15, under these reaction conditions gave
similar levels of diastereoselectivity to that found at ꢀ78 °C (94%
de at ꢀ78 °C/2 h vs 92% de at room temperature/12 h), however,
the yield was lower (70% vs 62%). This is unsurprising as the addi-
tion process and formation of the oxazolidin-2-one 4 would have
been completed within the initial 2 h at ꢀ78 °C. However, this oxaz-
olidin-2-one product appears to be unstable under the reaction
conditions for the remaining 10 h.12 For the sterically demanding
active ester (rac)-82, the formation of the oxazolidin-2-one 4 does
not occur even under these prolonged reaction conditions (room
temperature, 12 h), presumably illustrating the electron-donating
nature of the 2,6-dimethylphenol pro-leaving group and additional
steric congestion at both its C(2)- and C(6)-positions. Even for the
more electronically activated 4-nitro-2,6-dimethylphenyl 2-pro-
panoate (rac)-83, oxazolidin-2-one formation still does not occur
as the methyl groups at both C(2)- and C(6)-positions of the phenol
ring appear to disfavour nucleophilic addition to its carbonyl (C@O)
group. Herein it appears there is an electronic and steric threshold
associated with the phenolic pro-leaving group for efficient oxazoli-
din-2-one formation and diastereoisomeric control. For electron-
donating phenols, such as phenol, with a pKa >9.5, the formation
of oxazolidin-2-one 4 appears to be slow at ꢀ78 °C, whereas, for
electron-withdrawing phenols, such as pentafluorophenol, with a
pKa <9.5 this addition process is efficient, leading to the oxazoli-
din-2-one syn-4 in 70% yield with a 94% de (Table 1). One of the
In an attempt to gain a better understanding of this mutual ki-
netic resolution, we next investigated the coupling of the enantio-
merically pure oxazolidin-2-one (R)-1 with both enantiomerically
pure active esters (S)- and (R)-15 (Scheme 7). Treatment of oxazoli-
din-2-one (R)-1 with n-BuLi in THF at ꢀ78 °C, followed by the addi-
tion of the active ester (S)- and (R)-15, gave after 2 h, the
corresponding enantiomerically pure oxazolidin-2-ones (S,R)-syn-
and (R,R)-anti-4 in 60% and 58% yields with >96% de, respectively.
Under these conditions, the major diastereoisomer (S,R)-syn-4 was
found to be stable and was not epimerised in the presence of an
additional equivalent of lithiated oxazolidin-2-one (S)-1; the origi-
nal oxazolidin-2-one (S,R)-syn-4 was re-isolated from the reaction
mixture in 96% yield with 96% de (Scheme 7). However, a small
amount of the enantiomerically enriched 2-phenylpropanoic acid
(S)-6 in 6% yield with 88% ee was also isolated14 which was pre-
sumably formed by simple cleavage from the parent oxazolidin-
2-one (S,R)-syn-4 with trace amounts of lithium hydroxide
(Scheme 7).
We next investigated the nature of the metal counter-ion on the
levels of mutual recognition between the oxazolidin-2-one (rac)-1

N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
417
1. n-BuLi
THF, -78 oC
O
O
O
O
O
O
Ph
Me
Ph
1. n-BuLi, THF, -78 o
2.
C
N
O
HN
O
HN
O
N
O
2.
Me
O
H
Me
X
Ph
Ph
Ph
(rac)-1
Ph
(S,R)-syn-4
syn-:anti-4: >98:<2; 60%
Ph
syn-4:anti-4
Ph
(rac)-
OC6F5
(R)-1
O
Me
H
then RT, 12 h
(S)-15
syn-4:anti-4
Yield
62%
21%
48%
21%
43%
34%
27%
Entry
Active ester X =
C6F5O-
O
O
O
(rac)-15
(rac)-69
(rac)-73
(rac)-75
(rac)-76
(rac)-77
(rac)-78
1
2
3
4
5
6
7
8
96:4
Ph
1. n-BuLi, THF, -78 o
C
N
O
HN
O
C6H5O-
40:60
28:72
31:69
42:58
18:82
17:83
2.
O
H
Me
Ph
(R,R)-anti-4
4-MeC6H4O-
2-EtC6H4O-
3-EtC6H4O-
4-EtC6H4O-
4-i-PrC6H4O-
Ph
Ph
OC6F5
(R)-1
H
Me
(R)-15
syn-:anti-4: <2:>98; 58%
O
O
O
CO2H
Ph
Me
Ph
Me
1. n-BuLi, THF, -78 o
2.
C
N
O
HN
O
2-MeOC6H4O-
4-MeOC6H4O-
(rac)-79
(rac)-80
37:63
24:76
38%
52%
H
O
H
O
Ph
(S,R)-syn-4
Ph
9
Ph
Me
(S)-6
syn-:anti-4: >98:2; 94% 6%; 88% e.e.
(S)-1
N
O
10
2,6-Me2C6H3O-
(rac)-82
(rac)-83
H
Ph
(S,R)-syn-4
2,6-Me2(4-NO2)C6H2O-
11
Scheme 7. Stereospecific synthesis of oxazolidin-2-one adducts (S,R)-syn- and
(R,R)-anti-4.
Scheme 6. Mutual kinetic resolution of active esters (rac)-15, 69, 73, (rac)-75–80
and 82–83 using oxazolidin-2-one (rac)-1.
of a suitable crown ether, the levels of diastereocontrol remained
unchanged for lithium and sodium counter ions (Scheme 8: entries
4–9), with the exception of KHMDS, where the level of diastereose-
lectivity was reduced from 68% de to 52% de in the presence of
1 equiv of 18-crown-6 (Scheme 8: entries 10 and 11). Even in the
presence of HMPA, the diastereocontrol was only lowered from
94% de to 82% de using a lithium counter ion (Scheme 8: entry
3). The use of a magnesium counter ion gave the required oxazoli-
din-2-one syn-4 in low yield (<10%) with poor levels of diastereo-
control (60% de). Whether the reaction proceeds via a monomeric
species or aggregate, the diastereoselective outcome appears to
be the same. Some element of coordination is therefore important
for excellent levels of diastereocontrol.
and the active ester (rac)-15 (Scheme 8). We decided to deproto-
nate the parent oxazolidin-2-one (rac)-1 with either n-BuLi or a
variety of metal amides in the presence and absence of additives,
such as crown ethers and HMPA, to see the effect, if any, of aggre-
gration and/or co-ordination on the levels of diastereoselectivity.
The use of a lithium counter-ion gave similarly high levels of dia-
stereoselection (94% de) as
a sodium counter ion (92% de)
(Scheme 8: entries 6 and 8). The use of an organolithium or lith-
ium/sodium amide as a Brønsted base appeared to have little to
no effect on the stereochemical outcome of this reaction. In the
case of lithium/sodium amide, the conjugate base, the parent
amine, does not interfere with the stereochemical outcome of this
process. By comparison, the less coordinating potassium counter-
ion favoured formation of the syn-oxazolidin-2-one (rac)-syn-4,
but with lower levels of diastereocontrol; Li+ (94% de); Na+ (92%
de) and K+ (68% de) (Scheme 8: entries 6, 8 and 10). In the presence
We next changed the reaction temperature, from ꢀ78 °C to
+50 °C, to investigate the temperature dependence of this process.
Deprotonation of the oxazolidin-2-one (rac)-1 using n-BuLi in THF
at the required temperature (ꢀ78 °C, ꢀ50 °C; 0 °C; +25 °C and
Table 1
Diastereoselectivity versus pro-leaving group
O
1. n-BuLi
THF, -78 oC
O
O
Ph
HN
O
N
O
2.
Me
Me
2h
X
(rac)-
Ph
Ph
Ph
O
(rac)-1
(rac)-syn-:anti-4
Entry
Active ester X=
syn-:anti-4
de (%)
pKHA (H2O)
O
1
2
C6F5S–
C6F5O–
(rac)-72
(rac)-15
95:5
97:3
90
>94
est 2–3
5.50
3
4
5
6
7
8
9
C6H5S–
(rac)-71
(rac)-62
(rac)-58
(rac)-81
(rac)-69
(rac)-80
(rac)-73
95:5
98:2
95:5
90:10
—
90
>96
90
80
—
6.50
8.10
9.30
9.51
9.95
HN
O
2,4-Cl2C6H3O–
4-FC6H4O–
4-PhC6H4O–
C6H5O–
4-MeOC6H4O–
4-MeC6H4O–
Bn
pKA (H2O) = 12
—
—
—
—
10.20
10.26

418
N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
O
O
where the stereochemical outcome is lowered from 90% de to 60%
1. M-base, additive (3 equiv.)
THF, -78 oC
O
de. The formation and isolation of the oxazolidin-2-one adduct
(rac)-syn-4 appears to be more favoured for lower temperature
reactions; the yield was reduced from 70% to 45% when the
temperature was raised from ꢀ78 °C to +50 °C (Scheme 9). The dia-
stereoselectivity of this mutual kinetic resolution remained un-
changed even when this reaction time was lowered to 5 min; the
oxazolidin-2-one adduct syn-4 was formed in a reduced 38% yield
with 92% de (Scheme 9).
Ph
HN
O
N
O
2.
Me
Me
OC6F5
Ph
Ph
Ph
(rac)-15
O
(rac)-1
syn-4:anti-4
2 h
syn-4:anti-4
Yield
M-base
Entry
n-BuLi
1
2
97:3
97:3
70%
59%
We next probed the effect of temperature on the kinetic resolu-
tion of this active ester (rac)-15 using the enantiomerically pure
oxazolidin-2-one (S)-1 (Scheme 10). The treatment of oxazolidin-
2-one (S)-1 with n-BuLi in THF at ꢀ78 °C, followed by the addition
of 1 equiv of active ester (rac)-15 in THF, and quenching the reac-
tion after 5 min, 10 min, 20 min and 2 h gave, the oxazolidin-2-one
adduct (rac)-syn-4 in 30%?39% yield, with 94%?44% de. The levels
of diastereocontrol were found to be excellent (94% de) for short
reaction times (5 min). With increased reaction times, the levels
of diastereocontrol were reduced from 94% de to 44% de due to
the increased likelihood of the lithiated (S)-oxazolidin-2-one 1
adding to the less reactive enantiomer of (S)-15 to give the minor
diastereoisomeric oxazolidin-2-one (S,S)-anti-4. Using an excess of
this active ester (rac)-15 (2 equiv), this limited the formation of the
unwanted oxazolidin-2-one (S,S)-anti-4 by ensuring that the oxaz-
olidin-2-one (S)-1 had an additional equivalent of the more reac-
tive (R)-15 to form the preferred adduct (R,S)-syn-4 (Scheme 10).
The same diastereoisomeric outcome can also be obtained using
a shorter reaction time (5 min) even in the presence of a substoi-
chiometric amount of active ester (rac)-15 (0.25 equiv); the diaste-
reoselectivity remained constant (94% de) from 2 equiv? 0.25
equiv of active ester (rac)-15 (Scheme 10).
n-BuLi / 12-crown-4
n-BuLi / HMPA
3
4
91:9
97:3
65%
42%
LiN(i-Pr)2
LiN(i-Pr)2 / 12-crown-4
5
6
7
97:3
96:4
97:3
65%
56%
63%
LiHMDS
LiHMDS / 12-crown-4
8
9
NaHMDS
NaHMDS / 15-crown-5
KHMDS
96:4
97:3
57%
76%
10
11
84:16
76:24
44%
77%
KHMDS / 18-crown-6
MeMgBr
12
80:20
<10%
Scheme 8. Diastereoselectivity versus metal counter-ion.
In an attempt to probe the reaction rates, we next investigated a
double mutual kinetic resolution of oxazolidin-2-one (rac)-1 using
two racemic active esters (rac)-15 and (rac)-84 (Scheme 11).
Deprotonation of oxazolidin-2-one (rac)-1 with n-BuLi in THF at
ꢀ78 °C, followed by the addition of an equimolar amount of active
esters (rac)-15 and (rac)-84 gave, after 2 h at ꢀ78 °C, an insepara-
ble mixture of oxazolidin-2-ones (rac)-syn-4 and (rac)-syn-85 (ra-
tio 89:11) in 40% yield with a combined 94% de (Scheme 11). To
ensure this chemoselectivity was not dependent on the active
+50 °C), followed by the addition of the active ester (rac)-15 and
stirring the resulting solution at the same temperature for 2 h, gave
the oxazolidin-2-one (rac)-syn-4 in moderate to good yield
(Scheme 9). The levels of diastereoselectivity were excellent (90–
94% de) for the temperature range of ꢀ78 °C to +25 °C. However,
increasing the temperature to +50 °C, gave the oxazolidin-2-one
(rac)-syn-4 in a reduced 45% yield with 60% de. Interestingly, there
appears to be a temperature threshold between +25 °C and +50 °C
O
O
O
O
O
1. n-BuLi,
Ph
THF, - n o
C
Ph
Me
HN
O
N
O
N
O
2. (rac)-15, 2 h
H
Me
H
Ph
Ph
(rac)-anti-4
Ph
(rac)-syn-4
(rac)-1
syn-4:anti-4
96:4 (62 %)
0oC
95:5 (53 %)
+25oC
97:3 (70 %)
-78oC
96:4 (61 %)
-50oC
80:20 (45%)
+50oC
Temperature
O
O
O
O
O
1. n-BuLi,
Ph
H
THF, -78 oC
Ph
HN
O
N
O
N
O
2. (rac)-15, n h
Me
Me
H
Ph
Ph
(rac)-anti-4
Ph
(rac)-syn-4
(rac)-1
Time
5 min
2 h
syn-4:anti-4
96:4 (38 %)
37 %
97:3 (70 %)
12 %
recovered
(rac)-15
Scheme 9. Diastereoselectivity versus temperature and reaction time.

N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
419
O
O
O
O
O
1. n-BuLi,
Ph
Me
THF, - n o
C
Ph
HN
O
N
O
N
O
2. (rac)-15, n h
H
H
Me
Ph
(R,S)-syn-4
Ph
Ph
(S)-1
(S,S)-anti-4
syn-4:anti-4
86:14 (30 %)
20 min
72:28 (34 %)
2 h
97:3 (39 %)
5 min
93:7 (34 %)
10 min
Time
O
O
O
O
O
1. n-BuLi,
Ph
Me
THF, -78 oC
Ph
H
HN
O
N
O
N
O
2. (rac)-15
(n equiv.)
H
Me
Ph
Ph
(S,S)-anti-4
Ph
(R,S)-syn-4
(S)-1
syn-4:anti-4
97:3 (7 %)
0.5 equiv.
97:3 (3%)
97:3 (57 %)
97:3 (39 %)a
5 min
(rac)-15 n equiv.
2 equiv.
1 equiv.
0.25 equiv.
syn-4:anti-4
94:6 (61 %)
2 equiv.
72:28 (34 %)
1 equiv.
2 h
(rac)-15 n equiv.
aactive ester (S)-15 was isolated in 37 % yield with 44 % e.e.
Scheme 10. Kinetic resolution of active ester (rac)-15 using the oxazolidin-2-one (S)-1.
O
i-Bu
O
O
O
O
1. n-BuLi, THF, -78 oC
HN
Ph
O
Ph
Me
2.
N
O
N
O
O
H
Me
H
Ph
(rac)-1
OC6F5
Ph
Ph
Me
(rac)-syn-4
89:11
"syn-:anti-" = 97:3; 60%
(rac)-syn-85
(rac)-15
i-Bu
Cl
O
O
Me
Cl
(rac)-84
O
i-Bu
O
O
O
O
HN
O
1. n-BuLi, THF, -78 oC
Ph
2.
N
O
Cl
N
O
O
Ph
H
Me
Me
H
(rac)-1
Ph
Ph
Ph
(rac)-syn-85
O
(rac)-syn-4
13:87
Me
Cl
"syn-:anti-" = 97:3; 58%
(rac)-62
i-Bu
2 h
O
OC6F5
Me
(rac)-86
Scheme 11. Mutual kinetic resolution of oxazolidin-2-one (rac)-1 using active esters (rac)-15/84 and (rac)-62/86.
esters themselves, we repeated this resolution using the comple-
mentary active esters (rac)-62 and (rac)-86 (Scheme 11). Under
our standard reaction conditions, these active esters (rac)-62 and
(rac)-86, gave the reversed combination of oxazolidin-2-ones
(rac)-syn-4 and (rac)-syn-85 (ratio 13:87) in 58% yield with a com-
bined 94% de (Scheme 11). Evidently, the formation of the oxazoli-
din-2-one adducts 4 by addition of oxazolidin-2-one 1 to a
pentafluorophenyl ester [either (rac)-15 or (rac)-86] was at least
one order of magnitude faster than that of a related 2,4-dichloro-
phenyl ester [either (rac)-62 or (rac)-84] (Scheme 11).

420
N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
O
S
O
S
1. n-BuLi,
O
O
THF, -78 oC
Ph
Me
Ph
Me
O
HN
O
2.
HN
O
N
O
N
O
Ph
H
H
OC6F5
Ph
Ph
(rac)-87
Ph
Ph
Me
(rac)-1
(rac)-syn-4: (rac)-anti-4
(rac)-syn-88: (rac)-anti-88
(rac)-15 (2 equiv.)
5 min
2 h
93:7; 34%
99:1; 63%
92:8; 9%
98:2; 40%
O
S
1. n-BuLi,
O
S
O
O
THF, -78 oC
Ph
Me
Ph
HN
O
2.
O
HN
O
N
O
N
O
Ph
H
H
Me
OC6F5
Ph
Ph
Ph
Ph
Me
(R)-1
(S)-87
(R,S)-syn-88: (R,R)-anti-88
(S,R)-syn-4: (S,S)-anti-4
(rac)-15 (2 equiv.)
96:4; 8%
5 min
2 h
97:3; 42%
96:4; 51%
98:2; 24%
Scheme 12. Parallel and mutual kinetic resolution of active ester (rac)-15 using oxazolidin-2-(thi)ones 1 and 87.
OMe
We have also investigated the complementary double mutual
OMe
O
O
kinetic resolution of active ester (rac)-15 using the oxazolidin-2-
one (rac)-1 and oxazolidin-2-thione (rac)-8715 (Scheme 12). The
lithiated oxazolidin-2-one (rac)-1 was found to react at least four
times faster than the lithiated oxazolidin-2-thione (rac)-87 pre-
sumably due to it being less stable and a higher energy conjugate
base. The levels of diastereocontrol appear to be similar to those of
their individual mutual kinetic resolutions. However, for a shorter
reaction time (5 min), the levels of diastereoselectivity were low-
ered from 98% de to 86% de for (rac)-syn-4, and from 96% de to
84% de (Scheme 12).
The parallel resolution of racemic pentafluorophenyl 2-phenyl-
propanoate (rac)-15 can be achieved by two simultaneous
kinetic resolutions involving the oxazolidin-2-one (R)-1 and its
complementary quasi-enantiomeric oxazolidin-2-thione (S)-87
(Scheme 12). Treatment of oxazolidin-2-one (R)-1 and oxazoli-
din-2-thione (S)-87 in THF at ꢀ78 °C with n-BuLi (2 equiv), fol-
lowed by the addition of the active ester (rac)-15 in THF, gave
after 2 h the oxazolidin-2-one (S,R)-syn-4 as the major product in
51% yield with 92% de and the oxazolidin-2-thione (R,S)-syn-88
as the minor product in 24% yield in 96% de (Scheme 12). The level
of diastereocontrol remained unchanged, even when this reaction
was stopped after 5 min.
49
DCC, CH2Cl2
HO
Ph
Ph
OH
O
H
Me
H
Me
(R)-6
(R)-80; 55%
O
O
O
1. n-BuLi, THF, -78 o
C
Ph
2.
O
Ph
N
O
HN
O
OMe
H
Me
Ph
(R,S)-syn-4
syn-:anti-4: >95:<5; 33%
O
Ph
H Me
(S)-1
RT, 12 h
(R)-80
O
O
O
1. n-BuLi, THF, -78 o
C
Ph
2.
O
Ph
N
O
HN
O
OMe
H
Me
O
Ph
(R,R)-anti-4
syn-:anti-4: 35:65; 22%
Ph
Me
H
(R)-1
RT, 12 h
(rac)-80
Scheme 13. Stereospecific synthesis of oxazolidin-2-one adducts (S,R)-syn-4.
In an attempt to gain a better understanding on whether epi-
merisation or racemisation occurred during these addition pro-
cesses; we decided to investigate the stereospecific formation of
the oxazolidin-2-one adduct (R,S)-syn-4 using an enantiomerically
pure active ester (R)-80 that had low electrophilicity (Scheme 13).
This enantiomerically pure active ester (R)-80 was synthesised in
55% yield by the addition of DCC to a solution of enantiomerically
pure carboxylic acid (R)-6 and 4-methoxyphenol 49 in dichloro-
methane (Scheme 13). Treatment of the lithiated oxazolidin-2-
one (rac)-1-Li in THF at ꢀ78 °C with a solution of this active ester
(R)-80 in THF, and stirring the resulting solution at room tempera-
ture for 12 h gave the enantiomerically pure oxazolidin-2-one
(R,S)-syn-4 in 33% yield with >90% de. Under these reaction condi-
tions little or no epimerisation of the product oxazolidin-2-one
(R,S)-syn-4 nor racemisation of the active ester (R)-80 occurred
(Scheme 13). Under identical conditions, the kinetic resolution of
the racemic active ester (rac)-80 using an enantiomerically pure
oxazolidin-2-one (R)-1 gave the anti-diastereoisomeric oxazoli-
din-2-one (R,R)-anti-4 in 21% yield with 16% de (Scheme 13). Under
these conditions, it appears that formation of the anti-diastereoiso-
mer, (R,R)-anti-4, does not occur via epimerisation of the faster
forming syn-diastereoisomer.
As the stereoselectivity of this resolution is independent of the
concentration of the active ester 15 (up to ꢁ39% conversion—
Scheme 10); there must be an element of reversibility (reversion)
within this reaction to allow for the (R)- and (S)-enantiomers of
the active ester 15 to be interchanged. From our results, it seems
that this resolution proceeds via an addition–elimination
mechanism.
We calculated the total energies of 4-phenyloxazolidin-2-one 1,
pentafluorophenyl 2-phenylpropanoate 15 and the corresponding
products syn-(R,S)- and anti-(S,S)-4 (Table 2), the lithiated 4-phe-
nyloxazolidin-2-ones Li-1 (A and B) (Table 3) and intermediates,
W–Z, (Table 4) using dispersion-corrected density functional the-
ory (RI-TPSS-D/def2-TZVP) to obtain the potential energy pathway
(Fig. 1).
Deprotonation of 4-phenyloxazolidin-2-one 1 with n-BuLi ap-
pears to favour the formation of the more stable N-lithiated 4-
phenyloxazolidin-2-one,
B (+15) rather than the O-lithiated

N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
421
Table 2
Minimised structures of oxazolidin-2-one (S)-1, pentafluorophenyl 2-phenylpropanoate (R)-15, and oxazolidin-2-one adducts syn-(R,S)-4 and anti-(S,S)-4 obtained at the RI-TPSS-
D/def2-TZVP level of theory
Compound
Structure
Compound
Structure
1
15
syn-(R,S)-4
anti-(S,S)-4
Table 3
Minimised structures of lithiated oxazolidin-2-ones A, B, dimers (S,S)-D and (R,S)-E obtained at the RI-TPSSD/def2-TZVP level of theory
Compound
Structure
Compound
Structure
A
B
Dimer (S,S)-D
Dimer (R,S)-E
4-phenyloxazolidin-2-one A (+15) by 36 kJ molꢀ1 (Fig. 1). How-
ever, this N-lithiated 4-phenyloxazolidin-2-one can be further sta-
bilised by ꢀ123 kJ molꢀ1 in C (+15) by additional and co-operative
co-ordination16 via either dimer (S,S)-D or dimer (R,S)-E forma-
tion17 (Fig. 1 and Table 3).
Further stabilisation of this lithiated oxazolidin-2-one can be
achieved through aggregation with the active ester, pentafluor-
ophenyl 2-phenylpropanoate 15, to give the aggregates syn-(R,S)-
and anti-(S,S)-W (Table 4); the syn-aggregate (R,S)-W is preferred
over the anti-aggregate (S,S)-W by 5 kJ molꢀ1 (Fig. 1). In both
aggregates, the lithium atom is co-ordinated to the pentafluor-
ophenyl 2-phenylpropanoate (S/R)-15 [by its 2-fluoro-substituent
within the C6F5-ring and C(2)-phenyl group], and the oxazolidin-
2-one (S)-1 (by its O/N atoms) as shown in Figure 1. The only subtle
difference between these two complexes, (R,S)-W and (S,S)-W, is
the relative position of the methyl group within the active ester
15 (see Table 4).
The addition of the N-lithiated oxazolidin-2-one Li-1 (in B) to
the carbonyl (C@O) group of the active ester 15 leads to the two
diastereoisomeric tetrahedral intermediates syn-(R,S)-X and anti-
(S,S)-X (Fig. 1). The more stable being the anti-(S,S)-diastereoiso-
mer X by 8 kJ molꢀ1. The relative energy difference between the
syn-(R,S)-intermediates, W–X, was smaller (+3 kJ molꢀ1) than the
corresponding difference between anti-(S,S)- intermediates, W–Y
(ꢀ10 kJ molꢀ1). In both intermediates, syn-(R,S)- and anti-(S,S)-X,
the phenyl group of the oxazolidin-2-one 1 is positioned anti- to
the pentafluorophenyl group of the active ester 15, and additional
co-ordination comes from the Ph group of this active ester, and the
carbonyl (C@O) group of the parent oxazolidin-2-one 1 (Fig. 1 and
Table 2).

