Resolution of pentafluorophenyl esters using oxazolidin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2010.08.109

A series of structurally related racemic pentafluorophenyl active esters were resolved using an equimolar amount of (S)-4-phenyloxazolidin-2-one. The levels of diastereocontrol were found to be excellent (80-96% de) at ～40% conversion.

Full text of DOI:10.1016/j.tetlet.2010.08.109

Tetrahedron Letters 51 (2010) 5892–5895
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Tetrahedron Letters
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Resolution of pentafluorophenyl esters using oxazolidin-2-ones
⇑
Najla Al Shaye, Jason Eames
Department of Chemistry, University of Hull, Cottingham Road, Kingston Upon Hull HU6 7RX, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2010
Revised 9 August 2010
Accepted 31 August 2010
Available online 6 September 2010
A series of structurally related racemic pentafluorophenyl active esters were resolved using an equimolar
amount of (S)-4-phenyloxazolidin-2-one. The levels of diastereocontrol were found to be excellent (80-
96% de) at ꢀ40% conversion.
Ó 2010 Elsevier Ltd. All rights reserved.
The resolution and synthesis of pharmaceutically important 2-
aryl- and 2-phenylpropanoic acids are well documented.1 Since
2000, we have been interested in the resolution2 of pentafluor-
ophenyl active esters derived from 2-aryl- and 2-phenylpropanoic
acids, such as (rac)-2, using Evans’ 4-phenyloxazolidin-2-one (R)-1
(Scheme 1).3 For example, treatment of oxazolidin-2-one (R)-1
with n-BuLi at À78 °C, followed by the addition of an excess of pen-
tafluorophenyl 2-phenylpropanoate (rac)-2 in THF, gave after 2 h,
the corresponding oxazolidin-2-one adducts (S,R)-syn- and (R,R)-
anti-3 in 52% and 4% yields, respectively, in a diastereoisomeric ra-
tio of 92:8 (84% de) (Scheme 1).4 However, using one equivalent or
less of this (rac)-2, resulted in lower levels of diastereocontrol (40%
de) due to competitive oxazolidin-2-one in addition to the less
reactive (R)-enantiomer of 2 to give the minor diastereoisomer
(R,R)-anti-3 (Scheme 1).4
We now report the scope and limitation of this methodology for
the efficient resolution of pentafluorophenyl 2-aryl- and 2-phenyl-
propanoates, such as (rac)-2, using a variety of structurally related
oxazolidin-2-ones as the resolving agent.
We first investigated the time dependence for an efficient reso-
lution of pentafluorophenyl 2-phenylpropanoate (rac)-2 using an
equimolar amount of 4-phenyloxazolidin-2-one (S)-1 (Scheme 2).
Treatment of oxazolidin-2-one (S)-1 with n-BuLi in THF at
À78 °C, followed by addition of the active ester, (rac)-2, and stir-
ring the resulting solution from 1 min to 2 h, gave the correspond-
ing oxazolidin-2-one (R,S)-syn-35 in moderate yield (30–39%) with
poor to excellent levels of diastereocontrol (40–94% de) (Scheme
2).
attempt to improve the levels of diastereocontrol. For a short reac-
tion time (5 min), the relative diastereoselectivity remained con-
stant (94% de) from 2 to 0.25 equiv; however, the yields were
reduced from 57% to 3% (Scheme 3).8 For longer reaction times
(2 h), the diastereoselectivity was reduced by unavoidable addition
of (S)-1 to the less reactive (S)-enantiomer of 2, to give the minor
diastereoisomeric oxazolidin-2-one (S,S)-anti-3 (Scheme 1).
We next turned our attention to study a series of structurally re-
lated active esters (rac)-2, (rac)-4, (rac)-6, (rac)-8, (rac)-10, (rac)-12
and (rac)-14 using our optimum reaction conditions [oxazolidin-2-
one (S)-1, À78 °C, 5 min] (Scheme 4). Treatment of the oxazolidin-
2-one (S)-1 in THF at À78 °C, with n-BuLi, followed by the addition
of active esters (rac)-4, (rac)-8, (rac)-10, (rac)-12 and (rac)-14 in
THF, gave the corresponding oxazolidin-2-one adducts (R,S)-syn-5,
(R,S)-syn-9, (R,S)-syn-11, (R,S)-syn-13 and (R,S)-syn-15 in good yields
(36–54%)with good to excellent levels of diastereoisomeric excesses
(52–96% de) (Scheme 4, entries 2 and 4–7).9,10 From this study, there
O
O
O
O
1. n-BuLi (1.1 equiv.)
THF, -78 oC
O
Ph
Ph
N
O
HN
Ph
O
N
O
O
2.
Me
Me
Ph
Ph
(R,R)-anti-3; 4 %
Ph
OC6F5
Me
(rac)-2
(2 equiv.)
(R)-1
(1 equiv.)
92:8
(S,R)-syn-3; 52 %
Scheme 1. Resolution of active ester (rac)-2 using oxazolidin-2-one (R)-1.
The remaining active ester 2 was isolated by column chroma-
tography in good yield, and was found to have (S)-configuration
(Scheme 2).6,7 The optimum reaction time was found to be 5 min,
leading to the formation of oxazolidin-2-one (R,S)-syn-3 in 39%
yield (out of a possible 50% yield) with 94% de (Scheme 2). With
this information at hand, we next investigated the relative stoichi-
ometry of this active ester (rac)-2, from 0.25 to 2 equiv, in an
O
O
O
O
O
1. n-BuLi,
THF, -78 o
Ph
Me
Ph
C
HN
O
N
O
N
O
2. (rac)-2, n h
H
H
Me
Ph
(S)-1
Ph
(S,S)-anti-3
Ph
(R,S)-syn-3
87:13 (36%)7
1 min
syn-3:anti-3
86:14 (30%)
20 min
97:3 (39%) 93:7 (34%)
5 min
70:30 (34%)
2 h
Time
10