422
N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
Table 4
Minimised structures for aggregates W and intermediates X–Z obtained at the RI-TPSS-D/def2-TZVP level of theory
Compound
Structure
Compound
Structure
syn-(R,S)-W
anti-(S,S)-W
syn-(R,S)-X
anti-(S,S)-X
syn-(R,S)-Y
anti-(S,S)-Y
syn-(R,S)-Z
anti-(S,S)-Z
The reformation of the carbonyl (C@O) groups, in syn-(R,S)-Y
and anti-(S,S)-Y, by elimination of lithium pentafluorophenolate
(C6F5OLi), from syn-(R,S)-X and anti-(S,S)-X, further increases the
stabilisation by ꢀ80 kJ molꢀ1 [for syn-(R,S)-Y] and ꢀ77 kJ molꢀ1
[for anti-(S,S)-Y] (Fig. 1). The lithium pentafluorophenolate is also
stabilised by co-ordinating to both carbonyl (C@O) groups within
the products syn-(R,S)- and anti-(S,S)-Y. Removing this co-ordina-
tion, increases the relative energy of these intermediates; syn-
(R,S)-Y?syn-(R,S)-Z (+31 kJ molꢀ1)?syn-(R,S)-4 + C6F5OLi (+126
kJ molꢀ1) and anti-(S,S)-Y?anti-(S,S)-Z (+35 kJ molꢀ1)?anti-(S,S)-
4 + C6F5OLi (+153 kJ molꢀ1) (Fig. 1). The major diastereoisomeric
product of this resolution, oxazoldin-2-one syn-(R,S)-4, appears to
be more thermodynamically stable (ꢀ26 kJ molꢀ1) than the minor
diastereoisomer anti-(S,S)-4, and is significantly more stable
(ꢀ32 kJ molꢀ1) than the starting precursors (S)-1 and (S/R)-15.
The major product of this resolution is the more stable syn-
diastereoisomeric oxazolidin-2-one syn-(R,S)-4, and as there is ele-
ment of reversibility in its formation, the syn-aggregate (R,S)-W
[rather than anti-aggregate (S,S)-W] appears to be a governing fac-
tor in this outcome (Fig. 1). There appears to be little potential en-
ergy difference (+3 kJ molꢀ1
) between the initial tetrahedral
intermediate syn-(R,S)-X and its syn-aggregate (R,S)-W. The forma-
tion of the diastereoisomeric intermediate, anti-(S,S)-X, can be dis-
favoured by promoting either the addition process via the more
populated syn-aggregate (R,S)-W or by reversion back to the parent
anti-aggregate (S,S)-W and subsequent enantiomeric interchange
via C (+15) as the forward reaction to give anti-(S,S)-Y is presum-
ably slower.
With this preliminary study complete, we next probed the
structural nature of the oxazolidin-2-ones (rac)-2 and (rac)-89–

N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
423
A + 15
F
F
+64 kJ mol-1
F
F
F
O
N
Me
Ph
O
Li
B + 15
+28 kJ mol-1
Ph
O
0 kJ mol-1
1 + 15
O
-6 kJ mol-1
anti-(S,S)-4 + 15
syn-(R,S)-4 + 15
aggregates syn-W/anti-W
-32 kJ mol-1
Li
O
O
Ph
O
N
Me
F5C6O
-107 kJ mol-1
anti-W
Ph
-95 kJ mol-1
syn-X
anti-X
intermediates syn-X/anti-X
-109 kJ mol-1
C + 15
syn-W
-112 kJ mol-1
-117 kJ mol-1
F
F
F
F
F
F
F
F
syn-Z
anti-Z
-158 kJ mol-1
-159 kJ mol-1
O
O
Li
syn-Y
Li
F
F
-189 kJ mol-1
-194 kJ mol-1
O
O
O
O
anti-Y
Ph
Ph
N
O
N
O
Me
Me
Ph
syn-Y/anti-Y
Ph
syn-Z/anti-Z
Figure 1. Potential energy profile for the resolution of oxazolidin-2-one (S)-1 and pentafluorophenyl 2-phenylpropanoate (R)- and (S)-15. Potential energy values in kJ molꢀ1
relative to 1+15, computed at the RI-TPSS-D/def2-TZVP level of theory.
O
O
O
O
O
1. n-BuLi,
THF, -78 oC
Ph
Ph
Me
+
HN
R
O
N
O
N
O
O
2.
(rac)-15
H
Me
H
Ph
R
OC6F5
R
(rac)-
Me
THF, -78 oC, 2 h
anti-
syn-
O
O
O
O
O
HN
O
HN
O
HN
Ph
O
HN
i-Pr
O
HN
O
Me
Ph
EtO
Ph
O
Entry
5
1
2
3
4
Oxazolidinone
(rac)-89
(rac)-90
(rac)-1
(rac)-2
(rac)-91
Adduct (rac)- syn,syn-92:anti,syn-92 syn-93:anti-93
syn-4:anti-4
syn-5:anti-5
syn-94:anti-94
68:32
63%
70:30
71%
97:3
70%
95:5
58%
95:5
63%
Yield
Scheme 14. Mutual kinetic resolution of oxazolidin-2-ones (rac)-1, (rac)-2 and (rac)-89–91 using active esters (rac)-15.
91 in an attempt to gain a better understanding of the origin of this
and serine, respectively (Scheme 14). We first investigated the mu-
tual kinetic resolution of pentafluorophenyl 2-phenylpropanoate
(rac)-15 using these lithiated oxazolidin-2-ones. Deprotonation of
the oxazolidin-2-ones (rac)-89, (rac)-90, (rac)-2 and (rac)-91 with
diastereoselection (Scheme 14). Herein, we chose to use a series of
structurally related oxazolidin-2-ones, (rac)-89, (rac)-90, (rac)-2
and (rac)-91 derived from norephedrine, phenylalanine, valine

424
N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
n-BuLi in THF at ꢀ78 °C, followed by the addition of pentafluor-
ophenyl 2-phenylpropanoate (rac)-15 gave, after 2 h at ꢀ78 °C a
separable diastereoisomeric mixture of oxazolidin-2-one adducts
(rac)-syn,syn- and (rac)-syn,anti-92, (rac)-syn- and (rac)-anti-93,
(rac)-syn- and (rac)-anti-5, and (rac)-syn- and (rac)-anti-94 in good
yield (Scheme 14).
The levels of diastereoselection were excellent (>90% de) for the
oxazolidin-2-ones (rac)-2 and (rac)-91 (Scheme 14: entries 4 and
5) and more importantly comparable to those of 4-phenyloxazoli-
din-2-one (rac)-1 (Scheme 14). The oxazolidin-2-ones, (rac)-89 and
(rac)-90, which contained a less sterically demanding alkyl substi-
tuent at their C(4)-positions gave the corresponding oxazolidin-2-
one adducts (rac)-syn,syn-92 and (rac)-syn-93 in good yield with
lower levels of diastereocontrol, 36% and 40% de, respectively
(Scheme 14: entries 1 and 2).
six combinations of quasi-enantiomeric oxazolidin-2-ones, such
as (4R,5S)-89 and (S)-90, (4R,5S)-89 and (S)-2, (S)-91 and (S)-90,
(R)-1 and (S)-90, (S)-91 and (S)-2, and (R)-1 and (S)-2 (Scheme 15).
The treatment of these equimolar combinations of quasi-
enantiomeric oxazolidin-2-ones (4R,5S)-89 and (S)-90, (4R,5S)-89
and (S)-2, (S)-91 and (S)-90, (R)-1 and (S)-90, (S)-91 and (S)-2,
and (R)-1 and (S)-2 with n-BuLi in THF at ꢀ78 °C, followed by the
addition of pentafluorophenyl 2-phenylpropanoate (rac)-15 gave,
after 2 h at ꢀ78 °C, a diastereoisomeric mixture of oxazolidin-2-
ones syn,syn- and syn,anti-92 (ratio 64:36; 51%) and syn- and
anti-93 (ratio 71:29; 48%), syn,syn- and syn,anti-92 (ratio 83:17;
72%) and syn- and anti-5 (ratio 85:15; 74%), syn- and anti-94 (ratio
93:7; 43%) and syn- and anti-93 (ratio 80:20; 67%), syn- and anti-4
(ratio 91:9; 64%) and syn- and anti-93 (ratio 83:17; 48%), syn- and
anti-94 (ratio 95:5; 49%) and syn- and anti-5 (ratio 95:5; 60%), and
syn- and anti-4 (ratio 95:5; 60%) and syn- and anti-5 (ratio 95:5;
60%) (Scheme 15).
With this information in hand, we next chose to investigate the
resolution of pentafluorophenyl 2-phenylpropanoate (rac)-15 using
O
O
O
O
O
O
1. n-BuLi
Ph
Ph
Me
THF, -78 oC
N
O
N
O
HN
O
HN
O
2. (rac)-15
(2 equiv.)
H
Me
H
Me
Ph
Me
Ph
Ph
Ph
(4R,5S)-89
(S)-90
syn,syn-92:syn,anti-92
syn-93:anti-93
71:29 (48%)
64:36 (51%)
O
O
O
O
O
O
1. n-BuLi
THF, -78 oC
Ph
Me
Ph
HN
O
N
O
HN
O
N
O
2. (rac)-15
(2 equiv.)
H
H
Me
i-Pr
Me
Ph
Me
Ph
i-Pr
(4R,5S)-89
(S)-2
syn,syn-92:syn,anti-92
syn-5:anti-5
83:17 (72%)
85:15 (74%)
O
O
O
O
O
O
1. n-BuLi
Ph
Me
Ph
THF, -78 oC
N
O
N
O
HN
O
HN
O
2. (rac)-15
(2 equiv.)
H
Me
H
EtO2C
EtO2C
Ph
Ph
(S)-91
(S)-90
syn-94:anti-94
syn-93:anti-93
93:7 (43%)
80:20 (67%)
O
O
O
O
O
O
1. n-BuLi
Ph
Me
Ph
THF, -78 o
C
N
O
N
O
HN
O
HN
O
2. (rac)-15
(2 equiv.)
H
Me
H
Ph
Ph
Ph
Ph
(R)-1
(S)-90
syn-4:anti-4
syn-93:anti-93
83:17 (48%)
91:9 (64%)
O
O
O
O
O
O
1. n-BuLi
THF, -78 oC
Ph
Me
Ph
HN
O
HN
O
N
O
N
Me
O
2. (rac)-15
(2 equiv.)
H
H
EtO2C
i-Pr
EtO2C
i-Pr
(S)-91
(S)-2
syn-94:anti-94
syn-5:anti-5
95:5 (49%)
95:5 (60%)
O
O
O
O
O
O
1. n-BuLi
THF, -78 o
C
Ph
Me
Ph
N
O
HN
O
HN
O
N
O
2. (rac)-15
(2 equiv.)
H
H
Me
Ph
Ph
i-Pr
i-Pr
(R)-1
(S)-2
syn-4:anti-4
syn-5:anti-5
95:5 (60%)
95:5 (60%)
Scheme 15. Parallel kinetic resolution of active ester (rac)-15 using oxazolidin-2-ones (R)-1, (S)-2, (4S,5R)-89, (S)-90 and (S)-91.

N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
425
The levels of diastereocontrol were found to be excellent for
oxazolidin-2-ones (R)-1, (S)-2 and (S)-91 and comparable to the
high levels of diastereoselectivity that were obtained for their mu-
tual kinetic resolutions (Scheme 13). For combinations of these
quasi-enantiomeric oxazolidin-2-ones, such as (S)-91 and (S)-2,
and (R)-1 and (S)-2, the overall level of molecular recognition
was excellent leading to two separable diastereoisomeric combina-
tion of adducts syn-94 and syn-5, and syn-4 and syn-5, respectively
(Scheme 15). For combinations involving one of these oxazolidin-
2-ones (R)-1, (S)-2 and (S)-91 and a less stereoselective oxazoli-
din-2-one partner (4R,5S)-89 and (S)-90 [e.g., (4R,5S)-89 and
(S)-2, (S)-91 and (S)-90, and (R)-1 and (S)-90], the levels of diaste-
reocontrol were lowered for the oxazolidin-2-one adducts 4, 5 and
94 derived from (R)-1, (S)-2 and (S)-91, but were higher for those
oxazolidin-2-one adducts 92 and 93 derived from the less stereose-
lective complementary oxazolidin-2-ones (4R,5S)-89 and (S)-90
(Scheme 15). For resolutions involving two moderately stereose-
lective oxazolidin-2-ones, such as (4R,5S)-89 and (S)-90, the corre-
sponding oxazolidin-2-one adducts syn,syn- and syn,anti-92, and
syn- and anti-93, was obtained, respectively with similar levels of
stereocontrol to those obtained from their mutual kinetic resolu-
tions (Schemes 14 and 15).
In an attempt to determine the complementarity of these oxaz-
olidin-2-ones 1 and 91 and their relative rate of oxazolidin-2-one
formation, we next investigated the competitive addition of a pair
of oxazolidin-2-ones (R)-1 and (S)-91, which contained the same
sense of reagent control to our standard substrate pentafluorophe-
nyl 2-phenylpropanoate (rac)-15 (Scheme 16). Deprotonation of an
equimolar pair of oxazolidin-2-ones (R)-1 and (S)-91 followed by
the addition of pentafluorophenyl 2-phenylpropanoate (rac)-15
at ꢀ78 °C gave, after 2 h, the oxazolidin-2-ones (S,R)-syn- and
(R,R)-anti-4 (ratio 60:40; 75%) and (S,S)-syn- and (R,S)-anti-94 (ra-
tio 57:43; 57%), respectively (Scheme 16). The oxazolidin-2-ones
(R)-1 and (S)-91 appear to be equally diastereoselective in favour-
ing the formation of syn-oxazolidin-2-ones (S,R)-4 and (S,S)-94 in
20% de and 14% de, respectively (Scheme 15). As these oxazoli-
din-2-ones (R)-1 and (S)-91 were competing for the same (S)-enan-
tiomer of 15, simply lowering the %conversion by reducing the
reaction time would improve the overall levels of diastereocontrol.
By repeating this competitive kinetic resolution, and stopping
the reaction after 5 min, the syn-oxazolidin-2-ones (S,R)-4 and
(S,S)-94 were obtained in 37% yield (with 88% de) and 15% yield
(with 78% de), respectively with significantly improved levels of
diastereoselectivity (Scheme 16). In both cases, the oxazolidin-2-
one (R)-1 appeared to be more nucleophilic than its complemen-
tary oxazolidin-2-one (S)-91 (Scheme 16).
Access to the resolved and enantiomerically pure 2-phenyl-
propanoic acid 6 can be achieved by hydrolysis of two quasi-enan-
tiomeric oxazolidin-2-one adducts, such as (S,R)-syn-4 and
(R,S)-syn-5 (Scheme 15). Treatment of these oxazolidin-2-one
(S,R)-syn-4 and (R,S)-syn-5 with lithium hydroxide-monohydrate
in the presence of hydrogen peroxide in THF/H2O (3:1) gave, after
12 h, the corresponding 2-phenylpropanoic acid (S)- and (R)-6 in
90% and 85% yields with >98% ee and >98% ee, respectively
(Scheme 17).
3. Conclusion
In conclusion, we have developed an improved method for the
diastereoselective coupling of lithiated oxazolidin-2-ones to
racemic 2-phenylpropanoic acid (rac)-6 using a parallel kinetic
resolution involving two complementary (quasi)-enantiomeric
oxazolidin-2-ones [e.g., (R)-1 and (S)-2]. We have found that a
number of effects, such as the structural nature of the complemen-
tary (quasi)-enantiomeric oxazolidin-2-ones, choice of metal coun-
ter-ions and temperature, play an important role on the relative
diastereoselective outcome; a lithium counter-ion and low tem-
perature promotes formation of the syn-diastereoisomeric adduct.
The nearest analogy to this work is the parallel kinetic resolutions
reported by Fox,9 Vedejs4 and Davies.3 Fox9 has reported a related
parallel kinetic resolution of racemic mixed anhydrides using a
combination of quasi-enantiomeric designer oxazolidin-2-ones.
Vedejs4 has shown the efficient parallel kinetic resolution of 1-
phenylethanol using two complementary quasi-enantiomeric
O
O
O
O
O
O
1. n-BuLi
Ph
Me
Ph
Me
THF, -78 oC
N
O
HN
O
HN
O
N
O
H
2. (rac)-15
(2 equiv.)
H
EtO2C
Ph
EtO2C
Ph
(S,S)-syn-94:(R,S)-anti-94
57:43 (57%)
(S,R)-syn-4:(R,R)-anti-4
(R)-1
(S)-91
2 h
60:40 (75%)
5 min
94:6 (37%)
89:11 (15%)
Scheme 16. Resolution of active ester (rac)-15 using oxazolidin-2-ones (R)-1 and (S)-91.
O
O
O
O
O
Ph
Me
Ph
Me
LiOH, H2O
H2O2, THF
HCl (3 M)
Ph
Me
OLi
N
O
HN
O
OH
H
H
H
Ph
Ph
(S,R)-syn-4
(R)-1
(+)-(S)-6 >98% ee; 90%
O
O
O
O
O
Ph
Ph
LiOH, H2O
H2O2, THF
HCl (3 M)
Ph
OLi
HN
O
N
O
OH
H
Me
H
Me
H
Me
(-)-(R)-6 >98% ee; 85%
Scheme 17. Hydrolysis of oxazolidin-2-ones (S,R)-syn-4 and (R,S)-syn-5.
(R,S)-syn-5
(S)-2

426
N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
2
chlorocarbonates. In contrast, Davies3 has reported the use of two
quasi-enantiomeric lithium amides to resolve racemic enoates
Interestingly, these efficient parallel kinetic resolutions2 appear
to act independent of each other in an equal and opposite stereo-
chemical sense and give products with near perfect levels of enan-
tio- and diastereocontrol.
and 127.5 (3 ꢂ CH; Ar), ꢂCH; Ph), 125.2 (1C, tdt, JC,F = 14.2 Hz,
4JC,F = 4.2 Hz and JC,F = 2.0 Hz, i-CO; OC6F5), 45.1 (PhCH) and 18.5
3
3
(CH3CH); dF (378 MHz; CDCl3) ꢀ152.6 (2F, d, JF,F 20.9, Fortho),
3
3
ꢀ157.9 (1F, t, JF,F 20.9, Fpara) and ꢀ162.3 (2F, t, JF,F 20.9, Fmeta
)
(Found M+, 316.0514. C15H9F5O2 requires M+, 316.0517).
4.2.3. Pentafluorophenyl 2-phenylpropanoate (ꢀ)-(R)-15
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (R)-6 (3.0 g, 20.0 mmol), DCC (4.53 g, 22.00 mmol) and penta-
fluorophenol 8 (4.90 g, 26.70 mmol) gave, pentafluorophenyl 2-
phenylpropanoate (R)-15 (5.37 g, 85%) as a colourless oil; RF [light
4. Experimental
4.1. General
petroleum (40–60 °C)/diethyl ether (9:1)] 0.56; ½a D25
¼ ꢀ75:0 (c
ꢃ
3.3, CHCl3); mmax (CHCl3) cmꢀ1 1779 (C@O) (Found M+, 316.0521;
All solvents were distilled before use. All reactions were carried
out under nitrogen using oven-dried glassware. Flash column chro-
matography was carried out using Merck Kieselgel 60 (230–400
mesh). Thin layer chromatography (TLC) was carried out on com-
mercially available pre-coated plates (Merck Kieselgel 60F254 sil-
ica). 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 rotations
were measured using an automatic AA-10 Optical Activity Ltd
polarimeter.
C15H9F5O2 requires M+, 316.0517).
4.2.4. Pentafluorophenyl 2-phenylpropanoate (+)-(S)-15
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (R)-6 (4.0 g, 26.7 mmol), DCC (6.04 g, 29.3 mmol) and penta-
fluorophenol 8 (6.54 g, 35.64 mmol) gave, pentafluorophenyl 2-
phenylpropanoate (S)-15 (7.32 g, 87%) as a colourless oil; RF [light
petroleum (40–60 °C)/diethyl ether (9:1)] 0.56; ½a D25
¼ þ74:5 (c
ꢃ
4.9, CHCl3); mmax (CHCl3) cmꢀ1 1779 (C@O) (Found M+, 316.0521;
C15H9F5O2 requires M+, 316.0517).
4.2.5. 2-(4,5-Dihydro-oxazol-2-yl)phenyl 2-phenylpropanoate
(rac)-16
4.2. Synthesis of active esters
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (0.105 g, 0.7 mmol), DCC (0.163 g, 0.79 mmol) and 2-
(4,5-dihydro-oxazol-2-yl) phenol 9 (0.12 g, 0.7 mmol) gave, the
active ester (rac)-16 (70 mg, 34%) as a colourless oil; RF [light
petroleum (40–60 °C)/diethyl ether (7:3)] 0.5; mmax (film) cmꢀ1
1718 (C@O); dH (400 MHz; CDCl3) 7.65 (1H, dd, J 8.1 and 1.1, Ar),
7.40–7.25 (6H, m, 5 ꢂ CH; Ph and Ar), 7.00 (1H, dd, J 8.1 and 1.1,
CH; Ar), 6.86 (1H, td, J 8.1 and 1.1, CH; Ar), 4.45 (2H, t, J 9.4,
CH2O), 4.09 (2H, t, J 9.4, CH2N), 3.93 (1H, m, PhCHCH3) and 1.46
(3H, d, J 6.9, PhCHCH3); dC (100 MHz; CDCl3) 171.0 (C@O), 159.9
(C@N), 154.0 (i-CO; Ar), 141.6 (i-CC; Ph), 133.2 (i-CC; Ar), 128.8,1
127.9,1 127.2,1 127.0,2 118.51 and 116.61 (7 ꢂ CH; Ph and Ar),
66.7 (CH2O), 49.8 (CH2N), 45.7 (PhCHCH3) and 20.9 (PhCHCH3);
m/z 105.1 (100%, PhCH2þ).
4.2.1. 4-Nitrophenyl 2-phenylpropanoate (rac)-14
2-Phenylpropanoic acid (rac)-6 (1.02 g, 6.80 mmol) was added
to
a
stirred solution of N,N0-dicyclohexylcarbodiimide (DCC)
(1.61 g, 7.78 mmol) in dichloromethane (3 ml) and stirred for
15 min. A solution of 4-nitrophenol 7 (0.97 g, 6.97 mmol) in dichlo-
romethane (3 ml) was slowly added, and the resulting solution was
stirred for 12 h. The resulting precipitate N,N0-dicyclohexylurea
(DCU) was removed by filtration using suction filtration. Water
(10 mL) was added and the solution was extracted with dichloro-
methane (3 ꢂ 10 mL) and dried (over MgSO4). The combined or-
ganic layers were evaporated under reduced pressure. The crude
residue was purified by flash column chromatography on silica
gel eluting with light petroleum (40–60 °C)/diethyl ether (9:1) to
give 4-nitrophenyl 2-phenylpropanoate (rac)-14 (1.63 g, 87%) as a
colourless oil; RF [light petroleum (40–60 °C)/diethyl ether (9:1)]
0.5; mmax (film) cmꢀ1 1723 (C@O); dH (400 MHz; CDCl3) 8.23 (2H,
dt, J 8.8 and 2.4, 2 ꢂ CH; Ar), 7.40–7.30 (5H, m, 5 ꢂ CH; Ph), 7.18
(2H, dt, J 8.8 and 2.4, 2 ꢂ CH; Ar), 3.99 (1H, q, J 7.2, PhCHCH3)
and 1.63 (3H, d, J 7.2, PhCHCH3); dC (100 MHz; CDCl3) 172.1
(C@O), 155.5 (i-CO; Ar), 145.3 (i-CN; Ar), 139.2 (i-CC; Ph), 128.9,
4.2.6. 1-Phenyl-1-methylacetoxy-1-benzotriazole (rac)-17
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (5.01 g, 33.33 mmol), DCC (7.63 g, 37.03 mmol) and
BtOH 10 (5.49 g, 40.6 mmol) gave, the active ester (rac)-18
(4.37 g, 49%) as a colourless oil; RF [diethyl ether] 0.63; mmax (film)
cmꢀ1 1718 (C@O); dH (400 MHz; CDCl3) 8.40A (1H, d J 8.2, CH; Ar),
8.03B (1H, d J 8.2, CH; Ar), 7.96A (1H, d J 8.2, CH; Ar), 7.70B (1H, dd, J
8.2 and 7.1, CH; Ar), 7.50 (1H, dd, J 8.2 and 7.1, CH; Ar), 7.55–7.25
(6H, m, 5 ꢂ CH; Ph and CH;A Ar), 6.98B (1H, d, J 8.2, CH; Ar), 4.94A
(1H, q, J 7.3, PhCHCH3), 4.24B (1H, d, J 7.3, PhCHCH3), 1.73A (3H, d, J
7.3, PhCHCH3) and 1.70B (3H, d, J 7.3, PhCHCH3); dC (100 MHz;
CDCl3) 170.9 and 170.6 (2 ꢂ C@O), 143.3 (2 ꢂ i-CC; Ph), 138.6
and 137.9 (2 ꢂ i-CN; Ar), 132.7 (2 ꢂ i-CN; Ar), 129.2, 128.9, 127.9
and 127.4 (4 ꢂ CH; PhA and PhB), 132.9, 128.6, 128.2, 124.7,
120.4, 116.1, 115.4 and 107.9 (8 ꢂ CH; ArA and ArB), 44.4 and
43.5 (2 ꢂ PhCHCH3), 18.6 and 18.2 (2 ꢂ PhCHCH3) (Found MH+,
268.1082; C15H14N3O2 requires MH+, 268.1081). A and B are rota-
mers (ratio 43:57), where A is the minor and B is the major
rotamer.
127.7 and 127.4 (3 ꢂ CH; Ph), 125.1 and 122.2 (2 ꢂ CH; Ar), 45.6
þ
(PhCHCH3) and 18.3 (PhCHCH3) (Found MNH4
, 289.1185.
þ
C
15H17N2O4 requires MNH4 289.1183).
4.2.2. Pentafluorophenyl 2-phenylpropanoate (rac)-15
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (5.00 g, 33.32 mmol), DCC (7.58 g, 36.73 mmol) and
pentafluorophenol 8 (6.15 g, 33.43 mmol) gave, pentafluorophenyl
2-phenylpropanoate (rac)-15 (9.71 g, 92%) as a colourless oil; RF
[light petroleum (40–60 °C)/diethyl ether (9:1)] 0.56; mmax (film)
cmꢀ1 3100–2881 (aromatic, CH) and 1784 (C@O); dH (400 MHz;
CDCl3) 7.41–7.28 (5H, m, 5 ꢂ CH; Ph), 4.07 (1H, q, J 7.2, PhCHCH3)
and 1.64 (3H, d, J 7.2, PhCHCH3); dC (100 MHz; CDCl3) 170.6
1
2
(OC@O), 141.1 (142.40 and 139.90, 2C, ddt, JC,F = 251.3 Hz, JC,F
=
4.2.7. 2,5-Dioxo-pyrrolidin-1-yl 2-phenylpropanoate (rac)-18
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.01 g, 6.70 mmol), DCC (1.52 g, 7.38 mmol) and N-
hydroxysuccinimide 11 (0.79 g, 6.89 mmol) gave, the active ester
(rac)-18 (0.95 g, 57%) as a colourless oil; RF [light petroleum
3
12.2 Hz and JC,F = 3.8 Hz, C(2)–F), 139.4 (140.70 and 138.18, 1C,
1
2
3
dtt, JC,F = 253.2 Hz, JC,F = 13.4 Hz and JC,F = 4.2 Hz, C(4)-F), 138.7
1
(i-C; Ph), 137.8 (139.05 and 136.58, 2C, dtdd, JC,F = 249.1 Hz,
3
4
2JC,F = 14.5 Hz, JC,F = 5.7 Hz and JC,F = 3.1 Hz, C(3)-F), 128.9, 127.8

N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
427
(40–60 °C)/diethyl ether (7:3)] 0.33;
m
max (film) cmꢀ1 1714 (C@O);
PhCHCH3); dC (100 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 ꢂ CH; PhA and PhB), 69.6 (CH2O), 57.9
(PhCHN), 43.9 (PhCHCH3) and 18.6 (PhCHCH3) (Found MH+,
dH (400 MHz; CDCl3) 7.39–7.28 (5H, m, 5 ꢂ CH; Ph), 4.06 (1H, q, J
7.1, PhCHCH3), 2.80 (4H, m, 2 ꢂ CH2C@O) and 1.65 (3H, d, J 7.1,
PhCHCH3); dC (100 MHz; CDCl3) 169.8 and 169.0 (2 ꢂ C@O),
296.1286; C15H18NO3 requires 296.1287); m/z 295.1 (10%, M+),
þ
138.1 (i-CC; Ph), 128.8, 127.7 and 127.5 (3 ꢂ CH; Ph), 42.9
(PhCHCH3), 25.5 (2 ꢂ CH2) and 18.9 (PhCHCH3) (Found MNH4
,
132.1 (100, Ph(CH3)C@C@O+), 105.1 (25, PhCH2þ) and 77.1 (20,
Ph+); and (4RS)-4-phenyl-3-(2RS-phenylpropanoyl)oxazolidin-2-
one (rac)-anti-4; white solid; mp 106–108 °C; RF [light petroleum
(bp 40–60 °C)/diethyl ether (1:1)] 0.58; mmax (CHCl3) cmꢀ1 1780
(C@O) and 1700 (C@O); dH (400 MHz; CDCl3) 7.39–7.26 (10H, m,
10 ꢂ CH; 2 ꢂ 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, CHAHBO), 4.21 (1H, dd, J 8.8
and 3.2, CHAHBO) and 1.40 (3H, d, J 7.2, PhCHCH3); dC (100 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 ꢂ CH;
PhA and PhB), 69.7 (CH2O), 58.1 (PhCHN), 43.2 (PhCHCH3) and
þ
265.1186. C13H17N2O4 requires MNH4þ, 265.1183).
4.2.8. 2-Phenylpropanoyl 2-phenylpropanoate (rac)- and
(meso)-19
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.0 g, 6.65 mmol) and DCC (1.60 g, 7.77 mmol) gave,
2-phenylpropanoyl 2-phenylpropanoate (rac)- and (meso)-19
(0.6 g, 64%) as a colourless oil [ratio (rac)-:(meso)- = 50:50]; RF
[light petroleum (40–60 °C)/diethyl ether (7:3)] 0.56; mmax (film)
cmꢀ1 1770 (C@O) and 1712 (C@O); dH (400 MHz; CDCl3) 7.34–
7.23 (6H, m, 6 ꢂ CH; PhA+B), 7.14–7.08 (4H, m, 4 ꢂ CH; PhA+B),
3.69 (1H, q, J 7.1, PhCHCHA3orB), 3.67 (1H, q, J 7.1, PhCHCHA3orB),
19.4 (PhCHCH3) (Found MH+, 296.1282; C18H18NO3 requires
þ
296.1287).
J ) and 1.43 (3H, d, J 7.1,
7.1, PhCHCHA3orB
Active ester (rac)-14, gave a mixture (87:13) of oxazolidin-2-
ones syn- and anti-4 (0.201 g, 68%).
Active ester (rac)-15, gave a mixture (97:3) of oxazolidin-2-ones
syn- and anti-4 (0.206 g, 70%).
Active ester (rac)-16, gave a mixture (90:10) of oxazolidin-2-
ones syn- and anti-4 (0.103 g, 35%).
1.44 (3H, d,
PhCHCHA3orB); dC (100 MHz; CDCl3) 169.6 and 169.5 (2 ꢂ C@O),
138.6 and 138.5 (2 ꢂ i-CC; Ph), 128.8, 128.7 and 127.7 (6 ꢂ CH;
PhA+B), 46.4 and 46.3 (2 ꢂ PhCHCH3), 17.7 and 17.6 (2 ꢂ PhCHCH3);
m/z 104.9 (100%, PhCH+CH3) and 150.1 (10, PhCHMeCO2H).
Active ester (rac)-17, gave a mixture (76:24) of oxazolidin-2-
ones syn- and anti-4 (0.124 g, 42%).
Active ester (rac)-18, gave a mixture (84:16) of oxazolidin-2-
ones syn- and anti-4 (0.118 g, 40%).
Active ester (rac)-19, gave a mixture (43:57) of oxazolidin-2-
ones syn- and anti-4 (0.177 g, 60%).
Active ester (rac)-20, gave a mixture (54:46) of oxazolidin-2-
ones syn- and anti-4 (0.185 g, 63%).
4.2.9. 2-Phenyl-propanoic pivalonic anhydride (rac)-20
At first, n-BuLi (0.44 mL, 2.5 M in hexanes, 1.11 mmol) was
added to a stirred solution of 2-phenylpropanoic acid (rac)-6
(0.15 g, 1.01 mmol) in THF (5 mL) at ꢀ78 °C. The resulting solution
was stirred for 10 min. Pivaloyl chloride 12 (0.121 g, 1.01 mmol) in
THF (2 mL) was slowly added, and the resulting solution was stir-
red for 2 h. This solution of 2-phenyl-propanoic pivalonic anhy-
dride (rac)-20 was used as prepared.
Active ester (rac)-21, gave a mixture (65:35) of oxazolidin-2-
ones syn- and anti-4 (0.118 g, 40%).
4.2.10. 2-Phenyl-propanoic adamantanoic anhydride (rac)-21
At first, n-BuLi (0.44 mL, 2.5 M in hexanes, 1.11 mmol) was
added to a stirred solution of 2-phenylpropanoic acid (rac)-6
(0.15 g, 1.01 mmol) in THF (5 mL) at ꢀ78 °C. The resulting solution
was stirred for 10 min. Adamantyl carbonyl chloride (0.2 g,
1.01 mmol) in THF (2 mL) was slowly added, and the resulting
solution was stirred for 2 h. This solution of 2-phenyl-propanoic
adamantanoic anhydride (rac)-21 was used as prepared.
4.3.1. 2-Fluorophenyl 2-phenylpropanoate (rac)-53
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.01 g, 6.75 mmol), DCC (1.56 g, 7.54 mmol) and 2-
fluorophenol 22 (0.76 g, 0.61 mL, 6.78 mmol) gave, after purifica-
tion by column chromatography eluting with light petroleum
(40–60 °C)-diethyl ether, 2-fluorophenyl 2-phenylpropanoate
(rac)-53 (1.37 g, 83%) as a colourless oil; RF [light petroleum (40–
60 °C)/diethyl ether (9:1)] 0.28; mmax (film) cmꢀ1 1759 (C@O); dH
(400 MHz; CDCl3) 7.43–6.98 (9H, m, 9 ꢂ CH; Ar and Ph), 4.02
(1H, q, J 7.2, PhCHCH3) and 1.63 (3H, d, J 7.2, PhCHCH3); dC
(100 MHz; CDCl3) 172.1 (C@O), 154.1 (1C, d, J 249.6, i-CF; Ar),
139.8 (i-CC; Ph), 138.3 (1C, d, J 13.0, i-CO; Ar), 128.8, 127.6 and
127.4 (3 ꢂ CH; Ph), 127.0 (1C, d, J 7.1, CH; Ar), 124.3 (1C, d, J 4.0,
CH; Ar), 123.6 (CH; Ar), 116.6 (1C, d, J 19.1, CH; Ar), 45.4 (PhCHCH3)
and 18.7 (PhCHCH3) (Found MNH4þ, 262.1240. C15H17FNO2 re-
quires MNH4þ, 262.1238).
4.3. General procedure for the mutual kinetic resolutions of
active esters (rac)-14–21 using oxazolidin-2-one (rac)-1
At first, n-BuLi (0.44 ml, 2.5 M in hexane, 1.1 mmol) was added
to
a stirred solution of oxazolidin-2-one (rac)-1 (0.163 g,
1.0 mmol) in THF (5 ml) at ꢀ78 °C. After stirring for 1 h, a solution
of the given active ester (rac)-14–21 (1.1 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 ꢂ 10 ml), dried (over MgSO4)
and evaporated under reduced pressure to give a separable mix-
ture of two diastereoisomeric oxazolidin-2-ones syn- and anti-4.
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 oxazolidin-2-ones syn- and anti-4 as white
needle-like crystals.
Characterisation data for: (4RS)-4-phenyl-3-(2SR-phenylpropa-
noyl)oxazolidin-2-one (rac)-syn-4; white solid; mp 124–126 °C;
RF [light petroleum (bp 40–60 °C)/diethyl ether (1:1)] 0.42; mmax
(CHCl3); cmꢀ1 1778 (C@O) and 1701 (C@O); dH (400 MHz; CDCl3)
7.29–7.21 (10H, m, 10 ꢂ CH; 2 ꢂ 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, CHAHBO),
4.08 (1H, dd, J 9.0 and 5.1, CHAHBO) and 1.39 (3H, d, J 6.9,
4.3.2. 2-Chlorophenyl 2-phenylpropanoate (rac)-54
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-16 (1.02 g, 6.77 mmol), DCC (1.57 g, 7.59 mmol) and 2-
chlorophenol 23 (0.87 g, 0.70 mL, 6.77 mmol) gave, 2-chlorophenyl
2-phenylpropanoate (rac)-54 (1.54 g, 87%) as a colourless oil; RF
[light petroleum (40–60 °C)/diethyl ether (9:1)] 0.26; mmax (film)
cmꢀ1 1763 (C@O); dH (400 MHz; CDCl3) 7.45–7.11 (8H, m,
8 ꢂ CH; Ph and Ar), 7.02 (1H, dd, J 7.9 and 1.7, 1 ꢂ CH; Ph or Ar),
4.03 (1H, q, J 7.2, PhCHCH3) and 1.66 (3H, d, J 7.2, PhCHCH3); dC
(100 MHz; CDCl3) 172.1 (C@O), 147.1 (i-CO; Ar), 139.6 (i-CC; Ph),
127.4 (i-CCl; Ar), 130.3, 128.8, 128.5, 127.8, 127.6, 126.9 and
123.0 (7 ꢂ CH; Ph and Ar), 45.5 (PhCHCH3) and 18.5 (PhCHCH3)
þ
þ
(Found MNH4
278.0942).
,
278.0941. C15H17ClNO2 requires MNH4 ,

428
N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
4.3.3. 2-Bromophenyl 2-phenylpropanoate (rac)-55
4.3.7. 4-Chlorophenyl 2-phenylpropanoate (rac)-59
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.00 g, 6.66 mmol), DCC (1.52 g, 7.34 mmol) and 2-
bromophenol 24 (1.16 g, 6.71 mmol) gave, 2-bromophenyl 2-phe-
nylpropanoate (rac)-55 (1.62 g, 80%) as a colourless oil; RF [light
petroleum (40–60 °C)/diethyl ether (9:1)] 0.29; mmax (film) cmꢀ1
1750 (C@O); dH (400 MHz; CDCl3) 7.55 (1H, dd, J 7.9 and 1.5,
1 ꢂ CH, Ar), 7.46–7.18 (6H, m, 6 ꢂ CH, Ph and Ar), 7.07 (1H, td, J
7.9 and 1.5, 1 ꢂ CH; Ar), 7.01 (1H, dd, J 7.9 and 1.5, 1 ꢂ CH; Ar),
4.03 (1H, q, J 7.2, PhCHCH3) and 1.67 (3H, d, J 7.2, PhCHCH3); dC
(100 MHz; CDCl3) 172.1 (C@O), 148.2 (i-CO; Ar), 139.6 (i-CC; Ph),
116.1 (i-CBr; Ar), 133.4, 128.9, 128.3, 127.8, 127.5, 127.2 and
123.6 (7 ꢂ CH; Ph and Ar), 45.6 (PhCHCH3) and 18.5 (PhCHCH3)
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.01 g, 6.71 mmol), DCC (1.53 g, 7.43 mmol) and 4-
chlorophenol 28 (1.11 g, 8.64 mmol) gave, 4-chlorophenyl 2-
phenylpropanoate (rac)-59 (1.60 g, 91%) as a colourless oil; RF
[light petroleum (40–60 °C)/diethyl ether (9:1)] 0.38; mmax (film)
cmꢀ1 1756 (C@O); dH (400 MHz; CDCl3) 7.38–7.21 (7H, m,
7 ꢂ CH; Ph and Ar), 6.92 (2H, dt, J 8.9 and 2.2, 2 ꢂ CH; Ar), 3.94
(1H, q, J 7.2, PhCHCH3) and 1.60 (3H, d, J 7.2, PhCHCH3); dC
(100 MHz; CDCl3) 172.8 (C@O), 149.3 (i-CO; Ar), 139.8 (i-CC; Ph),
131.2 (i-CCl; Ar), 129.4, 128.9, 128.6, 127.5 and 122.8 (5 ꢂ CH;
þ
Ph and Ar), 45.6 (PhCHCH3) and 18.5 (PhCHCH3) (Found MNH4
,
278.0941. C15H17ClNO2 requires MNH4þ, 278.0942).
þ
þ
(Found MNH4
322.0437).
,
322.0435. C15H17BrNO2 requires MNH4 ,
4.3.8. 4-Bromophenyl 2-phenylpropanoate (rac)-60
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.01 g, 6.73 mmol), DCC (1.54 g, 7.46 mmol) and 4-
bromophenol 29 (1.19 g, 6.85 mmol) gave, 4-bromophenyl 2-
phenylpropanoate (rac)-60 (1.79 g, 87%) as a colourless oil; RF
[light petroleum (40–60 °C)/diethyl ether (9:1)] 0.39; mmax (film)
cmꢀ1 1750 (C@O); dH (400 MHz; CDCl3) 7.46–7.21 (7H, m,
7 ꢂ CH; Ph and Ar), 6.87 (2H, dt, J 8.7 and 2.0, 2 ꢂ CH; Ar), 3.94
(1H, q, J 7.2, PhCHCH3) and 1.60 (3H, d, J 7.2, PhCHCH3); dC
(100 MHz; CDCl3) 172.7 (C@O), 149.8 (i-CO; Ar), 139.8 (i-CC; Ph),
4.3.4. 3-Fluorophenyl 2-phenylpropanoate (rac)-56
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.50 g, 9.88 mmol), DCC (2.26 g, 10.86 mmol) and 3-
fluorophenol 25 (1.10 g, 0.91 mL, 9.88 mmol) gave, 3-fluorophenyl
2-phenyl-propanoate (rac)-56 (1.73 g, 72%) as a colourless oil; RF
[light petroleum (40–60 °C)/diethyl ether (1:1)] 0.61; mmax (CH2Cl2)
cmꢀ1 1760 (C@O); dH (400 MHz; CDCl3) 7.42–7.35 (3H, m, 3 ꢂ CH;
Ph), 7.32–7.27 (3H, m, 3 ꢂ CH; Ar and Ph), 6.95 (1H, td, J 8.2 and
2.4, CH; Ar), 6.82 (1H, br d, J 8.2, CH; Ar), 6.78 (1H, dt, J 8.2 and
2.4, CH; Ar), 3.97 (1H, q, J 7.1, PhCHCH3) and 1.63 (3H, d, J 7.1,
PhCHCH3); dC (100 MHz; CDCl3) 172.6 (C@O), 162.7 (1C, d,
118.8 (i-CBr; Ar), 132.2, 128.8, 128.6, 127.5 and 123.2 (5 ꢂ CH;
þ
Ph and Ar), 45.6 (PhCHCH3) and 18.5 (PhCHCH3) (Found MNH4
,
322.0438. C15H17BrNO2 requires MNH4þ, 322.0437).
3
1JC,F = 245.9, i-CF; Ar), 151.5 (1C, d, JC,F = 10.7, i-CO; Ar), 139.7
3
(i-C; Ph), 130.0 (1C, d, JC,F = 9.1, CH; Ar), 128.82 and 127.43
4.3.9. 2,3-Dichlorophenyl 2-phenylpropanoate (rac)-61
4
(5 ꢂ CH; Ph), 117.1 (1C, d, JC,F = 3.8, CH; Ar), 112.7 (1C, d,
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.22 g, 8.12 mmol), DCC (1.84 g, 8.93 mmol) and 2,3-
dichlorophenol 30 (1.32 g, 8.12 mmol) gave, 2,3-dichlorophenyl
2-phenylpropanoate (rac)-61 (1.59 g, 67%) as a colourless oil; RF
[light petroleum (40–60 °C)/diethyl ether (9:1)] 0.51; mmax (film)
cmꢀ1 1763 (C@O); dH (400 MHz; CDCl3) 7.45–7.30 (6H, m,
6 ꢂ CH; Ph and Ar), 7.17 (1H, t, J 8.1, CH; Ar), 6.96 (1H, dd, J 8.2
and 1.5, CH; Ar), 4.05 (1H, q, J 7.2, PhCHCH3) and 1.68 (3H, d, J
7.2, PhCHCH3); dC (100 MHz; CDCl3) 171.7 (C@O), 148.2 (i-CO;
Ar), 139.2 (i-CC; Ph), 133.8 (i-CCl; Ar), 128.7,2 127.8,1 127.7,2
127.5,1 127.31 and 121.71 (8 ꢂ CH; Ar and Ph), 126.4 (i-CCl; Ar),
45.4 (PhCHCH3) and 18.4 (PhCHCH3) (Found MNH4þ, 312.0555
2
2JC,F = 20.6, CH; Ar), 109.4 (1C, d, JC,F = 24.4, CH; Ar), 45.5
(PhCHCH3) and 18.4 (PhCHCH3); dF (378 MHz; CDCl3) ꢀ111.0 (1F,
s, CF) (Found MNH4þ, 262.1240. C15H17FNO2 requires MNH4
262.1240).
,
þ
4.3.5. 3-Chlorophenyl 2-phenylpropanoate (rac)-57
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.50 g, 9.98 mmol), DCC (2.26 g, 10.86 mmol) and 3-
chlorophenol 26 (1.28 g, 9.98 mmol) gave, 3-chlorophenyl 2-
phenyl-propanoate (rac)-57 (1.58 g, 61%) as a colourless oil; RF
[light petroleum (40–60 °C)/diethyl ether (1:1)] 0.55; mmax (CH2Cl2)
cmꢀ1 1758 (C@O); dH (400 MHz; CDCl3) 7.42–7.38 (3H, m, 3 ꢂ CH;
Ph), 7.36–7.32 (2H, m, 2 ꢂ CH; Ph), 7.27 (1H, t, J 8.1, CH; Ar), 7.20
(1H, ddd, J 8.1, 2.4 and 1.2, CH; Ar), 7.05 (1H, t, J 2.4, CH; Ar), 6.92
(1H, ddd, J 8.1, 2.4 and 2.1, CH; Ar), 3.97 (1H, q, J 7.1, PhCHCH3) and
1.63 (3H, d, J 7.1, PhCHCH3); dC (100 MHz; CDCl3) 172.5 (C@O),
151.2 (i-CO; Ar), 139.6 (i-C; Ph), 134.5 (i-CCl; Ar), 130.0, 126.0,
C
15H16Cl2NO2 requires MNH4þ, 312.0553).
4.3.10. 2,4-Dichlorophenyl 2-phenylpropanoate (rac)-62
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (5.01 g, 33.36 mmol), DCC (7.58 g, 36.72 mmol) and
2,4-dichlorophenol 31 (5.45 g, 33.44 mmol) gave, 2,4-dichloro-
phenyl 2-phenylpropanoate (rac)-62 (9.01 g, 92%) as a colourless
oil; RF [light petroleum (40–60 °C)/diethyl ether (9:1)] 0.35; mmax
(film) cmꢀ1 1762 (C@O); dH (400 MHz; CDCl3) 7.43–7.26 (6H, m,
6 ꢂ CH; Ph and Ar), 7.20 (1H, dd, J 8.4 and 2.5, 1 ꢂ CH; Ar), 6.96
(1H, d, J 8.4, 1 ꢂ CH; Ar), 4.01 (1H, q, J 7.2, PhCHCH3) and 1.65
(3H, d, J 7.2, PhCHCH3); dC (100 MHz; CDCl3) 172.3 (C@O); 146.1
(i-CO; Ar), 139.7 (i-CC; Ph), 132.2 and 128.2 (2 ꢂ i-CCl; Ar), 130.4,
122.0 and 119.7 (4 ꢂ CH; Ar), 128.8,2 127.5,1 and 127.42 (5 ꢂ CH;
þ
Ph), 45.3 (PhCHCH3) and 18.4 (PhCHCH3) (Found MNH4
,
278.0942 C15H17ClNO2 requires MNH4þ, 278.0946).
4.3.6. 4-Fluorophenyl 2-phenylpropanoate (rac)-58
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.02 g, 6.76 mmol), DCC (1.54 g, 7.48 mmol) and 4-
fluorophenol 27 (0.77 g, 6.83 mmol) gave, 4-fluorophenyl 2-
phenylpropanoate (rac)-58 (1.38 g, 84%) as a colourless oil; RF
[light petroleum (40–60 °C)/diethyl ether (9:1)] 0.31; mmax (film)
cmꢀ1 1755 (C@O); dH (400 MHz; CDCl3) 7.40–7.26 (5H, m,
5 ꢂ CH; Ph and Ar), 7.05–6.91 (4H, m, 4 ꢂ CH; Ph and Ar), 3.94
(1H, q, J 7.2, PhCHCH3) and 1.60 (3H, d, J 7.2, PhCHCH3); dC
(100 MHz; CDCl3) 173.1 (C@O), 160.2 (1C, d, J 244.4, i-CF; Ar),
146.6 (i-CO; Ar), 139.9 (i-CC; Ph), 128.8, 127.5 and 127.4
(3 ꢂ CH; Ph), 122.8 (1C, d, J 9.0, CH; Ar), 116.0 (1C, d, J 23.1, CH),
129.1, 128.3, 128.1, 129.9 and 124.8 (6 ꢂ CH; Ph and Ar), 45.8
þ
(PhCHCH3) and 18.8 (PhCHCH3) (Found MNH4
C
, 312.0553.
15H16Cl2NO2 requires MNH4þ, 312.0553).
4.3.11. 2,5-Dichlorophenyl 2-phenylpropanoate (rac)-63
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (2.01 g, 13.41 mmol), DCC (3.08 g, 14.91 mmol) and
2,5-dichlorophenol 32 (2.20 g, 13.48 mmol) gave, 2,5-dichloro-
phenyl 2-phenylpropanoate (rac)-63 (3.44 g, 87%) as a colourless
oil; RF [light petroleum (40–60 °C)/diethyl ether (9:1)] 0.41; mmax
(film) cmꢀ1 1767 (C@O); dH (400 MHz; CDCl3) 7.43–7.25 (6H, m,
6 ꢂ CH; Ph and Ar), 7.14 (1H, dd, J 8.7 and 2.5, 1 ꢂ CH; Ar), 7.05
45.6 (PhCHCH3) and 18.5 (PhCHCH3) (Found MNH4þ, 262.1240.
þ
C
15H17FNO2 requires MNH4 262.1238).

N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
429
(1H, d, J 2.5, 1 ꢂ CH; Ar), 4.02 (1H, q, J 7.2, PhCHCH3) and 1.66 (3H,
d, J 7.2, PhCHCH3); dC (100 MHz; CDCl3) 172.1 (C@O), 147.8 (i-OC;
Ar), 139.7 (i-CC; Ph), 133.2 and 126.0 (2 ꢂ i-CCl; Ar), 131.2, 129.2,
128.1, 128.0, 127.5 and 124.5 (6 ꢂ CH; Ph and Ar), 45.8 (PhCHCH3)
and 18.8 (PhCHCH3) (Found MNH4þ, 312.0554. C15H16Cl2NO2 re-
quires MNH4þ, 312.0553).
4.3.16. 2,4,6-Trichlorophenyl 2-phenylpropanoate (rac)-68
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (4.02 g, 26.77 mmol), DCC (6.13 g, 29.71 mmol) and
2,4,6-trichlorophenol 37 (5.29 g, 26.81 mmol) gave, 2,4,6-trichlor-
ophenyl 2-phenylpropanoate (rac)-68 (5.66 g, 64%) as a colourless
oil; RF [light petroleum (40–60 °C)/diethyl ether (9:1)] 0.53; mmax
(film) cmꢀ1 1769 (C@O); dH (400 MHz; CDCl3) 7.44–7.25 (7H, m,
7 ꢂ CH; Ph and Ar), 4.07 (1H, q, J 7.2, PhCHCH3) and 1.68 (3H, d, J
7.2, PhCHCH3); dC (100 MHz; CDCl3) 170.7 (C@O), 142.9 (i-CO;
Ar), 138.9 (i-CC; Ph), 131.1 and 129.6 (2 ꢂ i-CCl; Ar), 128.7,
4.3.12. 2,6-Dichlorophenyl 2-phenylpropanoate (rac)-64
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (2.01 g, 13.38 mmol), DCC (3.04 g, 14.73 mmol) and
2,6-dichlorophenol 33 (2.20 g, 13.48 mmol) gave, 2,6-dichloro-
phenyl 2-phenylpropanoate (rac)-64 (3.33 g, 84%) as a colourless
oil; RF [light petroleum (40–60 °C)/diethyl ether (9:1)] 0.33; mmax
(film) cmꢀ1 1771 (C@O); dH (400 MHz; CDCl3) 7.46 (2H, dd, J 8.2
and 1.2, 2 ꢂ CH; Ar), 7.37 (2H, td, J 7.1 and 2.2, 2 ꢂ CH; Ph),
7.33–7.28 (3H, m, 3 ꢂ CH; Ph), 7.08 (1H, td, 8.2 and 1.2, CH; Ar),
4.09 (1H, q, J 7.2, PhCHCH3) and 1.70 (3H, d, J 7.2, PhCHCH3); dC
(100 MHz; CDCl3) 171.2 (C@O), 144.4 (i-CO; Ar), 139.5 (i-CC; Ph),
128.5, 127.9 and 127.6 (4 ꢂ CH; Ar), 45.2 (PhCHCH3) and 18.3
þ
(PhCHCH3) (Found MNH4
, 346.0166. C15H15Cl3NO2 requires
MNH4þ, 346.0163).
4.3.17. Phenyl 2-phenylpropanoate (rac)-69
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.02 g, 6.80 mmol), DCC (1.57 g, 7.60 mmol) and phe-
nol 38 (0.67 g, 7.12 mmol), gave phenyl 2-phenylpropanoate (rac)-
69 (1.16 g, 76%) as colourless cubic crystals; RF [light petroleum
(40–60 °C)/diethyl ether (9:1)] 0.21; mp 34–42 °C; mmax (CHCl3)
cmꢀ1 1751 (C@O); dH (400 MHz; CDCl3) 7.41–7.25 (7H, m,
7 ꢂ CH; 2 ꢂ Ph), 7.18 (1H, t, J 7.2, 1 ꢂ CH; Ph), 6.98 (2H, d, J 7.2,
2 ꢂ CH; Ph), 3.96 (1H, q, J 7.2, PhCHCH3) and 1.61 (3H, d, J 7.2,
PhCHCH3); dC (100 MHz; CDCl3) 173.0 (C@O), 150.9 (i-CO; Ph),
140.1 (i-CC; Ph), 129.3, 128.8, 127.6, 127.4, 125.8 and 121.4 (6
ꢂCH; 2 ꢂ Ph), 45.7 (PhCHCH3) and 18.6 (PhCHCH3) (Found
MNH4þ, 244.1322. C15H18NO2 requires MNH4þ, 244.1332).
129.4 (i-CCl; Ar), 129.0, 128.6, 128.3, 127.9 and 127.4 (5 ꢂ CH;
þ
Ph and Ar), 45.7 (PhCHCH3) and 18.8 (PhCHCH3) (Found MNH4
,
312.0549. C15H14Cl2NO2 requires MNH4þ, 312.0533).
4.3.13. 3,4-Dichlorophenyl 2-phenylpropanoate (rac)-65
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.53 g, 10.2 mmol), DCC (2.31 g, 11.2 mmol) and 3,4-
dichlorophenol 34 (1.66 g, 10.2 mmol) gave, 3,4-dichlorophenyl
2-phenylpropanoate (rac)-65 (2.00 g, 67%) as a colourless oil; RF
[light petroleum (40–60 °C)/diethyl ether (9:1)] 0.67; mmax (CH2Cl2)
cmꢀ1 1760 (C@O); dH (400 MHz; CDCl3) 7.40–7.36 (6H, m, 6 ꢂ CH;
Ar and Ph), 7.14 (1H, d, J 2.5, CH; Ar), 7.14 (1H, dd, J 8.8 and 2.5, CH;
Ar), 3.93 (1H, q, J 7.2, PhCHCH3) and 1.61 (3H, d, J 7.2, PhCHCH3); dC
(100 MHz; CDCl3) 172.4 (C@O), 149.3 (i-CO; Ar), 139.4 (i-CC; Ph),
132.8 (i-CCl; Ar), 129.6 (i-CCl; Ar), 128.9,2 127.5,1 and 127.42
(5 ꢂ CH; Ar), 130.5, 123.6 and 121.0 (3 ꢂ CH; Ar), 45.5 (PhCHCH3)
and 18.4 (PhCHCH3) (Found M(35Cl)+, 294.0209. C15H12Cl2O2 re-
quires M(35Cl)+, 294.0209).
4.3.18. Pentachlorophenyl 2-phenylpropanoate (rac)-70
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.5 g, 9.99 mmol), DCC (2.27 g, 10.9 mmol) and penta-
chlorophenol 39 (2.66 g, 9.99 mmol) gave, pentachlorophenyl 2-
phenylpropanoate (rac)-70 (1.19 g, 30%) as a white solid; RF [light
petroleum (40–60 °C)/diethyl ether (9:1)] 0.5; mp 64–66 °C; mmax
(CH2Cl2) cmꢀ1 1772 (C@O); dH (400 MHz; CDCl3) 7.37–7.28 (4H,
m, 4 ꢂ CH; Ph), 7.27–7.22 (1H, m, CH; Ph), 4.01 (1H, q, J 7.2,
PhCHCH3) and 1.61 (3H, d, J 7.2, PhCHCH3); dC (100 MHz; CDCl3)
170.2 (C@O), 144.0,2 131.82 and 131.41 (5 ꢂ CCl; Ar), 138.4 (i-CC;
Ph), 128.7,2 127.92 and 127.81 (5 ꢂ CH; Ph), 127.7 (i-CO; Ar), 45.2
(PhCHCH3) and 18.2 (PhCHCH3) (Found M(35Cl)+, 395.9035.
C15H9Cl5O2 requires M(35Cl)+, 395.9040).
4.3.14. 3,5-Dichlorophenyl 2-phenylpropanoate (rac)-66
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.5 g, 9.99 mmol), DCC (2.27 g, 10.9 mmol) and 3,5-
dichlorophenol 35 (1.63 g, 9.99 mmol) gave, 3,5-dichlorophenyl
2-phenylpropanoate (rac)-66 (1.52 g, 52%) as a colourless oil; RF
[light petroleum (40–60 °C)/diethyl ether (9:1)] 0.47;
mmax (CH2Cl2)
4.3.19. Phenylthio 2-phenylpropanoate (rac)-71
cmꢀ1 1766 (C@O); dH (400 MHz; CDCl3) 7.42–7.35 (4H, m, 4 ꢂ CH;
Ph), 7.35–7.30 (1H, m, CH; Ph), 7.21 (1H, t, J 1.8, CH; Ar), 6.95 (2H,
d, J 1.8, 2 ꢂ CH; Ar), 3.95 (1H, q, J 7.2, PhCHCH3) and 1.60 (3H, d, J
7.2, PhCHCH3); dC (100 MHz; CDCl3) 172.1 (C@O), 151.4 (i-CO; Ar),
139.7 (i-CC; Ph), 135.02 (2 ꢂ CCl; Ar), 128.9,2 127.42 and 126.21
(5 ꢂ CH; Ph), 127.61 and 120.62 (3 ꢂ CH; Ar), 45.5 (PhCHCH3) and
18.3 (PhCHCH3) (Found M(35Cl)+, 294.0209. C15H12Cl2O2 requires
M(35Cl)+, 294.0209).
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.00 g, 6.67 mmol), DCC (1.52 g, 7.37 mmol) and thio-
phenol 40 (0.73 g, 0.68 mL, 6.63 mmol) gave, phenylthio 2-phenyl-
propanoate (rac)-71 (1.48 g, 92%) as a colourless oil; RF [light
petroleum (40–60 °C)/diethyl ether (9:1)] 0.38; mmax (film) cmꢀ1
1699 (C@O); dH (400 MHz; CDCl3) 7.39–7.26 (10H, m, 10 ꢂ CH;
2 ꢂ Ph), 4.00 (1H, q, J 7.2, PhCHCH3) and 1.57 (3H, d, J 7.2,
PhCHCH3); dC (100 MHz; CDCl3) 199.0 (C@O), 139.6 (i-CC; Ph),
134.4, 129.2, 128.7, 128.5, 128.0 and 127.6 (6 ꢂ CH; 2 ꢂ Ph),
127.7 (i-CS; SPh), 54.1 (PhCHCH3) and 18.7 (PhCHCH3) (Found
MNH4þ, 260.1104. C15H20NOS requires MNH4þ, 260.1104).
4.3.15. 2,4,5-Trichlorophenyl 2-phenylpropanoate (rac)-67
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.02 g, 6.76 mmol), DCC (1.55 g, 7.52 mmol) and 2,4,5-
trichlorophenol 36 (1.34 g, 6.80 mmol) gave, 2,4,5-trichlorophenyl
2-phenylpropanoate (rac)-67 (1.92 g, 86%) as a colourless oil; RF
[light petroleum (40–60 °C)/diethyl ether (9:1)] 0.31; mmax (film)
cmꢀ1 3100–2876 (aromatic, CH) and 1767 (C@O); dH (400 MHz;
CDCl3) 7.50 (1H, s, 1 ꢂ CH; Ar), 7.39–7.25 (5H, m, 5 ꢂ CH; Ph),
7.16 (1H, s, 1 ꢂ CH; Ar), 4.01 (1H, q, J 7.2, PhCHCH3) and 1.65
(3H, d, J 7.2, PhCHCH3); dC (100 MHz; CDCl3) 171.6 (C@O), 145.1
(i-CO; Ar), 139.1 (i-CC; Ph), 131.4, 130.5 and 126.2 (3 ꢂ i-CCl; Ar),
131.0, 128.8, 127.9, 127.6 and 125.2 (5 ꢂ CH; Ph and Ar), 45.4
4.3.20. Pentafluorothiophenyl 2-phenylpropanoate (rac)-72
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.00 g, 6.69 mmol), DCC (1.53 g, 7.43 mmol) and pen-
tafluorothiophenol 41 (1.34 g, 0.89 mL, 6.70 mmol) gave, pentaflu-
orothiophenyl 2-phenylpropanoate (rac)-72 (1.86 g, 84%) as a
colourless oil; RF [light petroleum (40–60 °C)/diethyl ether (9:1)]
0.54; mmax (film) cmꢀ1 1729 (C@O); dH (400 MHz; CDCl3) 7.41–
7.24 (5H, m, 5 ꢂ CH; Ph), 4.04 (1H, q, J 7.2, PhCHCH3) and 1.61
(3H, d, J 7.2, PhCHCH3); dC (100 MHz; CDCl3) 194.4 (C@O), 146.8
(PhCHCH3) and 18.4 (PhCHCH3) (Found M+
15H11Cl3O2 requires M+ 35Cl), 327.9819).
(
35Cl), 327.9825.
(148.09 and 145.62, 2C, ddt, JC,F = 246.4 Hz, JC,F = 11.5 Hz and
1
2
C
(
3JC,F = 4.5 Hz, C(2)-F), 142.6 (143.87 and 141.31, 1C, dtt,

430
N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
2
3
1JC,F = 256.0 Hz, JC,F = 13.7 Hz and JC,F = 5.3 Hz), C(4)-F), 138.2
br d, J 7.5, CH; Ar), 6.88–6.83 (2H, m, 2 ꢂ CH; Ar), 3.97 (1H, q, J 7.1,
PhCHCH3), 2.66 (2H, q, J 7.7, CH2CH3), 1.63 (3H, d, J 7.1, PhCHCH3)
and 1.23 (3H, t, J 7.7, CH2CH3); dC (100 MHz; CDCl3) 173.3 (C@O),
150.7 (i-CO; Ar), 145.8 (i-CC; Ar), 140.0 (i-C; Ph), 129.1, 125.3,
120.6 and 118.5 (4 ꢂ CH; Ar), 128.7,2 127.5,2 and 127.31 (5 ꢂ CH;
1
(i-CC; Ph), 137.7 (138.99 and 136.45, 2C, dtdd, JC,F = 253.6 Hz,
2JC,F = 12.9 Hz, JC,F = 4.5 and JC,F = 1.5 Hz, C(3)-F), 129.01 and
3
4
128.22 (3 ꢂ CH; Ph), 103.3 (1C, tt, , JF,F 22.1 and JF,F 5.3, i-CS;
3
4
Ar), 54.3 (PhCHCH3) and 18.2 (PhCHCH3); dF (378 MHz; CDCl3)
3
4
3
ꢀ130.7 (2F, dd, JF,F 20.9 and JF,F 4.6, Fortho), ꢀ149.3 (1F, tt, JF,F
Ph), 45.6 (PhCHCH3), 28.5 (CH2CH3), 18.5 (PhCHCH3) and 15.2
4
3
4
þ
20.9 and JF,F 4.6, Fpara) and ꢀ160.4 (2F, td, JF,F 20.9 and JF,F 4.6,
(CH2CH3) (Found MNH4þ, 272.1647 C17H22NO2 requires MNH4
,
þ
F
meta) (Found MNH4þ, 350.0640. C15H13F5NOS requires MNH4
272.1645).
350.0638).
4.3.25. 4-Ethylphenyl 2-phenylpropanoate (rac)-77
4.3.21. 4-Methylphenyl 2-phenylpropanoate (rac)-73
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.51 g, 10.0 mmol), DCC (2.28 g, 11.1 mmol) and
4-ethylphenol 46 (1.23 g, 10.0 mmol) gave, 4-ethylphenyl-2-phe-
nylpropanoate (rac)-77 (1.45 g, 57%) as a colourless oil; RF [light
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.01 g, 6.69 mmol), DCC (1.54 g, 7.45 mmol) and 4-
methylphenol 42 (0.72 g, 6.66 mmol) gave, 4-methylphenyl 2-
phenylpropanoate (rac)-73 (1.27 g, 80%) as a white solid; RF [light
petroleum (40–60 °C)/diethyl ether (9:1)] 0.30; mp 34–38 °C; mmax
(CH2Cl2) cmꢀ1 1751 (C@O); dH (400 MHz; CDCl3) 7.43–7.35 (4H, m,
4 ꢂ CH; Ph), 7.32–7.29 (1H, m, CH; Ph), 7.12 (2H, dt, J 8.4 and 2.1,
2 ꢂ CH; Ar), 6.87 (2H, dt, J 8.4 and 2.1, 2 ꢂ CH; Ar), 3.98 (1H, q, J 7.2,
PhCHCH3), 2.32 (3H, s, CH3; Ar) and 1.61 (3H, d, J 7.2, PhCHCH3); dC
(100 MHz; CDCl3) 173.2 (C@O), 148.5 (i-CO; Ar), 140.1 (i-CC; Ph),
135.3 (i-CC; Ar), 129.8, 128.7, 127.5, 127.2 and 120.9 (5 ꢂ CH; Ar
and Ph), 45.9 (PhCHCH3), 20.8 (CH3; Ar), and 18.5 (PhCHCH3)
petroleum (40–60 °C)/diethyl ether (8:2)] 0.53; m
max (CH2Cl2) cmꢀ1
1751 (C@O); dH (400 MHz; CDCl3) 7.44–7.36 (4H, m, 4 ꢂ CH; Ph),
7.35–7.29 (1H, m, CH; Ph), 7.17 (2H, dt, J 8.2 and 2.1, 2 ꢂ CH; Ar),
6.92 (2H, dt, J 8.2 and 2.1, 2 ꢂ CH; Ar), 3.97 (1H, q, J 7.2, PhCHCH3),
2.64 (2H, q, J 7.7, CH2Ar), 1.63 (3H, d, J 7.2, PhCHCH3) and 1.22 (3H,
d, J 7.7, CH2CH3); dC (100 MHz; CDCl3) 173.1 (C-O), 148.6 (i-CO;
Ar), 141.6 (i-CC; Ar), 140.1 (i-CC; Ph), 128.7,2 127.5,2 and 127.3,1
(5 ꢂ CH; Ph), 128.62 and 121.02 (4 ꢂ CH; Ar), 45.6 (PhCHCH3), 28.1
þ
(CH2), 18.4 (PhCHCH3) and 15.6 (CH3CH2) (Found MNH4
272.1644. C17H22NO2 requires MNH4 272.1645).
,
þ
þ
(Found MNH4þ, 285.1486. C16H20NO2 requires MNH4 258.1489).
4.3.22. 4-Methylthiophenyl 2-phenyl-propanoate (rac)-74
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.01 g, 6.71 mmol), DCC (1.72 g, 7.38 mmol) and 4-
methylthiophenol 43 (0.83 g, 6.71 mmol) gave, 4-methylthiophenyl
2-phenyl-propanoate (rac)-74 (1.19 g, 69%) as a yellow oil; RF [light
4.3.26. 4-Isopropylphenyl 2-phenylpropanoate (rac)-78
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.01 g, 6.73 mmol), DCC (1.53 g, 7.40 mmol) and 4-
isopropylphenol 47 (0.92 g, 6.73 mmol) gave, 4-isopropylphenyl
2-phenylpropanoate (rac)-78 (1.01 g, 56%) as a colourless oil; RF
petroleum (40–60 °C)/diethyl ether (8:2)] 0.45;
m
max (CH2Cl2) cmꢀ1
[light petroleum (40–60 °C)/diethyl ether (8:2)] 0.69; mmax (CH2Cl2)
1735 (C@O); dH (400 MHz; CDCl3) 7.39–7.35 (4H, m, 4 ꢂ CH; Ph),
7.34–7.29 (1H, m, CH; Ph), 7.25 (2H, dt, J 8.2 and 2.1, 2 ꢂ CH;
Ar), 7.19 (2H, br d, J 8.2, 2 ꢂ CH; Ar), 4.01 (1H, q, J 7.2, PhCHCH3),
2.36 (3H, s, CH3; Ar) and 1.58 (3H, d, J 7.2, PhCHCH3); dC
(100 MHz; CDCl3) 199.4 (C@O), 139.6 (i-CCH3; Ar), 139.5 (i-CC;
Ph), 134.72 and 129.82 (4 ꢂ CH; Ar), 128.7,2 128.02 and 127.51
(5 ꢂ CH; Ph), 124.2 (i-CS; Ar), 53.9 (PhCHCH3), 21.3 (CH3; Ar) and
18.7 (PhCHCH3) (Found MNH4þ, 274.1254. C16H20NOS requires
cmꢀ1 1751 (C@O); dH (400 MHz; CDCl3) 7.35–7.28 (4H, m, 4 ꢂ CH;
Ph), 7.25–7.19 (1H, m, CH; Ph), 7.10 (2H, dt, J 8.4 and 2.1, 2 ꢂ CH;
Ar), 6.83 (2H, dt, J 8.4 and 2.1, 2 ꢂ CH; Ar), 3.86 (1H, q, J 7.2,
PhCHCH3), 2.81 (1H, septet, J 7.0, CH(CH3)2), 1.54 (3H, d, J 7.2,
PhCHCH3) and 1.13 (6H, d, J 7.0, CH(CH3)2); dC (100 MHz; CDCl3)
173.2 (C@O), 148.7 (i-CO; Ar), 146.3 (i-CC; Ar), 140.1 (i-CC; Ph),
128.7,2 127.52 and 127.31 (5 ꢂ CH; Ph), 127.22 and 120.92
(4 ꢂ CH; Ar), 45.5 (PhCHCH3), 33.5 (CH(CH3)2), 24.0 (CH(CH3)2)
and 18.5 (PhCHCH3) (Found MNH4þ, 286.1800. C18H24NO2 requires
þ
MNH4 274.1260).
þ
MNH4 286.1802).
4.3.23. 2-Ethylphenyl 2-phenylpropanoate (rac)-75
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.41 g, 9.36 mmol), DCC (2.12 g, 10.29 mmol) and 2-
ethylphenol 44 (1.14 g, 1.10 ml, 9.36 mmol) gave, 2-ethylphenyl
2-phenylpropanoate (rac)-75 (1.27 g, 53%) as a colourless oil; RF
4.3.27. 2-Methoxyphenyl 2-phenylpropanoate (rac)-79
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (2.01 g, 13.39 mmol), DCC (7.57 g, 36.55 mmol) and 2-
methoxyphenol 48 (1.67 g, 6.65 mmol) gave, 2-methoxyphenyl 2-
phenylpropanoate (rac)-79 (2.39 g, 70%) as a colourless oil; RF
[light petroleum (40–60 °C)/diethyl ether (7:3)] 0.5; mmax (film)
cmꢀ1 1723 (C@O); dH (400 MHz; CDCl3) 7.45 (2H, dt, J 7.3 and
1.6, 2 ꢂ CH; Ph), 7.38 (2H, tt, J 7.3 and 1.6, 2 ꢂ CH; Ph), 7.32 (1H,
tt, J 7.3 and 1.6, CH; Ph), 7.18 (1H, m, CH; Ar), 6.96–6.88 (3H, m,
3 ꢂ CH; Ar), 4.01 (1H, q, J 7.2, PhCHCH3), 3.72 (3H, s, OCH3) and
1.64 (3H, d, J 7.2, PhCHCH3); dC (100 MHz; CDCl3) 172.6 (C@O),
151.1 (i-COCH3; Ar), 140.2 (i-CO; Ar) and 139.9 (i-CC; Ar), 128.5,
127.7 and 127.1 (3 ꢂ CH; Ph), 126.7, 122.5, 120.6 and 112.4
(4 ꢂ CH; Ar), 55.7 (OCH3), 45.3 (PhCHCH3), 18.7 (PhCHCH3) (Found
MNH4þ, 274.1440. C16H20NO requires MNH4þ, 274.1438).
[light petroleum (40–60 °C)/diethyl ether (1:1)] 0.82; mmax (CH2Cl2)
cmꢀ1 1756 (C@O); dH (400 MHz; CDCl3) 7.48–7.36 (4H, m, 4 ꢂ CH;
Ph), 7.34–7.29 (1H, m, CH; Ph), 7.22–7.14 (3H, m, 3 ꢂ CH; Ar), 6.94
(1H, br dd, J 7.7 and 1.8, CH; Ar), 4.01 (1H, q, J 7.1, PhCHCH3), 2.29
(1H, q, J 7.5, CHAHBCH3), 2.28 (1H, q, J 7.5, CHAHBCH3), 1.67 (3H, d, J
7.1, PhCHCH3) and 0.97 (3H, t, J 7.5, CH2CH3); dC (100 MHz; CDCl3)
172.9 (C@O), 148.7 (i-CO; Ar), 139.9 (i-C; Ph), 135.9 (i-C; Ar), 129.4,
126.7, 126.0 and 121.9 (4 ꢂ CH; Ar), 128.8,2 127.6,2 and 127.31
(5 ꢂ CH; Ph), 45.6 (PhCH), 23.0 (CH2Ar), 18.1 (CHCH3) and 14.2
þ
(CH2CH3) (Found MNH4þ, 272.1647 C17H22NO2 requires MNH4
,
272.1647).
4.3.24. 3-Ethylphenyl 2-phenylpropanoate (rac)-76
4.3.28. 4-Methoxyphenyl 2-phenylpropanoate (rac)-80
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.07 g, 7.10 mmol), DCC (1.61 g, 7.81 mmol) and 3-
ethylphenol 45 (0.89 g, 0.87 ml, 7.10 mmol) gave, 3-ethylphenyl
2-phenylpropanoate (rac)-76 (1.18 g, 65%) as a colourless oil; RF
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.01 g, 6.73 mmol), DCC (1.53 g, 7.40 mmol) and 4-
methoxyphenol 49 (0.85 g, 6.73 mmol) gave, 4-methoxyphenyl 2-
phenylpropanoate (rac)-80 (1.06 g, 62%) as a colourless oil; RF
[light petroleum (40–60 °C)/diethyl ether (1:1)] 0.54;
mmax (CH2Cl2)
[light petroleum (40–60 °C)/diethyl ether (8:2)] 0.34; mmax (CH2Cl2)
cmꢀ1 1755 (C@O); dH (400 MHz; CDCl3) 7.47–7.38 (4H, m, 4 ꢂ CH;
Ph), 7.36–7.31 (1H, m, CH; Ph), 7.27 (1H, t, J 7.8, CH; Ar), 7.07 (1H,
cmꢀ1 1751 (C@O); dH (400 MHz; CDCl3) 7.42–7.34 (4H, m, 4 ꢂ CH;
Ph), 7.32–7.27 (1H, m, CH; Ph), 6.90 (2H, dt, J 9.3 and 3.1, 2 ꢂ CH;

N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
431
Ar), 6.82 (2H, dt, J 9.3 and 3.1, 2 ꢂ CH; Ar), 3.94 (1H, q, J 7.2,
PhCHCH3), 3.76 (3H, s, CH3O; Ar) and 1.59 (3H, d, J 7.2, PhCHCH3);
dC (100 MHz; CDCl3) 173.4 (C@O), 157.1 (i-CO; Ar), 144.2 (i-CO;
Ar), 140.1 (i-CC; Ph), 128.7,2 127.52 and 127.21 (5 ꢂ CH; Ph),
122.02 and 114.32 (4 ꢂ CH; Ar), 55.5 (OCH3), 45.5 (PhCHCH3) and
18.5 (PhCHCH3) (Found MNH4þ, 274.1435. C16H20NO3 requires
Ar), 128.92, 127.81 and 127.72 (5 ꢂ CH; Ph), 123.72 (2 ꢂ CH; Ar),
45.4 (PhCHCH3), 17.82 (2 ꢂ CH3; Ar) and 16.2 (PhCHCH3) (Found
MNH4þ, 317.1489. C17H21N2O4 requires MNH4þ, 317.1496).
4.4. General procedure for the mutual kinetic resolutions of
active esters (rac)-53–83 using oxazolidin-2-one (rac)-1 at
ꢀ78 °C for 2 h
þ
MNH4 274.1438).
4.3.29. 4-Methoxyphenyl 2-phenylpropanoate (R)-80
At first, n-BuLi (0.44 mL, 2.5 M in hexane, 1.1 mmol) was added
to a stirred solution of oxazolidin-2-one (rac)-1 (0.163 g, 1.0 mmol)
in THF (5 mL) at ꢀ78 °C. After stirring for 1 h, a solution of given
active ester (rac)-53–83 (1.1 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 ꢂ 10 mL), dried (over MgSO4) and evaporated
under reduced pressure to give a separable mixture of two diaste-
reoisomeric oxazolidin-2-ones syn- and anti-4. 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
oxazolidin-2-ones syn- and anti-4 as white needle-like crystals.
Active ester (rac)-53, gave a mixture (95:5) of oxazolidin-2-ones
syn- and anti-4 (0.115 g, 39%).
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (R)-6 (0.30 g, 2.00 mmol), DCC (0.45 g, 2.20 mmol) and 4-
methoxyphenol 48 (0.25 g, 2.00 mmol) gave, 4-methoxyphenyl 2-
phenylpropanoate (R)-80 (0.28 g, 55%) as a white solid; RF [light
petroleum (40–60 °C)/diethyl ether (1:1)] 0.49; ½a D25
¼ ꢀ103:2 (c
ꢃ
0.5, CHCl3); mp 54–56 °C; mmax (CH2Cl2) cmꢀ1 1751 (C@O); dH
(400 MHz; CDCl3) 7.42–7.34 (4H, m, 4 ꢂ CH; Ph), 7.32–7.27 (1H,
m, CH; Ph), 6.90 (2H, dt, J 9.3 and 3.1, 2 ꢂ CH; Ar), 6.82 (2H, dt, J
9.3 and 3.1, 2 ꢂ CH; Ar), 3.94 (1H, q, J 7.2, PhCHCH3), 3.76 (3H, s,
CH3O; Ar) and 1.59 (3H, d, J 7.2, PhCHCH3); dC (100 MHz; CDCl3)
173.4 (C@O), 157.1 (i-CO; Ar), 144.2 (i-CO; Ar), 140.1 (i-CC; Ph),
128.7,2 127.52 and 127.21 (5 ꢂ CH; Ph), 122.02 and 114.32
(4 ꢂ CH; Ar), 55.5 (OCH3), 45.5 (PhCH) and 18.5 (CHCH3) (Found
þ
MNH4þ, 274.1437. C16H20NO3 requires MNH4 274.1438).
Active ester (rac)-54, gave a mixture (98:2) of oxazolidin-2-ones
syn- and anti-4 (0.106 g, 36%).
4.3.30. Biphenyl-4-yl 2-phenyl-propanoate (rac)-81
Active ester (rac)-55, gave a mixture (96:4) of oxazolidin-2-ones
syn- and anti-4 (89 mg, 30%).
Active ester (rac)-56, gave a mixture (98:2) of oxazolidin-2-ones
syn- and anti-4 (0.165 g, 56%).
Active ester (rac)-57, gave a mixture (98:2) of oxazolidin-2-ones
syn- and anti-4 (0.197 g, 67%).
Active ester (rac)-58, gave a mixture (95:5) of oxazolidin-2-ones
syn- and anti-4 (0.115 g, 39%).
Active ester (rac)-59, gave a mixture (95:5) of oxazolidin-2-ones
syn- and anti-4 (0.114 g, 39%).
Active ester (rac)-60, gave a mixture (95:5) of oxazolidin-2-ones
syn- and anti-4 (0.100 g, 34%).
Active ester (rac)-61, gave a mixture (98:2) of oxazolidin-2-ones
syn- and anti-4 (0.132 g, 45%).
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.00 g, 6.67 mmol), DCC (1.51 g, 7.34 mmol) and
biphenyl-4-ol 50 (1.14 g, 6.67 mmol) gave, biphenyl-4-yl 2-
phenyl-propanoate (rac)-81 (1.29 g, 64%) as a white solid; RF [light
petroleum (40–60 °C)/diethyl ether (8:2)] 0.53; mp 50–52 °C; mmax
(CH2Cl2) cmꢀ1 1734 (C@O); dH (400 MHz; CDCl3) 7.56–7.52 (4H, m,
4 ꢂ CH; PhA), 7.45–7.28 (8H, m, CH; Ar, PhA and PhB), 7.08 (2H, dt, J
8.8 and 2.7, 2 ꢂ CH; Ar), 3.98 (1H, q, J 7.2, PhCHCH3) and 1.59 (3H,
d, J 7.2, PhCHCH3); dC (100 MHz; CDCl3) 173.1 (C@O), 150.2 (i-CO;
Ar), 140.3, 140.0 and 138.9 (3 ꢂ i-CC; Ar, PhA, and PhB), 128.8,2
128.7,2 128.0,2 127.5,2 127.4,1 127.31 and 127.02 (12 ꢂ CH; PhA,
and PhB), 121.62 (2 ꢂ CH; Ar), 45.6 (PhCHCH3) and 18.5 (PhCHCH3)
þ
(Found MNH4þ, 320.1647. C21H22NO2 requires MNH4 320.1645).
Active ester (rac)-62, gave a mixture (98:2) of oxazolidin-2-ones
syn- and anti-4 (0.144 g, 49%).
4.3.31. 2,6-Dimethylphenyl 2-phenylpropanoate (rac)-82
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.01 g, 6.70 mmol), DCC (1.53 g, 7.42 mmol) and 2,6-
dimethylphenol 51 (0.82 g, 6.72 mmol) gave, 2,6-dimethylphenyl
2-phenylpropanoate (rac)-82 (0.73 g, 43%) as colourless cubic crys-
tals; RF [light petroleum (40–60 °C)/diethyl ether (9:1)] 0.39; mp
48–52 °C; mmax (CHCl3) cmꢀ1 3100–2800 (aromatic, CH) and 1751
(C@O); dH (400 MHz; CDCl3) 7.46–7.24 (5H, m, 5 ꢂ CH; Ph and/or
Ar), 6.98 (3H, s, 3 ꢂ CH; Ph and/or Ar), 4.02 (1H, q, J 7.2, PhCHCH3),
1.92 (6H, s, 2 ꢂ CH3; Ar) and 1.67 (3H, d, J 7.2, PhCHCH3); dC
(100 MHz; CDCl3) 172.1 (C@O), 148.0 (i-CO; Ar), 139.9 (i-CC; Ph),
130.2, 128.7, 128.5, 127.8, 127.7 and 125.7 (5 ꢂ CH; Ph and Ar),
Active ester (rac)-63, gave a mixture (93:7) of oxazolidin-2-ones
syn- and anti-4 (0.123 g, 42%).
Active ester (rac)-64, gave a mixture (69:31) of oxazolidin-2-
ones syn- and anti-4 (59 mg, 20%).
Active ester (rac)-65, gave a mixture (98:2) of oxazolidin-2-ones
syn- and anti-4 (86 mg, 29%).
Active ester (rac)-66, gave a mixture (86:14) of oxazolidin-2-
ones syn- and anti-4 (94 mg, 32%).
Active ester (rac)-67, gave a mixture (87:13) of oxazolidin-2-
ones syn- and anti-4 (0.121 g, 41%).
Active ester (rac)-68, gave a mixture (55:45) of oxazolidin-2-
ones syn- and anti-4 (59 mg, 20%).
Active ester (rac)-69, gave recovered stating materials.
Active ester (rac)-15, gave a mixture (97:3) of oxazolidin-2-ones
syn- and anti-4 (0.206 g, 70%).
127.5 (i-CCH3; Ar), 45.6 (PhCHCH3), 18.1 (PhCHCH3) and 16.0
þ
(2 ꢂ CH3; Ar) (Found MNH4
,
272.1644. C17H22O2N requires
MNH4þ, 272.1645).
4.3.32. 2,6-Dimethyl-4-nitrophenylpropanoate (rac)-83
Active ester (rac)-70, gave a mixture (83:17) of oxazolidin-2-
ones syn- and anti-4 (59 mg, 20%).
Active ester (rac)-71, gave a mixture (95:5) of oxazolidin-2-ones
syn- and anti-4 (62 mg, 21%).
Active ester (rac)-72, gave a mixture (95:5) of oxazolidin-2-ones
syn- and anti-4 (0.109 g, 37%).
Active ester (rac)-73, gave recovered stating materials.
Active ester (rac)-74, gave a mixture (95:5) of oxazolidin-2-ones
syn- and anti-4 (86 mg, 29%).
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (0.89 g, 5.98 mmol), DCC (1.35 g, 6.58 mmol), DMAP
(0.15 g, 1.20 mmol) and 2,6-dimethyl-4-nitrophenol 52 (1.00 g,
5.89 mmol) gave, 2,6-dimethyl-4-nitrophenylpropanoate (rac)-83
(0.87 g, 49%) as a colourless oil; RF [light petroleum (40–60 °C)/
diethyl ether (9:1)] 0.50; mmax (CHCl3) cmꢀ1 1723 (OC@O); dH
(400 MHz; CDCl3) 7.92 (2H, s, 2 ꢂ CH; Ar), 7.44–7.25 (5H, m,
5 ꢂ CH; Ph), 4.05 (1H, q, J 7.2, PhCHCH3), 2.08–1.98 (6H, br s,
2 ꢂ CH3; Ar), 1.68 (3H, d, J 7.2, PhCHCH3); dC (100 MHz; CDCl3)
171.4 (C@O), 152.9 (i-C-N; Ar), 139.1 (i-C-O; Ar), 132.3 (i-C-CH3;
Active ester (rac)-75, gave a mixture (69:39) of oxazolidin-2-
ones syn- and anti-4 (24 mg, 8%).

432
N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
Active ester (rac)-76, gave recovered stating materials.
Active ester (rac)-77, gave recovered stating materials.
Active ester (rac)-78, gave recovered stating materials.
Active ester (rac)-79, gave a mixture (63:37) of oxazolidin-2-
(OC@O) and 1701 (NC@O); ½a D25
¼ þ128:9 (c 3.5, CHCl3) (Found
ꢃ
MH+ 262.1434; C15H20NO3 requires 262.1443).
þ
4.5.2. Stereospecific formation of oxazolidin-2-one (R,R)-anti-4
At first, n-BuLi (0.44 mL, 2.5 M in hexane, 1.1 mmol) was added
to a stirred solution of oxazolidin-2-one (R)-1 (0.163 g, 1.0 mmol)
in THF (5 mL) at ꢀ78 °C. After stirring for 1 h, a solution of the gi-
ven active ester (R)-15 (1.0 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 ꢂ 10 mL), dried (over MgSO4) and evaporated
under reduced pressure to give a single diastereoisomeric oxazoli-
din-2-one (R,R)-anti-4. The crude mixture was purified by flash col-
umn chromatography on silica gel eluting with light petroleum (bp
40–60 °C)/diethyl ether (7:3) to give the oxazolidin-2-one (R,R)-
anti-4 (0.171 g, 58%) as a colourless oil; RF [light petroleum ether
(bp 40–60 °C)/diethyl ether (1:1)] 0.64; vmax (CHCl3) cmꢀ1 1774
ones syn- and anti-4 (50 mg, 17%).
Active ester (rac)-80, gave recovered stating materials.
Active ester (rac)-81, gave a mixture (90:10) of oxazolidin-2-
ones syn- and anti-4 (0.165 g, 56%).
Active ester (rac)-82, gave recovered stating materials.
Active ester (rac)-83, gave recovered stating materials.
4.5. General procedure for the mutual kinetic resolutions of
active esters (rac)-15, (rac)-69, (rac)-73, (rac)-75–80 and (rac)-
82–83 using oxazolidin-2-one (rac)-1 at ꢀ78 °C (2 h)?rt (for
10 h)
At first, n-BuLi (0.44 ml, 2.5 M in hexane, 1.1 mmol) was added
to
a
stirred solution of oxazolidin-2-one (rac)-1 (0.163 g,
(OC@O) and 1703 (NC@O);
½
a 2D5
ꢃ
¼ ꢀ19:8 (c 3.3, CHCl3) {lit.
a 2D5
ꢃ
¼ ꢀ19:2 (c 1.15, CHCl3)} (Found MH+ 262.1432; C15H20NO3
þ
1.0 mmol) in THF (5 ml) at ꢀ78 °C. After stirring for 1 h, a solution
of given active ester (rac)-15, (rac)-69, (rac)-73, (rac)-75–80 and
(rac)-82–83 (1.1 mmol) in THF (1 ml) was added. The resulting
mixture was stirred for 2 h at ꢀ78 °C, then allowed to warm up
to room temperature. The resulting solution was stirred for 10 h.
The reaction was quenched with water (10 mL). The organic layer
was extracted with diethyl ether (2 ꢂ 10 mL), dried (over MgSO4)
and evaporated under reduced pressure to give a separable mix-
ture of two diastereoisomeric oxazolidin-2-ones syn- and anti-4.
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 oxazolidin-2-ones syn- and anti-4 as white
needle-like crystals.
Active ester (rac)-15, gave a mixture (96:4) of oxazolidin-2-ones
syn- and anti-4 (0.115 g, 62%).
Active ester (rac)-68, gave a mixture (40:60) of oxazolidin-2-
ones syn- and anti-4 (62 mg, 21%).
Active ester (rac)-73, gave a mixture (28:72) of oxazolidin-2-
ones syn- and anti-4 (0.141 g, 48%).
Active ester (rac)-75, gave a mixture (31:69) of oxazolidin-2-
ones syn- and anti-4 (63 mg, 21%).
½
requires 262.1443).
4.6. General procedure for probing the mutual kinetic
resolutions of active ester (rac)-15 and oxazolidin-2-one (rac)-1
using different additives and metal amides at ꢀ78 °C (for 2 h)
At first, n-BuLi/LDA/LiHMDS/NaHMDS/KHMDS (1.1 mmol) was
added to a stirred solution of oxazolidin-2-one (rac)-1 (0.163 g,
1.0 mmol) with and without HMPA/crown ether (1.1 mmol) in
THF (5 mL) at ꢀ78 °C. After stirring for 1 h, a solution of given ac-
tive ester (rac)-15 (0.347 g, 1.1 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 ꢂ 10 mL), dried (over MgSO4) and evaporated
under reduced pressure to give a separable mixture of two diaste-
reoisomeric oxazolidin-2-ones syn- and anti-4. 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
oxazolidin-2-ones syn- and anti-4 as white needle-like crystals.
Using n-BuLi (0.44 mL, 2.5 M in hexanes, 1.1 mmol) and 12-
crown-4 (0.19 g, 1.1 mmol) gave a mixture (97:3) of oxazolidin-
2-ones syn- and anti-4 (0.174 g, 59%).
Active ester (rac)-76, gave a mixture (42:58) of oxazolidin-2-
ones syn- and anti-4 (0.127 g, 43%).
Active ester (rac)-77, gave a mixture (18:82) of oxazolidin-2-
ones syn- and anti-4 (0.100 g, 34%).
Active ester (rac)-78, gave a mixture (17:83) of oxazolidin-2-
ones syn- and anti-4 (80 mg, 27%).
Active ester (rac)-79, gave a mixture (37:63) of oxazolidin-2-
ones syn- and anti-4 (0.113 g, 38%).
Active ester (rac)-80, gave a mixture (24:76) of oxazolidin-2-
ones syn- and anti-4 (0.153 g, 52%).
Using n-BuLi (0.44 mL, 2.5 M in hexanes, 1.1 mmol) and HMPA
(0.59 g, 0.57 mL, 3.3 mmol) gave a mixture (91:9) of oxazolidin-
2-ones syn- and anti-4 (0.191 g, 65%).
Using LDA (0.55 mL, 2 M in THF, 1.1 mmol) gave a mixture
(97:3) of oxazolidin-2-ones syn- and anti-4 (0.123 g, 42%).
Using LDA (0.55 mL, 2 M in THF, 1.1 mmol) and 12-crown-4
(0.19 g, 1.1 mmol) gave a mixture (97:3) of oxazolidin-2-ones
syn- and anti-4 (0.190 g, 65%).
Active ester (rac)-82, gave recovered stating materials.
Active ester (rac)-83, gave recovered stating materials.
Using LiHMDS (1.1 mL, 1 M in THF, 1.1 mmol) gave a mixture
(96:4) of oxazolidin-2-ones syn- and anti-4 (0.165 g, 56%).
Using LiHMDS (1.1 mL, 1 M in THF, 1.1 mmol) and 12-crown-4
(0.19 g, 1.1 mmol) gave a mixture (97:3) of oxazolidin-2-ones
syn- and anti-4 (0.185 g, 63%).
Using NaHMDS (1.1 mL, 1 M in THF, 1.1 mmol) gave a mixture
(96:4) of oxazolidin-2-ones syn- and anti-4 (0.168 g, 57%).
Using NaHMDS (1.1 mL, 1 M in THF, 1.1 mmol) and 15-crown-5
(0.24 g, 0.21 mL, 1.1 mmol) gave a mixture (97:3) of oxazolidin-2-
ones syn- and anti-4 (0.224 g, 76%).
Using KHMDS (2.2 mL, 0.5 M in toluene, 1.1 mmol) gave a mix-
ture (84:16) of oxazolidin-2-ones syn- and anti-4 (0.129 g, 44%).
Using KHMDS (2.2 mL, 0.5 M in toluene, 1.1 mmol) and 18-
crown-8 (0.29 g, 1.1 mmol) gave a mixture (76:26) of oxazolidin-
2-ones syn- and anti-4 (0.227 g, 77%).
4.5.1. Stereospecific formation of oxazolidin-2-one (S,R)-syn-4
n-BuLi (0.44 mL, 2.5 M in hexane, 1.1 mmol) was added to a
stirred solution of oxazolidin-2-one (R)-1 (0.163 g, 1.0 mmol) in
THF (5 mL) at ꢀ78 °C. After stirring for 1 h, a solution of given ac-
tive ester (S)-15 (1.0 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 ꢂ 10 mL), dried (over MgSO4) and evaporated under re-
duced pressure to give a single diastereoisomeric oxazolidin-2-
one (S,R)-syn-4. 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 oxazolidin-2-one (S,R)-
syn-4 (0.177 g, 60%) as a colourless oil; RF [light petroleum ether
(bp 40–60 °C)/diethyl ether (1:1)] 0.43; vmax (film) cmꢀ1 1774
Using MeMgBr (0.55 mL, 2 M in diethyl ether, 1.1 mmol) a mix-
ture (80:20) of oxazolidin-2-ones syn- and anti-4 (29 mg, 10%).

N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
433
4.7. General procedure for probing the mutual kinetic
resolutions of active ester (rac)-15 and oxazolidin-2-one (rac)-1
at different temperatures and reaction times
At ꢀ78 °C, using 1 equiv of (rac)-15 for 2 h, gave a mixture
(72:28) of oxazolidin-2-ones (R,S)-syn- and (S,S)-anti-4 (0.100 g,
34%).
At ꢀ78 °C, using 2 equiv of (rac)-15 for 2 h, gave a mixture
(94:6) of oxazolidin-2-ones (R,S)-syn- and (S,S)-anti-4 (0.179 g,
61%).
At first, n-BuLi (0.44 mL, 2.5 M in hexanes, 1.1 mmol) was
added to a stirred solution of oxazolidin-2-one (rac)-1 (0.163 g,
1.0 mmol) in THF (5 mL) at the chosen temperature n °C. After
stirring for 1 h, a solution of given active ester (rac)-15 (0.347 g,
1.1 mmol) in THF (1 mL) (at the same n °C) was added. The result-
ing mixture was stirred for 2 h at n °C. The reaction was quenched
with water (10 mL). The organic layer was extracted with diethyl
ether (2 ꢂ 10 mL), dried (over MgSO4) and evaporated under re-
duced pressure to give a separable mixture of two diastereoiso-
meric oxazolidin-2-ones syn- and anti-4. 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 oxazolidin-2-ones syn- and anti-4 as white needle-like
crystals.
At ꢀ78 °C for 2 h, gave a mixture (97:3) of oxazolidin-2-ones
syn- and anti-4 (0.206 g, 70%), and the active ester (rac)-15
(41 mg, 12%).
At ꢀ78 °C for 5 min, gave a mixture (97:3) of oxazolidin-2-ones
syn- and anti-4 (0.116 g, 39%), and the active ester (rac)-15
(0.109 g, 37%).
4.8.1. Synthesis of 2,4-dichlorophenyl 2-(4-
isobutylphenyl)propanoate (rac)-84
In the same way as the active ester (rac)-14, 2-(4-isobutyl-
phenyl)propanoic acid (rac)- (1.0 g, 4.87 mmol), DCC (1.10 g,
5.35 mmol) and 2,4-dichlorophenol 31 (0.79 g, 4.87 mmol) gave,
2,4-dichlorophenyl
2-(4-isobutylphenyl)propanoate
(rac)-84
(1.28 g, 75%) as a colourless oil; RF [light petroleum (40–60 °C)/
diethyl ether (9:1)] 0.40; mmax (film) cmꢀ1 1760 (C@O); dH
(400 MHz; CDCl3) 7.41 (1H, d, J 2.5, CH; C6H3Cl2), 7.33 (2H, br d, J
8.1, 2 ꢂ CH; Ar), 7.18 (1H, dd, J 8.6 and 2.5, CH; C6H3Cl2), 7.16
(2H, br d, J 8.1, 2 ꢂ CH; Ar), 6.98 (1H, d, J 8.6, CH; C6H3Cl2), 4.03
(1H, q, J 7.2, ArCHCH3), 2.50 (2H, br d, J 7.2, ArCH2), 1.90 (1H, m,
CH(CH3)2), 1.67 (3H, d, J 7.2, ArCHCH3) and 0.93 (6H, br d, J ꢁ6.7,
2 ꢂ CH3, CH(CH3)2); dC (100 MHz; CDCl3) 172.4 (C@O), 146.2
(i-CCl; C6H3Cl2), 141.4 (i-CO; C6H3Cl2), 137.0 (i-CCl; C6H3Cl2),
132.1 (i-CC; Ar), 130.4 (CH; C6H3Cl2), 130.12 (2C, 2 ꢂ CH; Ar),
128.3 (i-CC; Ar), 127.82 (2C, 2 ꢂ CH; Ar), 124.9 (CH; C6H3Cl2),
45.5 (ArCHCH3 and CH(CH3)2), 32.0 (ArCH2), 22.82 (2 ꢂ CH3;
CH(CH3)2) and 18.8 (ArCHCH3) (Found M(35Cl)+, 294.0209.
At ꢀ50 °C for 2 h, gave a mixture (96:4) of oxazolidin-2-ones
syn- and anti-4 (0.179 g, 61%).
At 0 °C for 2 h, gave a mixture (96:4) of oxazolidin-2-ones syn-
and anti-4 (0.182 g, 62%).
C
15H12Cl2O2 requires M+ 294.0209).
At +25 °C for 2 h, gave a mixture (95:5) of oxazolidin-2-ones
syn- and anti-4 (0.156 g, 53%).
4.8.2. Synthesis of pentafluorophentyl 2-(4-
isobutylphenyl)propanoate (rac)-86
At +50 °C for 2 h, gave a mixture (80:20) of oxazolidin-2-ones
syn- and anti-4 (0.132 g, 45%).
In the same way as the active ester (rac)-14, 2-phenylpropanoic
acid (rac)-6 (1.0 g, 4.87 mmol), DCC (1.10 g, 5.35 mmol) and penta-
fluorophenol 8 (0.89 g, 4.85 mmol) gave, pentafluorophenyl 2-(4-
4.8. General procedure for probing the kinetic resolutions of
different amounts of active ester (rac)-15 and oxazolidin-2-one
(S)-1 at ꢀ78 °C
isobutylphenyl)propanoate (rac)-86 (1.48 g, 82%) as a white
needle-like solid; mp 48–49 °C; RF [light petroleum (40–60 °C)/
ether (9:1)] 0.63; mmax (CHCl3) cmꢀ1 1782 (CO); dH (400 MHz;
CDCl3) 7.26 (2H, dt, J 8.2 and 2.2, 2 ꢂ CH; Ar), 7.14 (2H, dt, J 8.2
and 2.2, 2 ꢂ CH; Ar), 4.04 (1H, q, J 7.2, ArCHCH3), 2.46 (2H, d, J
7.2, ArCH2), 1.92–1.80 (1H, m, CH(CH3)2), 1.62 (3H, d, J 7.2,
ArCHCH3), 0.99 (3H, d, J 6.7, CHACHCHB) and 0.88 (3H, d, J 6.7,
At first, n-BuLi (0.44 mL, 2.5 M in hexanes, 1.1 mmol) was added
to a stirred solution of oxazolidin-2-one (S)-1 (0.163 g, 1.0 mmol)
in THF (5 mL) at ꢀ78 °C. After stirring for 1 h, a solution of given
active ester (rac)-15 (0.315 g, per 1 mmol) in THF (1 mL per
1 mmol) was added. The resulting mixture was stirred for n h at
ꢀ78 °C. The reaction was quenched with water (10 mL). The organ-
ic layer was extracted with diethyl ether (2 ꢂ 10 mL), dried (over
MgSO4) and evaporated under reduced pressure to give a separable
mixture of two diastereoisomeric oxazolidin-2-ones syn- and anti-
4. 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 enantiomerically pure oxazolidin-2-ones
(R,S)-syn- and (S,S)-anti-4 as white needle-like crystals.
At ꢀ78 °C, using 2 equiv of (rac)-15 for 5 min, gave a mixture
(97:3) of oxazolidin-2-ones (R,S)-syn- and (S,S)-anti-4 (0.168 g,
57%).
3
3
CHBCHCHA); dC (100 MHz; CDCl3) 170.3 (OC@O), 140.8 (i-C; Ar),
3
3
1
2
141.2 (142.92 and 139.42, 2C, ddt, JC,F = 251.3 Hz, JC,F = 11.9 Hz
3
and JC,F = 4.2 Hz, C(2)-F), 138.9 (140.18 and 137.66, 1C, dtt,
1JC,F = 253.2 Hz, JC,F = 13.8 Hz and JC,F = 3.8 Hz), C(4)-F), 137.3
2
3
1
2
(138.61 and 136.08, 2C, dtdd, JC,F = 254.7 Hz, JC,F = 14.5 Hz,
3JC,F = 5.3 and JC,F = 3.0 Hz, C(3)-F), 135.5 (i-C; Ar), 129.1 and
4
2
4
126.7 (2 ꢂ CH; Ar), 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 (CH2; Ar), 44.4 (ArCHCH3), 29.7
(CH(CH3)2), 21.9 (CH(CH3)2) and 18.0 (ArCHCH3) (Found M,
372.1144; C19H17F5O2 requires 372.1143).
4.9. Procedure for probing the mutual kinetic resolutions of
active esters (rac)-15 and (rac)-84 using oxazolidin-2-one (rac)-1
At ꢀ78 °C, using 1 equiv of (rac)-15 for 5 min, gave a mixture
(97:3) of oxazolidin-2-ones (R,S)-syn- and (S,S)-anti-4 (0.116 g,
39%).
At ꢀ78 °C, using 0.5 equiv of (rac)-15 for 5 min, gave a mixture
(97:3) of oxazolidin-2-ones (R,S)-syn- and (S,S)-anti-4 (21 mg, 7%).
At ꢀ78 °C, using 0.25 equiv of (rac)-15 for 5 min, gave a mixture
(97:3) of oxazolidin-2-ones (R,S)-syn- and (S,S)-anti-4 (9 mg, 3%).
At ꢀ78 °C, using 1 equiv of (rac)-15 for 10 min, gave a mixture
(93:17) of oxazolidin-2-ones (R,S)-syn- and (S,S)-anti-4 (0.100 g,
34%).
At first, n-BuLi (0.44 mL, 2.5 M in hexanes, 1.1 mmol) was added
to a stirred solution of oxazolidin-2-one (rac)-1 (0.163 g, 1.0 mmol)
in THF (5 mL) at the chosen temperature ꢀ78 °C. After stirring for
1 h, a solution of active esters (rac)-15 (0.347 g, 1.1 mmol) and
(rac)-84 (0.386 g, 1.1 mmol) in THF (1 mL) was added. The result-
ing mixture was stirred for 2 h. The reaction was quenched with
water (10 mL). The organic layer was extracted with diethyl ether
(2 ꢂ 10 mL), dried (over MgSO4) and evaporated under reduced
pressure to give a mixture of two diastereoisomeric oxazolidin-2-
ones adducts (rac)-syn- and (rac)-anti-4, and (rac)-syn- and (rac)-
anti-85 (0.18 g, 60%; ratio 89:11) with a diastereoisomeric excess
of 94%.
At ꢀ78 °C, using 1 equiv of (rac)-15 for 20 min, gave a mixture
(86:14) of oxazolidin-2-ones (R,S)-syn- and (S,S)-anti-4 (89 mg,
30%).

434
N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
Characterisation data for: 3-[2-(4-isobutylphenyl)propanoyl]-
ether (bp 40–60 °C)/diethyl ether: (1:1)] 0.67; mp 118–119 °C;
vmax (CHCl3) cmꢀ1 1700 (C@S); dH (400 MHz; CDCl3) 7.20–7.08
(6H, m, 6 ꢂ CH; PhA and PhB), 6.94 (2H, dt, J 6.9 and 1.8, 2 ꢂ CH;
PhA), 6.88 (2H, dt, J 7.0 and 1.8, 2 ꢂ CH; PhB), 5.98 (1H, q, J 6.9,
PhCHCH3), 5.61 (1H, dd, J 9.2 and 6.1, CHN), 4.68 (1H, t, J 9.2, CHAH-
BO), 4.20 (1H, dd, J 9.2 and 6.1, CHAHBO) and 1.35 (3H, d, J 6.9,
PhCHCH3), dC (100 MHz; CDCl3) 185.2 (C@S), 174.8 (C@O),
139.1 and 136.9 (2 ꢂ i-C; 2 ꢂ Ph), 128.8,2 128.7,1 128.5,2 128.3,2
127.11 and 126.42 (10 ꢂ CH; 2 ꢂ Ph), 73.6 (CH2O), 62.6 (CHN),
43.9 (PhCHCH3) and 18.7 (PhCHCH3) (Found MH+, 312.1054;
4-phenyloxazolidin-2-one (rac)-anti-85; RF [light petroleum ether
(bp 40–60 °C)/diethyl ether (1:1)] 0.62; mmax (CHCl3) cmꢀ1 1780
(OC@O) and 1701 (NC@O); mp 150–154 °C; dH (400 MHz; CDCl3)
7.39–7.23 (7H, m, 7 ꢂ CH; Ar and Ph), 7.07 (2H, dt, J 8.2 and 2.1,
2 ꢂ CH; Ar), 5.33 (1H, dd, J 8.4 and 3.2, PhCHN), 5.10 (1H, q, J 7.1,
ArCHCH3), 4.55 (1H, t, J 8.9, CHAHBO), 4.20 (1H, dd J 8.9 and 3.2,
CHAHBO), 2.42 (2H, d, J 7.2, ArCH2), 1.88–1.78 (1H, m, CH(CH3)2),
1.39 (3H, d, J 7.1, ArCHCH3), 0.89 (3H, d, J 6.7, CHACHCHB) and
3
3
0.88 (3H, d, J 6.7, CHACHCHB); dC(100.6 MHz; CDCl3) 173.9 (NC@O),
3
3
153.2 (OC@O), 140.6 (i-C; Ar), 138.3 (i-C; Ar), 137.0 (i-C; Ph), 129.32
and 128.02 (4 ꢂ CH; Ar), 128.8,2 128.51 and 125.82 (5 ꢂ CH; Ph),
69.6 (CH2O), 57.8 (PhCHN), 45.1 (CH(CH3)2), 43.3 (ArCHCH3), 30.2
(ArCH2), 22.4 (2C, CH(CH3)2) and 18.5 (ArCHCH3) (Found MH+,
352.1913; C22H26NO3 requires MH+, 352.1907); and 3-[2-(4-isobu-
tylphenyl)propanoyl]-4-phenyloxazolidin-2-one (rac)-syn-85 as a
white crystalline solid; RF [light petroleum ether (bp 40–60 °C)/
diethyl ether (1:1)] 0.41; mmax (CHCl3) cmꢀ1 1779 (OC@O) and
1705 (NC@O); mp 67–71 °C; dH (400 MHz; CDCl3) 7.28–7.15 (3H,
m, 3 ꢂ CH; Ph and/or Ar), 7.03–7.00 (4H, m, 4 ꢂ CH; Ph and Ar),
6.90 (2H, dt, J 7.9 and 2.1, 2 ꢂ 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, ArCH2),
1.89–1.79 (1H, m, CH(CH3)2), 1.38 (3H, d, J 6.9, ArCHCH3), 0.91
(3H, d, J 6.7, CHACHCHB) and 0.91 (3H, d, J 6.7, CHACHCHB); dC
C
18H17NO2S requires 312.1053).
At ꢀ78 °C, using 2 equiv of (rac)-15 for 5 min, gave a diastereo-
isomeric mixture of oxazolidin-2-ones (rac)-syn- and (rac)-anti-4
(50 mg, 34%) with 86% de; and oxazolidin-2-thiones (rac)-syn-
and (rac)-anti-88 (14 mg, 9%) with 84% de.
4.12. Procedure for probing the parallel kinetic resolution of
active ester (rac)-15 using oxazolidin-2-one (R)-1 and
oxazolidin-2-thione (S)-87
At first, n-BuLi (0.44 mL, 2.5 M in hexanes, 1.1 mmol) was added
to a stirred solution of oxazolidin-2-one (R)-1 (81 mg, 0.5 mmol)
and oxazolidin-2-thione (S)-87 (89 mg, 0.5 mmol) in THF (5 mL)
at the chosen temperature ꢀ78 °C. After stirring for 1 h, a solution
of active ester (rac)-15 (0.347 g, 1.1 mmol) in THF (1 mL) was
added. The resulting mixture was stirred for 2 h. The reaction
was quenched with water (10 mL). The organic layer was extracted
with diethyl ether (2 ꢂ 10 mL), dried (over MgSO4) and evaporated
under reduced pressure to give a separable mixture of two diaste-
reoisomeric oxazolidin-2-ones adducts (S,R)-syn- and (R,R)-anti-4
(75 mg, 51%) with 92% de; and (R,S)-syn- and (S,S)-anti-88
(37 mg, 24%) with 96% de.
3
3
3
3
(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), 129.32 and 127.02 (4 ꢂ CH; Ar),
129.2,2 128.71 and 125.82 (5 ꢂ CH; Ph), 69.7 (CH2O), 58.1 (PhCHN),
45.1 (CH(CH3)2), 42.7 (ArCHCH3), 30.2 (ArCH2), 22.4 (2C, CH(CH3)2)
and 19.4 (ArCHCH3) (Found MH+, 352.1909; C22H26NO3 requires
MH+, 352.1907).
4.10. Procedure for probing the mutual kinetic resolutions of
active esters (rac)-62 and (rac)-86 using oxazolidin-2-one (rac)-1
Characterisation data for: 3-(2-phenylpropanoyl)-4-phenylox-
azolidin-2-thione (R,S)-syn-88; white solid; RF [light petroleum
ether (bp 40–60 °C)/diethyl ether: (1:1)] 0.67; mp 87–89 °C [lit.15
At first, n-BuLi (0.44 mL, 2.5 M in hexanes, 1.1 mmol) was added
to a stirred solution of oxazolidin-2-one (rac)-1 (0.163 g, 1.0 mmol)
in THF (5 mL) at the chosen temperature ꢀ78 °C. After stirring for
1 h, a solution of active esters (rac)-62 (0.323 g, 1.1 mmol) and
(rac)-86 (0.409 g, 1.1 mmol) in THF (1 mL) was added. The result-
ing mixture was stirred for 2 h. The reaction was quenched with
water (10 mL). The organic layer was extracted with diethyl ether
(2 ꢂ 10 mL), dried (over MgSO4) and evaporated under reduced
pressure to give a mixture of two diastereoisomeric oxazolidin-2-
ones adducts (rac)-syn- and (rac)-anti-4, and (rac)-syn- and (rac)-
anti-85 (0.174 g, 58%; ratio 13:87) with a diastereoisomeric excess
of 94%.
(S,R)- 84–86 °C]; ½a D25
ꢃ
¼ þ66:1 (c 3.6, CHCl3) [lit.15 (S,R)- ½a D25
¼
ꢃ
ꢀ58:3 (c 4.0, CHCl3)]; vmax (CHCl3) cmꢀ1 1708 (C@O) and 1216
(C@S); dH (400 MHz; CDCl3) 7.20–7.08 (6H, m, 6 ꢂ CH; PhA and
PhB), 6.94 (2H, dt, J 6.9 and 1.8, 2 ꢂ CH; PhA), 6.88 (2H, dt, J 7.0
and 1.8, 2 ꢂ CH; PhB), 5.98 (1H, q, J 6.9, PhCHCH3), 5.62 (1H, dd, J
9.2 and 6.1, PhCHN), 4.68 (1H, t, J 9.2, CHAHBO), 4.20 (1H, dd, J
9.2 and 6.1, CHAHBO) and 1.35 (3H, d, J 6.9, PhCHCH3), dC
(100 MHz; CDCl3) 185.2 (C@S), 174.8 (C@O), 139.1 and 136.9
(2 ꢂ i-C; 2 ꢂ Ph), 128.8,2 128.7,1 128.5,2 128.3,2 127.11 and 126.42
(10 ꢂ CH; 2 ꢂ Ph), 73.6 (CH2O), 62.6 (PhCHN), 43.9 (PhCHCH3)
and 18.7 (PhCHCH3) (Found MH+, 312.1054; C18H18NO2S requires
MH+, 312.1053).
At ꢀ78 °C, using 2 equiv of (rac)-15 for 5 min, gave a diastereo-
isomeric mixture of oxazolidin-2-ones (S,R)-syn- and (R,R)-anti-4
(62 mg, 42%) with 94% de; and oxazolidin-2-thiones (R,S)-syn-
and (S,S)-anti-88 (12 mg, 8%) with 92% de.
4.11. Procedure for probing the mutual kinetic resolution of
active ester (rac)-15 using oxazolidin-2-one (rac)-1 and
oxazolidin-2-thione (rac)-87
At first, n-BuLi (0.44 mL, 2.5 M in hexanes, 1.1 mmol) was added
to a stirred solution of oxazolidin-2-one (rac)-1 (81 mg, 0.5 mmol)
and oxazolidin-2-thione (rac)-87 (89 mg, 0.5 mmol) in THF (5 mL)
at the chosen temperature ꢀ78 °C. After stirring for 1 h, a solution
of active ester (rac)-15 (0.347 g, 1.1 mmol) in THF (1 mL) was
added. The resulting mixture was stirred for 2 h. The reaction
was quenched with water (10 mL). The organic layer was extracted
with diethyl ether (2 ꢂ 10 mL), dried (over MgSO4) and evaporated
under reduced pressure to give a separable mixture of two diaste-
reoisomeric oxazolidin-2-ones adducts (rac)-syn- and (rac)-anti-4
(93 mg, 63%) with 98% de; and (rac)-syn- and (rac)-anti-88
(63 mg, 40%) with 96% de.
4.13. Procedure for probing the mutual kinetic resolution of
active ester (rac)-15 using oxazolidin-2-ones (rac)-2 and (rac)-
89–91
4.13.1. Synthesis of 4-methyl-5-phenyl-3-(2-
phenylpropanoyl)oxazolidin-2-one (rac)-anti,syn-92 and 4-
methyl-5-phenyl-3-(2-phenylpropanoyl)oxazolidin-2-one (rac)-
syn,syn-92
In the same way as the oxazolidin-2-one (rac)-4, n-butyl lithium
(0.6 mL, 2.5 M in hexane, 1.50 mmol), 4-methyl-5-phenyloxazoli-
din-2-one (rac)-89 (0.24 g, 1.36 mmol) and pentafluorophenyl
2-phenylpropanoate (rac)-15 (0.47 g, 1.50 mmol), gave the oxazoli-
din-2-ones syn,syn- and anti,syn-92 (ratio 68:32: syn,syn-:anti,
Characterisation data for: 3-(2-phenylpropanoyl)-4-phenylox-
azolidin-2-thione (rac)-syn-88; white solid; RF [light petroleum

N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
435
syn-). The crude residue was purified by flash chromatography on
4.13.3. Synthesis of 4-isopropyl-3-(2-
silica gel eluting with light petroleum ether (bp 40–60 °C)/diethyl
ether (7:3) to give the oxazolidin-2-one (rac)-anti,syn-92 (89 mg,
21%) as a colourless oil; RF [light petroleum ether (bp 40–60 °C)/
diethyl ether (1:1)] 0.76; mmax (CHCl3) cmꢀ1 1778 (OC@O) and
1697 (NC@O); dH (400 MHz; CDCl3) 7.43–7.38 (3H, m, 3 ꢂ CH;
Ph), 7.37–7.30 (4H, m, 4 ꢂ CH; 2 ꢂ Ph), 7.28–7.22 (3H, m, 3 ꢂ CH;
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 (100 MHz; CDCl3) 174.1 (NC@O), 152.4 (OC@O),
140.3 (i-C; Ph; PhCHCH3), 133.0 (i-C; Ph; PhCHO), 129.4,5 127.9,2
127.01 and 125.42 (10 ꢂ CH; 2 ꢂ Ph), 78.4 (OCHPh), 55.1 (CH3CHN),
43.1 (PhCHCH3), 19.0 (CH3CHN) and 14.3 (PhCHCH3) (Found MH+
phenylpropanoyl)oxazolidin-2-one (rac)-anti-5 and 4-
isopropyl-3-(2-phenylpropanoyl)oxazolidin-2-one (rac)-syn-5
In the same way as the oxazolidin-2-one (rac)-4, n-butyl lithium
(0.6 mL, 2.5 M in hexane, 1.50 mmol), 4-isopropyl-oxazolidin-2-
one (rac)-2 (0.17 g, 1.36 mmol) and pentafluorophenyl 2-phenyl-
propanoate (rac)-15 (0.47 g, 1.50 mmol), gave the oxazolidin-2-
ones syn- and anti-5 (ratio 95:5:syn-:anti-). The crude residue
was purified by flash chromatography on silica gel eluting with
light petroleum ether (bp 40–60 °C)/diethyl ether (7:3) to give
the oxazolidin-2-one (rac)-anti-5 (10 mg, 3%) as a colourless oil;
RF [light petroleum ether (bp 40–60 °C)/diethyl ether (1:1)] 0.64;
vmax (film) cmꢀ1 1774 (OC@O) and 1701 (NC@O); dH (400 MHz;
CDCl3) 7.38–7.21 (5H, m, 5 ꢂ CH; Ph), 5.15 (1H, q, J 7.0, PhCHCH3),
4.39–4.33 (1H, dt, J 9.1 and 3.2, i-PrCHN), 4.10 (1H, dd, J 9.1 and 3.2,
CHAHBO), 4.02 (1H, t, J 9.1, CHAHBO), 2.46–2.38 (1H, m, CH(CH3)2),
1.51 (3H, d, J 7.0, PhCHCH3), 0.91 (3H, d, J 7.0, CHACHCHB) and 0.90
310.1430. C19H20NO3 requires MH+, 310.1443); and the oxazoli-
+
din-2-one (rac)-syn,syn-92 (0.18 g, 42%) as white crystalline solid;
RF [light petroleum ether (bp 40–60 °C)/diethyl ether (1:1)] 0.63;
mp 92–95 °C; mmax (CHCl3) cmꢀ1 1774 (OC@O) and 1701 (NC@O);
dH (400 MHz; CDCl3) 7.42–7.37 (2H, m, 2 ꢂ CH; Ph), 7.36–7.30
(5H, m, 5 ꢂ CH; 2 ꢂ Ph), 7.28–7.24 (1H, m, CH; Ph), 7.21–7.16
(2H, m, 2 ꢂ CH; Ph), 5.64 (1H, d, J 7.2, OCHPh), 5.08 (1H, q, J 7.1,
PhCHCH3), 4.82 (1H, m, CH3CHN), 1.51 (3H, d, J 7.1, PhCHCH3)
and 0.74 (3H, d, J 6.6, CH3CHN); dC (100 MHz; CDCl3) 174.0 (NC@O),
152.3 (OC@O), 140.1 (i-C; Ph; PhCHCH3), 133.3 (i-C; Ph; PhCHO),
128.5,1 128.4,4 127.9,2 126.91 and 125.52 (10 ꢂ CH; 2 ꢂ Ph), 78.8
(OCHPh), 54.4 (CH3CHN), 43.3 (PhCHCH3), 19.3 (CH3CHN) and
3
3
(3H, d, J 6.9, CHACHCHB); dC (100 MHz; CDCl3) 174.3 (NC@O), 153.4
3
3
(OC@O), 140.1 (i-C; Ph), 128.3,2 127.92 and 126.91 (5 ꢂ CH; Ph),
62.8 (CH2O), 58.7 (i-PrCHN), 42.7 (PhCHCH3), 28.3 (CH(CH3)2),
19.5 (CHACHCHB), 17.7 (CHACHCHB) and 14.5 (PhCHCH3) (Found
3
3
3
3
MH+ 262.1434; C15H20NO3 requires 262.1443); the oxazolidin-2-
one (rac)-syn-5 (0.196 g, 55%) as a white crystalline solid; RF [light
petroleum ether (bp 40–60 °C)/diethyl ether (1:1)] 0.43; mp 44–
47 °C; vmax (CHCl3) cmꢀ1 1774 (OC@O) and 1703 (NC@O); dH
(400 MHz; CDCl3) 7.37–7.32 (3H, m, 4 ꢂ CH; Ph), 7.23–7.18 (2H,
m, 2 ꢂ CH; Ph), 5.13 (1H, q, J 6.9, PhCHCH3), 4.47 (1H, dt, J 8.9
and 3.5, i-PrCHN), 4.22 (1H, t, J 8.9, CHAHBO), 4.09 (1H, dd, J 8.9
and 3.5, CHAHBO), 2.21–2.12 (1H, m, CH(CH3)2), 1.46 (3H, d, J 6.9,
PhCHCH3), 0.79 (3H, d, J 7.0, CHACHCHB) and 0.44 (3H, d, J 6.9,
þ
14.0 (PhCHCH3) (Found MH+ 310.1460. C19H20NO3 requires
+
310.1443).
4.13.2. Synthesis of 4-benzyl-3-(2-
3
3
CHACHCHB); dC (100 MHz; CDCl3) 174.4 (NC@O), 153.4 (OC@O),
phenylpropanoyl)oxazolidine-2-one (rac)-anti-93 and 4-
benzyl-3-(2-phenylpropanoyl)oxazolidine-2-one (rac)-syn-93
In the same way as the oxazolidin-2-one (rac)-4, n-butyl lithium
(0.6 mL, 2.5 M in hexane, 1.50 mmol), 4-benzyl-oxazolidin-2-one
(rac)-90 (0.24 g, 1.36 mmol) and pentafluorophenyl 2-phenylpro-
panoate (rac)-15 (0.47 g, 1.50 mmol), gave the oxazolidin-2-ones
syn- and anti-27 (ratio 70:30:syn-:anti-). The crude residue was
purified by flash chromatography on silica gel eluting with light
petroleum ether (bp 40–60 °C)/diethyl ether (7:3) to give the oxaz-
olidin-2-one (rac)-anti-93 (93 mg, 22%) as a white crystalline solid;
RF [light petroleum ether (bp 40–60 °C)/diethyl ether (1:1)] 0.66;
mp 64–67 °C; mmax (CHCl3) cmꢀ1 1780 (OC@O) and 1699 (NC@O);
dH (400 MHz; CDCl3) 7.39–7.21 (10H, m, 10 ꢂ CH; 2 ꢂ Ph), 5.12
(1H, q, J 7.0, PhCHCH3), 4.61–4.55 (1H, m, BnCHN), 4.10 (1H, dd, J
9.2 and 2.4, CHAHBO), 4.01 (1H, t, J 9.2, CHAHBO), 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) 174.5
(NC@O), 152.7 (OC@O), 140.2 (i-C; Ph), 135.3 (i-C; Ph), 129.3,2
128.8,2 128.5,2 128.0,2 127.21 and 127.11 (10 ꢂ CH; 2 ꢂ Ph), 65.7
3
3
140.4 (i-C; Ph), 128.4,2 127.92 and 127.01 (5 ꢂ CH; Ph), 62.8
(CH2O), 57.9 (i-PrCHN), 43.2 (PhCHCH3), 27.8 (CH(CH3)2), 18.8
(CH3ACHCH3B), 17.7 (CHA3 CHCH3B) and 13.9 (PhCHCH3) (Found MH+
þ
262.1432; C15H20NO3 requires 262.1443).
4.13.4. Synthesis of ethyl 2-oxa-3-(2-
phenylpropanoyl)oxazolidin-4-carboxylate (rac)-anti-94 and
ethyl 2-oxa-3-(2-phenylpropanoyl)oxazolidin-4-carboxylate
(rac)-syn-94
In the same way as the oxazolidin-2-one (rac)-4, n-butyl lithium
(0.6 mL, 2.5 M in hexane, 1.50 mmol), ethyl oxazolidin-2-one 4-
carboxylate (rac)-91 (0.40 g, 1.36 mmol) and pentafluorophenyl
2-phenylpropanoate (rac)-15 (0.21 g, 1.50 mmol), gave the oxazoli-
din-2-ones syn- and anti-94 (ratio 95:5:syn-:anti-). The crude resi-
due was purified by flash chromatography on silica gel eluting with
light petroleum ether (bp 40–60 °C)/diethyl ether (7:3) to give the
oxazolidin-2-one (rac)-anti-94 (12 mg, 3%) as a colourless oil; RF
[light petroleum ether (bp 40–60 °C)/diethyl ether (1:1)] 0.42; mmax
(CHCl3) cmꢀ1 1794 (OC@O), 1747 (CC@O) and 1705 (NC@O); dH
(400 MHz; CDCl3) 7.33–7.20 (5H, m, 5 ꢂ CH; Ph), 5.10 (1H, q, J
7.0, PhCHCH3), 4.77 (1H, dd, J 9.2 and 3.5, EtO2CCHN), 4.38 (1H, t,
J 9.2, CHAHBO), 4.29 (1H, q, J 7.2, CH3CHAHBO), 4.28 (1H, q, J 7.2,
CH3CHAHBO), 4.26 (1H, dd, J 9.2 and 3.5, CHAHBO), 1.50 (3H, d, J
7.0, PhCHCH3) and 1.30 (3H, t, J 7.2, CH3CH2O); dC (100 MHz;
CDCl3) 174.5 (NC@O), 168.7 (CC@O), 152.1 (OC@O), 140.0 (i-C;
Ph), 128.7,2 128.32 and 127.41 (5 ꢂ CH; Ph), 64.3 (CH2O), 62.6
(CH2O), 55.9 (EtO2CCHN), 43.0 (PhCHCH3), 19.3 (PhCHCH3) and
(CH2O), 55.8 (BnCHN), 42.8 (PhCHCH3), 37.8 (CH2Ph) and 19.3
+
(PhCHCH3) (Found MH+ 310.1442. C19H20NO3
requires
310.1443); and the oxazolidin-2-one (rac)-syn-93 (0.206 g, 49%)
as a colourless oil; RF [light petroleum ether (bp 40–60 °C)/diethyl
ether (1:1)] 0.43; mmax (CHCl3) cmꢀ1 1775 (OC@O) and 1700
(NC@O); dH (400 MHz; CDCl3) 7.49–7.45 (2H, m, 2 ꢂ CH; Ph),
7.40–7.34 (2H, m, 2 ꢂ CH; Ph), 7.31–7.28 (1H, m, CH; Ph), 7.23–
7.18 (3H, m, 3 ꢂ CH; Ph), 6.98–6.94 (2H, m, 2 ꢂ CH; Ph), 5.11
(1H, q, J 6.9, PhCHCH3), 4.78–4.72 (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) 174.1
(NC@O), 152.7 (OC@O), 149.9 (i-C; PhA), 134.7 (i-C; PhB), 129.2,2
128.5,2 128.4,2 128.0,2 127.01 and 126.91 (10 ꢂ CH; 2 ꢂ Ph), 65.5
(CH2O), 54.6 (BnCHN), 42.9 (PhCHCH3), 37.0 (CH2Ph) and
14.1 (CH3CH2O) (Found MH+, 292.1195; C15H18NO5 requires
þ
292.1185); and the oxazolidin-2-one (rac)-syn-94 (0.236 g, 60%)
as a colourless oil; RF [light petroleum ether (bp 40–60 °C)/diethyl
ether (1:1)] 0.30; mmax (CHCl3) cmꢀ1 1793 (OC@O), 1747 (CC@O)
and 1705 (NC@O); dH (400 MHz; CDCl3) 7.40–7.20 (5H, m,
5 ꢂ 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, CH3CH2O), 1.48 (3H, d, J 7.0,
18.9 (PhCHCH3) (Found MH+ 310.1438. C19H20NO3 requires
+
310.1443).

436
N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
PhCHCH3) and 1.11 (3H, t, J 7.2, CH3CH2O); dC (100 MHz; CDCl3)
174.1 (NC@O), 167.9 (CC@O), 151.8 (OC@O), 139.6 (i-C; Ph),
128.4,2 128.12 and 127.11 (5 ꢂ CH; Ph), 64.1 (CH2O), 62.3 (CH2O),
mp 121–12 °C; m
max (CHCl3) cmꢀ1 1780 (OC@O) and 1701 (NC@O);
½
a 2D5
ꢃ
¼ þ105:9 (c 2.6, CHCl3) (Found MH+ 310.1460. C19H20NO3+ re-
quires 310.1443); the oxazolidin-2-one (S,S)-anti-5 (19 mg, 11%) as
a white crystalline solid; RF [light petroleum ether (bp 40–60 °C)/
diethyl ether (1:1)] 0.58; mp 158–160 °C; mmax (CHCl3) cmꢀ1
55.6 (EtO2CCHN), 43.0 (PhCHCH3), 19.2 (PhCHCH3) and 13.7
(CH3CH2O) (Found MH+, 292.1195; C15H18NO5
requires
þ
292.1185).
1780 (OC@O) and 1700 (NC@O); ½a D25
¼ ꢀ165:2 (c 2.0, CHCl3)
ꢃ
(Found MH+, 296.1282; C18H18NO3 requires 296.1287); and the
þ
4.14. Parallel kinetic resolutions of active ester (rac)-15 using a
quasi-enantiomeric combination of oxazolidin-2-ones (S)-2,
(R)-1, (4R,5S)-89, (S)-90 and (S)-818
oxazolidin-2-one (R,S)-syn-5 (0.106 g, 63%) as a white solid;
RF [light petroleum ether (bp 40–60 °C)/diethyl ether (1:1)] 0.42;
mp 140–142 °C; mmax (CHCl3) cmꢀ1 1778 (OC@O) and 1701
(NC@O); ½a 2D5
ꢃ
¼ þ88:5 (c 4.0, CHCl3) (Found MH+, 296.1286;
þ
4.14.1. Parallel kinetic resolution of pentafluorophenyl 2-
phenylpropanoate (rac)-15 with 4-methyl-5-phenyloxazolidin-
2-one (4R,5S)-89 and 4-benzyl oxazolidin-2-one (S)-90
C15H18NO3 requires 296.1287). RF differences [light petroleum
ether (bp 40–60 °C)/diethyl ether (1:1)]—(R,R,S)-anti-92 (RF 0.76);
(S,R,S)-syn-92 (RF 0.63); (R,S)-anti-5 (RF 0.58); and (S,S)-syn-5 (RF
0.42).
In the same way as the oxazolidin-2-one (rac)-4, n-butyl lithium
(0.58 mL, 2.5 M in hexane, 1.45 mmol), 4-methyl-5-phenyloxazoli-
din-2-one (4R,5S)-89 (0.115 g, 0.65 mmol), 4-benzyl oxazolidin-2-
one (S)-90 (0.115 g, 0.65 mmol) and pentafluorophenyl 2-phenyl-
propanoate (rac)-15 (0.458 g, 1.45 mmol), gave a mixture of two
diastereoisomeric oxazolidin-2-ones (S,R,S)-syn,syn- and (R,R,S)-
anti,syn-92 (ratio 64:36:syn,syn-:anti,syn-) and oxazolidin-2-ones
(R,S)-syn- and (S,S)-anti-93 (ratio 71:29:syn-:anti-). The crude resi-
due was purified by flash chromatography on silica gel eluting with
light petroleum ether (bp 40–60 °C)/diethyl ether (7:3) to give the
oxazolidin-2-one (2R,4R,5S)-anti,syn-92 (36 mg, 18%) as a white
crystalline solid; RF [light petroleum ether (bp 40–60 °C)/diethyl
ether (1:1)] 0.76; mp 89–92 °C; mmax (CHCl3) cmꢀ1 1779 (OC@O)
4.14.3. Parallel kinetic resolution of pentafluorophenyl 2-
phenylpropanoate (rac)-15 with ethyl oxazolidin-2-one 4-
carboxylate (S)-91 and 4-benzyl oxazolidin-2-one (S)-90
In the same way as the oxazolidin-2-one (rac)-4, n-butyl lithium
(0.58 mL, 2.5 M in hexane, 1.45 mmol), ethyl oxazolidin-2-one
4-carboxylate (S)-91 (0.103 g, 0.65 mmol), 4-benzyl-oxazolidin-2-
one (S)-90 (0.115 g, 0.65 mmol) and pentafluorophenyl 2-phenyl-
propanoate (rac)-15 (0.458 g, 1.45 mmol), gave a mixture of two
diastereoisomeric oxazolidin-2-ones (S,S)-syn- and (R,S)-anti-93
(ratio 93:7:syn-:anti-) and oxazolidin-2-ones (R,S)-syn- and (S,S)-
anti-93 (ratio 80:20:syn-:anti-). The crude residue was purified
by flash chromatography on silica gel eluting with light petroleum
ether (bp 40–60 °C)/diethyl ether (7:3) to give the oxazolidin-2-
one (R,S)-anti-94 (6 mg, 3%) as a colourless oil; RF [light petroleum
ether (bp 40–60 °C)/diethyl ether (1:1)] 0.42; mmax (CHCl3) cmꢀ1
and 1700 (NC@O);
½
a 2D5
ꢃ
¼ ꢀ42:7 (c 3.0, CHCl3) (Found MH+
310.1430. C19H20NO3 requires MH+, 310.1443); the oxazolidin-2-
one (2S,4R,5S)-syn,syn-92 (66 mg, 33%) as a white crystalline solid;
RF [light petroleum ether (bp 40–60 °C)/diethyl ether (1:1)] 0.63;
mp 121–123 °C; mmax (CHCl3) cmꢀ1 1780 (OC@O) and 1701
+
1794 (OC@O), 1747 (CC@O) and 1705 (NC@O); ½a D25
¼ ꢀ130:5 (c
ꢃ
(NC@O); ½a 2D5
ꢃ
¼ þ105:9 (c 2.6, CHCl3) (Found MH+ 310.1460.
2.1, CHCl3); and the oxazolidin-2-one (S,S)-syn-94 (76 mg, 40%)
as a white powder; RF [light petroleum ether (bp 40–60 °C)/diethyl
+
C
19H20NO3 requires 310.1443); the oxazolidin-2-one (S,S)-anti-
93 (28 mg, 14%) as a colourless oil; RF [light petroleum ether (bp
ether (1:1)] 0.30; mp 97–99 °C; ½a D25
¼ þ24:8 (c 5.3, CHCl3); mmax
ꢃ
40–60 °C)/diethyl ether (1:1)] 0.66; mmax (CHCl3) cmꢀ1 1780
(CHCl3) cmꢀ1 1793 (OC@O), 1747 (CC@O) and 1705 (NC@O);
(OC@O) and 1700 (NC@O); ½a D25
ꢃ
¼ þ130:4 (c 1.8, CHCl3) (Found
(Found MH+, 292.1195; C15H18NO5 requires 292.1185); the oxaz-
þ
MH+ 310.1438. C19H20NO3 requires 310.1443); and the oxazoli-
din-2-one (R,S)-syn-93 (6 mg, 34%) as a colourless oil; RF [light
petroleum ether (bp 40–60 °C)/diethyl ether (1:1)] 0.43; mmax
olidin-2-one (S,S)-anti-93 (26 mg, 13%) as a colourless oil; RF [light
petroleum ether (bp 40–60 °C)/diethyl ether (1:1)] 0.66;
+
mmax (CHCl3) cmꢀ1 1780 (OC@O) and 1700 (NC@O);
½
a 2D5
ꢃ
¼
(CHCl3) cmꢀ1 1775 (OC@O) and 1700 (NC@O); ½a 2D5
ꢃ
¼ þ2:8 (c 5.5,
þ130:4 (c 1.8, CHCl3) (Found MH+ 310.1438. C19H20NO3 requires
310.1443); and the oxazolidin-2-one (R,S)-syn-93 (0.108 g, 54%)
as a colourless oil; RF [light petroleum ether (bp 40–60 °C)/diethyl
ether (1:1)] 0.43; mmax (CHCl3) cmꢀ1 1775 (OC@O) and 1700
+
CHCl3) (Found MH+ 310.1438. C19H20NO3 requires 310.1443).
RF differences [light petroleum ether (bp 40–60 °C)/diethyl
ether (1:1)]—(R,R,S)-anti-92 (RF 0.76); (S,R,S)-syn-92 (RF 0.63);
(R,S)-anti-93 (RF 0.66); and (S,S)-syn-93 (RF 0.43).
+
(NC@O);
½
a 2D5
ꢃ
¼ þ2:8 (c 5.5, CHCl3) (Found MH+ 310.1438.
+
C19H20NO3 requires 310.1443). RF differences [light petroleum
4.14.2. Parallel kinetic resolution of pentafluorophenyl 2-
phenylpropanoate (rac)-15 with 4-methyl-5-phenyloxazolidin-
2-one (4R,5S)-89 and 4-isopropyl oxazolidin-2-one (S)-2
ether (bp 40–60 °C)/diethyl ether (1:1)]—(R,S)-anti-94 (RF 0.42);
(S,S)-syn-94 (RF 0.30); (S,S)-anti-93 (RF 0.66); and (R,S)-syn-93 (RF
0.43).
In the same way as the oxazolidin-2-one (rac)-4, n-butyl lithium
(0.58 mL, 2.5 M in hexane, 1.45 mmol), 4-methyl-5-phenyloxazoli-
din-2-one (4R,5S)-89 (0.115 g, 0.65 mmol), 4-isopropyl oxazolidin-
2-one (S)-2 (83 mg, 0.65 mmol) and pentafluorophenyl 2-phenyl-
propanoate (rac)-15 (0.458 g, 1.45 mmol), gave a mixture of two
diastereoisomeric oxazolidin-2-ones (S,R,S)-syn,syn- and (R,R,S)-
anti,syn-92 (ratio 83:17:syn,syn-:anti,syn-) and oxazolidin-2-ones
(R,S)-syn- and (S,S)-anti-5 (ratio 85:15:syn-:anti-). The crude resi-
due was purified by flash chromatography on silica gel eluting with
light petroleum ether (bp 40–60 °C)/diethyl ether (7:3) to give the
oxazolidin-2-one (2R,4R,5S)-syn,anti-92 (26 mg, 13%) as a white
crystalline solid; RF [light petroleum ether (bp 40–60 °C)/diethyl
ether (1:1)] 0.76; mp 89–92 °C; mmax (CHCl3) cmꢀ1 1779 (OC@O)
4.14.4. Parallel kinetic resolution of pentafluorophenyl 2-
phenylpropanoate (rac)-15 with 4-phenyloxazolidin-2-one (R)-
1 and 4-benzyl oxazolidin-2-one (S)-90
In the same way as the oxazolidin-2-one (rac)-4, n-butyl lithium
(0.58 mL, 2.5 M in hexane, 1.45 mmol), 4-phenyloxazolidin-2-one
(R)-1 (0.106 g, 0.65 mmol), 4-benzyl-oxazolidin-2-one (S)-90
(0.115 g, 0.65 mmol) and pentafluorophenyl 2-phenylpropanoate
(rac)-15 (0.458 g, 1.45 mmol), gave a mixture of two diastereoiso-
meric oxazolidin-2-ones (S,R)-syn- and (R,R)-anti-4 (ratio 91:9:syn-
:anti-) and oxazolidin-2-ones (R,S)-syn- and (S,S)-anti-93 (ratio
83:17:syn-:anti-). The crude residue was purified by flash chroma-
tography on silica gel eluting with light petroleum ether (bp 40–
60 °C)/diethyl ether (7:3) to give oxazolidin-2-one (R,R)-anti-4
(11 mg, 6%) as a colourless oil; RF [light petroleum ether (bp 40–
60 °C)/diethyl ether (1:1)] 0.64; vmax (film) cmꢀ1 1774 (OC@O)
and 1700 (NC@O);
½
a 2D5
ꢃ
¼ ꢀ42:7 (c 3.0, CHCl3) (Found MH+
310.1430. C19H20NO3 requires MH+, 310.1443); oxazolidin-2-one
(2S,4R5S)-syn,syn-92 (0.121 g, 59%) as a white crystalline solid; RF
[light petroleum ether (bp 40–60 °C)/diethyl ether (1:1)] 0.63;
+
and 1701 (NC@O); ½a D25
ꢃ
¼ þ128:9 (c 3.5, CHCl3) (Found MH+

N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
437
þ
262.1434; C15H20NO3 requires 262.1443); the oxazolidin-2-one
(S,R)-syn-4 (0.111 g, 58%) as a colourless oil; RF [light petroleum
ether (bp 40–60 °C)/diethyl ether (1:1)] 0.43; vmax (CHCl3) cmꢀ1
and 1701 (NC@O); ½a D25
ꢃ
¼ þ128:9 (c 3.5, CHCl3) (Found MH+
þ
262.1434; C15H20NO3 requires 262.1443); the oxazolidin-2-one
(S,R)-syn-4 (0.108 g, 57%) as a colourless oil; RF [light petroleum
ether (bp 40–60 °C)/diethyl ether (1:1)] 0.43; vmax (CHCl3) cmꢀ1
1774 (OC@O) and 1703 (NC@O); ½a D25
¼ ꢀ19:8 (c 3.3, CHCl3)
ꢃ
(Found MH+ 262.1432; C15H20NO3 requires 262.1443); the
oxazolidin-2-one (S,S)-anti-93 (16 mg, 8%) as a colourless oil; RF
[light petroleum ether (bp 40–60 °C)/diethyl ether (1:1)] 0.66; mmax
1774 (OC@O) and 1703 (NC@O); ½a D25
ꢃ
¼ ꢀ19:8 (c 3.3, CHCl3)
þ
(Found MH+ 262.1432; C15H20NO3 requires 262.1443); the oxaz-
olidin-2-one (S,S)-anti-5 (5 mg, 3%) as a white crystalline solid; RF
[light petroleum ether (bp 40–60 °C)/diethyl ether (1:1)] 0.58;
mp 158–160 °C; mmax (CHCl3) cmꢀ1 1780 (OC@O) and 1700
þ
(CHCl3) cmꢀ1 1780 (OC@O) and 1700 (NC@O); ½a 2D5
¼ þ130:4 (c
+
ꢃ
1.8, CHCl3) (Found MH+ 310.1438. C19H20NO3
requires
310.1443); and the oxazolidin-2-one (R,S)-syn-93 (80 mg, 40%) as
a colourless oil; RF [light petroleum ether (bp 40–60 °C)/diethyl
ether (1:1)] 0.43; mmax (CHCl3) cmꢀ1 1775 (OC@O) and 1700
(NC@O); ½a 2D5
ꢃ
¼ ꢀ165:2 (c 2.0, CHCl3) (Found MH+, 296.1282;
þ
C
18H18NO3 requires 296.1287); the oxazolidin-2-one (R,S)-syn-5
(0.11 g, 57%) as a white solid; RF [light petroleum ether (bp 40–
(NC@O);
½
a 2D5
ꢃ
¼ þ2:8 (c 5.5, CHCl3) (Found MH+ 310.1438.
60 °C)/diethyl ether (1:1)] 0.42; mp 140–142 °C; mmax (CHCl3)
cmꢀ1 1778 (OC@O) and 1701 (NC@O); ½a 2D5
¼ þ88:5 (c 4.0, CHCl3)
ꢃ
+
C19H20NO3 requires 310.1443). RF differences [light petroleum
ether (bp 40–60 °C)/diethyl ether (1:1)]—(R,R)-anti-4 (RF 0.64);
(S,R)-syn-4 (RF 0.43); (S,S)-anti-93 (RF 0.66); and (R,S)-syn-93 (RF
0.43).
(Found MH+, 296.1286; C15H18NO3 requires 296.1287). RF differ-
ences [light petroleum ether (bp 40–60 °C)/diethyl ether (1:1)]—
(R,R)-anti-4 (RF 0.64); (S,R)-syn-4 (RF 0.43); (R,S)-anti-5 (RF 0.58)
and (S,S)-syn-5 (RF 0.42).
þ
4.14.5. Parallel kinetic resolution of pentafluorophenyl 2-
phenylpropanoate (rac)-15 with 4-isopropyl-oxazolidin-2-one
(S)-2 and ethyl oxazolidin-2-one 4-carboxylate (S)-91
4.15. Hydrolysis of oxazolidin-2-ones (S,R)-4 and (R,S)-5
In the same way as the oxazolidin-2-one (rac)-4, n-butyl lithium
(0.58 mL, 2.5 M in hexane, 1.45 mmol), 4-isopropyl-oxazolidin-2-
one (S)-2 (84 mg, 0.65 mmol), ethyl oxazolidin-2-one 4-carboxylate
(S)-91 (0.103 g, 0.65 mmol) and pentafluorophenyl 2-phenylpro-
panoate (rac)-15 (0.458 g, 1.45 mmol), gave a mixture of two dia-
stereoisomeric oxazolidin-2-ones (R,S)-syn- and (S,S)-anti-5 (ratio
95:5:syn-:anti-) and oxazolidin-2-ones (S,S)-syn- and (R,S)-anti-94
(ratio 95:5:syn-:anti-). The crude residue was purified by flash
chromatography on silica gel eluting with light petroleum ether
(bp 40–60 °C)/diethyl ether (7:3) to give oxazolidin-2-one (R,S)-
anti-94 (4 mg, 2%) as a colourless oil; RF [light petroleum ether
(bp 40–60 °C)/diethyl ether (1:1)] 0.42; mmax (CHCl3) cmꢀ1 1794
4.15.1. 2-Phenyl-propanoic acid (+)-(S)-6
Lithium hydroxide monohydrate (71 mg, 1.69 mmol) was
slowly added to a stirred solution of oxazolidin-2-one (S,R)-syn-4
(0.25 g, 0.84 mmol) and hydrogen peroxide (0.47 mL, 3.53 M in
H2O, 1.69 mmol) 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 ꢂ 10 mL). The combined organic layers were dried (over MgSO4)
and evaporated under reduced pressure to give the recovered 4-
phenyl oxazolidin-2-one (R)-1 (127 mg, 93%) as a white solid; RF
[ethyl acetate/ethanol (9:1)] 0.71; mp 130–133 °C; ½a D25
¼ ꢀ54:0
ꢃ
(c 1.0, CHCl3); mmax (CHCl3) cmꢀ1 3262 (NH) and 1736 (C@O); dH
(400 MHz; CDCl3) 7.41–7.31 (5H, m, 5 ꢂ CH; Ph), 5.69 (1H, s,
NH), 4.93 (1H, dd, J 8.6 and 6.9, PhCHN), 4.72 (1H, t, J 8.6, CHAHBO)
and 4.17 (1H, dd, J 8.6 and 6.9, CHAHBO); dC (100 MHz; CDCl3) 159.4
(C@O), 139.3 (i-C; Ph), 129.2,2 128.91 and 126.02 (5 ꢂ CH; Ph), 72.5
(CH2O) and 56.3 (PhCHN) (Found MNH4þ, 181.0970; C9H13N2O2 re-
quires 181.0972). The aqueous phase was acidified using HCl (3 M
HCl) until the pH 3, and extracted with diethyl ether (3 ꢂ 10 mL).
The combined organic phases were dried (over MgSO4) and evapo-
rated under reduced pressure to give 2-phenylpropanoic acid (S)-6
(113 mg, 90%) as a colourless oil; RF [light petroleum spirit (bp 40–
(OC@O), 1747 (CC@O) and 1705 (NC@O); ½a D25
¼ ꢀ130:5 (c 2.1,
ꢃ
CHCl3); the oxazolidin-2-one (S,S)-syn-94 (90 mg, 47%) as a white
powder; RF [light petroleum ether (bp 40–60 °C)/diethyl ether
(1:1)] 0.30; mp 97–99 °C; ½a D25
ꢃ
¼ þ24:8 (c 5.3, CHCl3);
mmax (CHCl3)
cmꢀ1 1793 (OC@O), 1747 (CC@O) and 1705 (NC@O); (Found MH+,
þ
292.1195; C15H18NO5 requires 292.1185); oxazolidin-2-one (S,S)-
anti-5 (5 mg, 3%) as a colourless oil; RF [light petroleum ether (bp
40–60 °C)/diethyl ether (1:1)] 0.64; v
max (film) cmꢀ1 1774 (OC@O)
and 1701 (NC@O); ½a D25
ꢃ
¼ þ128:9 (c 3.5, CHCl3) (Found MH+
þ
262.1434; C15H20NO3 requires 262.1443); and the oxazolidin-2-
one (R,S)-syn-5 (96 mg, 57%) as a colourless oil; RF [light petroleum
ether (bp 40–60 °C)/diethyl ether (1:1)] 0.43; vmax (CHCl3) cmꢀ1
60 °C)/diethyl ether (1:9)] 0.5; ½a D25
¼ þ69:5 (c 8.2, CHCl3); mmax
ꢃ
(CHCl3) cmꢀ1 1706 (C@O); dH (400 MHz; CDCl3) 7.26–7.10 (5H,
m, 5 ꢂ CH; Ph), 3.75 (1H, q, J 7.2, PhCHCH3) and 1.50 (3H, d, J 7.2,
PhCHCH3); dC (100 MHz; CDCl3) 180.4 (C@O), 139.7 (i-C; Ph),
128.7,2 127.62 and 127.41 (5 ꢂ CH; Ph), 45.3 (PhCHCH3) and
18.1 (PhCHCH3) (Found MNH4þ, 151.0753; C9H11NO2 requires
151.0759).
1774 (OC@O) and 1703 (NC@O); ½a D25
¼ ꢀ19:8 (c 3.3, CHCl3)
ꢃ
(Found MH+ 262.1432; C15H20NO3 requires 262.1443). RF differ-
ences [light petroleum ether (bp 40–60 °C)/diethyl ether (1:1)]—
(S,S)-anti-5 (RF 0.64); (R,S)-syn-5 (RF 0.43); (R,S)-anti-94 (RF 0.42)
and (S,S)-syn-94 (RF 0.30).
þ
4.14.6. Parallel kinetic resolution of pentafluorophenyl 2-
phenylpropanoate (rac)-15 with 4-phenyl oxazolidin-2-one (R)-
1 and 4-isopropyl-oxazolidin-2-one (S)-2
4.15.2. 2-Phenylpropanoic acid (ꢀ)-(R)-6
In the same way as the 2-phenylpropanoic acid (S)-6, oxazoli-
din-2-one (R,S)-syn-5 (0.2 g, 0.76 mmol), lithium hydroxide mono-
hydrate (64 mg, 1.53 mmol) and hydrogen peroxide (0.43 mL,
3.53 M in H2O, 1.53 mmol) in THF/water (1:1; 3 mL) gave, the
recovered 4-isopropyl-oxazolidin-2-one (S)-2 (76 mg, 78%) as a
white solid; RF [ethyl acetate/ethanol (9:1)] 0.82; mp 71–73 °C;
In the same way as the oxazolidin-2-one (rac)-4, n-butyl lithium
(0.58 mL, 2.5 M in hexane, 1.45 mmol), 4-isopropyl-oxazolidin-2-
one (S)-2 (84 mg, 0.65 mmol), 4-phenyloxazolidin-2-one (R)-1
(0.106 g, 0.65 mmol) and pentafluorophenyl 2-phenylpropanoate
(rac)-15 (0.458 g, 1.45 mmol), gave a mixture of two diastereoiso-
meric oxazolidin-2-ones (S,R)-syn- and (R,R)-anti-4 (ratio 95:8:syn-
:anti-) and oxazolidin-2-ones (R,S)-syn- and (S,S)-anti-5 (ratio
95:5:syn-:anti-). The crude residue was purified by flash chroma-
tography on silica gel eluting with light petroleum ether (bp 40–
60 °C)/diethyl ether (7:3) to give oxazolidin-2-one (R,R)-anti-4
(6 mg, 3%) as a colourless oil; RF [light petroleum ether (bp 40–
60 °C)/diethyl ether (1:1)] 0.64; vmax (film) cmꢀ1 1774 (OC@O)
½
a 2D5
ꢃ
¼ þ13:0 (c 2.6, CHCl3); mmax (CHCl3) cmꢀ1 3455 (NH) and
1750 (C@O); dH (400 MHz; CDCl3) 7.26 (1H, broad s, NH), 4.34
(1H, t, J 8.7, CHAHBO), 4.00 (1H, dd, J 8.7 and 6.4, CHAHBO) and
3.53 (1H, tdd, J 8.7, 6.7 and 6.4, CHN); 1.67–1.57 (1H, br octet, J
ꢁ6.7, CH(CH3)2, 0.86 (3H, d, J 6.7, CHACHCHB) and 0.80 (3H, d, J
3
3
6.7, CHA3 CHCH3B); dC (100 MHz, CDCl3) 160.6 (C@O), 68.4
(CH2O), 58.2 (CHN), 32.6 (CH(CH3)2), 17.7 (CHACHCHB) and 17.4
3
3
(CHA3 CHCH3B) (Found MNH4
, 147.1129; C9H15N2O2 requires
þ

438
N. A. Shaye et al. / Tetrahedron: Asymmetry 22 (2011) 413–438
MNH4þ, 147.1128); and 2-phenylpropanoic acid (R)-6 (97 mg, 85%)
as a colourless oil; RF [light petroleum spirit (bp 40–60 °C)/diethyl
Dehli, J. R.; Gotor, V. Chem. Soc. Rev. 2002, 31, 365–370; (d) Dehli, J. R.; Gotor, V.
ARKIVOC 2002, v, 196–202.
3. (a) Davies, S. G.; Diez, D.; El Hammouni, M. M.; Garner, A. C.; Garrido, N. M.;
Long, M. J.; Morrison, R. M.; Smith, A. D.; Sweet, M. J.; Withey, J. M. Chem.
Commun. 2003, 2410–2411; (b) Davies, S. G.; Garner, A. C.; Long, M. J.; Smith, A.
D.; Sweet, M. J.; Withey, J. M. Org. Biomol. Chem. 2004, 2, 3355–3362; (c) Davies,
S. G.; Garner, 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;
(d) Aye, Yimon.; Davies, S. G.; Garner, A. C.; Roberts, P. M.; Smith, A. D.;
Rhomson, J. E. Org. Biomol. Chem. 2008, 6, 2195–2203.
ether (1:9)] 0.5; ½a D25
ꢃ
¼ ꢀ68:5 (c 2.4, CHCl3); mmax (CHCl3) cmꢀ1
þ
1710 (C@O) (Found MNH4
, 151.0755; C9H11NO2 requires
151.0759).
Butyl 2-phenylpropanoate can form by the addition of n-BuLi to
the active ester. Characterisation data for butyl 2-phenylpropano-
ate (rac)-; RF [light petroleum (40–60 °C)/diethyl ether (1:1)]
0.85; mmax (film) cmꢀ1 1674 (C@O); dH (400 MHz; CDCl3) 7.28–
7.15 (5H, m, 5 ꢂ CH; Ph), 3.99 (2H, td, J 6.8 and 1.5, OCH2), 3.63
(1H, q, J 7.2, PhCHCH3), 1.52–1.43 (2H, m, CH2), 1.42 (3H, d, J 7.2,
PhCHCH3), 1.28–1.18 (2H, m, CH2) and 0.79 (3H, t, J 7.5, CH3CH2);
dC (100 MHz; CDCl3) 174 (C@O), 140.6 (i-C; Ph), 128.4,2 127.42
and 126.91 (5 ꢂ CH; Ph), 64.5 (OCH2), 45.5 (PhCHCH3), 30.4 and
18.9 (2 ꢂ CH2), 18.4 (PhCHCH3) and 13.6 (CH3CH2) (Found
MNH4þ, 224.1545. C13H22NO2 requires MNH4þ, 224.1645).
4. (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119, 2584–2585; (b) Vedejs, E.;
Rozners, E. J. Am. Chem. Soc. 2001, 123, 2428–2429; (c) Vedejs, E.; Daugulis, O.;
Mackay, J. A.; Rozners, E. Synlett 2001, 1499–1505.
5. (a) Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.; Northen, J.; Yohannes,
Y. Tetrahedron Lett. 2005, 46, 2897–2902; (b) Coumbarides, G. S.; Dingjan, M.;
Eames, J.; Flinn, A.; Motevalli, M.; Northen, J.; Yohannes, Y. Synlett 2006, 101–
105; (c) 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; (d) Coumbarides, G. S.;
Dingjan, M.; Eames, J.; Flinn, A.; Northen, J. Chirality 2007, 19, 321–328; (e)
Chavda, S.; Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.; Northen, J.
Chirality 2007, 19, 321–328; (f) Boyd, E.; Chavda, S.; Eames, J.; Yohannes, Y.
Tetrahedron: Asymmetry 2007, 18, 476–482; (g) Chavda, S.; Coulbeck, E.;
Dingjan, M.; Eames, J.; Flinn, A.; Northen, J. Tetrahedron: Asymmetry 2008, 19,
1536–1548; (h) Coulbeck, E.; Eames, J. Tetrahedron: Asymmetry 2008, 19, 2223–
2233.
4.16. Computational details
The conformational space of each structure was first explored
using the UFF molecular-mechanics force field19 combined with a
Monte Carlo search over 5000 independent conformers using the
openbabel package [[openbabel.org]]. The structures were then
re-optimised using dispersion-corrected density functional theory
(DFT) at the RI-PBE-D/6-311++G(d,p) level of theory using the
ORCA ab initio package.20 The usage of dispersion-corrected
DFT21 is crucial in this case due to the presence of significant
6. Zhang, Q. S.; Curran, D. P. Chem. Eur. J. 2005, 4866–4880.
7. (a) Coumbarides, G. S.; Eames, J.; Flinn, A.; Northen, J.; Yohannes, Y. Tetrahedron
Lett. 2005, 46, 849–853; (b) Chavda, S.; Coulbeck, E.; Coumbarides, G. S.;
Dingjan, M.; Eames, J.; Ghilagaber, S.; Yohannes, Y. Tetrahedron: Asymmetry
2006, 17, 3386–3399.
8. Bodanszky, M.; Bednarek, M. A. J. Protein Chem. 1989, 8, 461–469; For a recent
example, see: Zhang, F.; Fox, J. M. Org. Lett. 2006, 8, 2965–2968.
9. Using the method outlined in: Liao, L.; Zhang, F.; Dmitrenko, O.; Bach, R. D.;
Fox, J. M. J. Am. Chem. Soc. 2004, 126, 4490–4491.
10. For oxazolidin-2-one (rac)-anti-4, the PhCHN double doublet appeared at
5.32 ppm (1H, dd, J = 8.8 and 3.2), whereas, for oxazolidin-2-one (rac)-syn-4,
the PhCHN double doublet appeared at 5.45 ppm (1H, dd, J = 9.0 and 5.1).
11. Chavda, S.; Coulbeck, E.; Eames, J. Tetrahedron Lett. 2008, 49, 7398–
7402.
12. From these studies, it appears that the syn-oxazolidin-2-one is preferentially
formed, but decomposes faster to give 2-phenylpropanoic acid than its
corresponding anti-diastereoisomer.
p–p interactions. In order to obtain reliable total energies, we re-
optimise the RI-PBE-D structures at the RI-TPSS-D/def2-TZVP level
of theory. The TPSS functional22 has been shown to provide a reli-
able description of energetics and reaction barriers for a number of
test sets.23
13. For
pKa
values
see:
www2.lsdiv.harvard.edu/labs/evans
and
Acknowledgements
www.chem.wisc.edu/areas/reich.
14. The enantiomeric excess can also be determined by self-coupling to form an
anhydride, see: Coulbeck, E.; Eames, J. Tetrahedron: Asymmetry 2009, 20, 635–
640.
15. Al Shaye, N.; Broughton, T. W.; Coulbeck, E.; Eames, J. Synlett 2009, 960–
964.
16. Benoit, D.; Coulbeck, E.; Eames, J.; Motevalli, M. Tetrahedron: Asymmetry 2008,
19, 1069–1077.
17. The relative energy of C is estimated from half the energy of each dimer D and
E.
18. In some cases, the faster eluting major diastereoisomeric oxazolidinone (e.g.,
syn-A) can co-elute with the slower minor diastereoisomer (e.g., anti-B). When
the diastereoselectivity of these processes is high (>96% de); isolation of the
minor diastereoisomers is difficult.
19. Rappe, A. K.; Casewit, C. J.; Colwell, K. S.; Goddard, W. A., III; Skiff, W. M. J. Am.
Chem. Soc. 1992, 114, 10024–10039.
We are grateful to the EPSRC (to E.C. and Y.Y), and Queen Mary,
University of London, Onyx Scientific Limited (to M.D.) and Syn-
genta (to S.C.) for studentships, The Royal Society, The University
of London Central Research Fund and The University of Hull for
their financial support (to E.C. and J.E.), and the EPSRC National
Mass Spectrometry Service (Swansea) for accurate mass determi-
nations. We are indebted to the Deutsche Forschungsgemeinschaft
for generous support (SFB569-TPN1 to D.M.B.) and we gratefully
acknowledge the bwGRiD project for computational resources
(www.bw-grid.de).
20. Neese, F. ORCA—an ab initio, Density Functional and Semiempirical program
package, Version 2.6.35; University of Bonn: 2008.
References
21. Grimme, S. J. Comput. Chem. 2006, 27, 1787–1799.
22. Tao, J.; Perdew, J. P.; Staroverov, V. N.; Scuseria, G. E. Phys. Rev. Lett. 2003, 91,
146401.
1. Fogassy, E.; Nogradi, M.; Palovicsc, E.; Schindlerc, J. Synthesis 2005, 20, 1555–
1568.
2. Reviews: see: (a) Eames, J. Angew. Chem., Int. Ed. 2000, 39, 885–888; (b) Eames,
J. Organic Synthesis Highlights; VCH: Wiley, 2003. Chapter 17, pp 151–164; (c)
23. Kanai, Y.; Wang, X.; Selloni, A.; Car, R. J. Chem. Phys. 2006, 125, 234104.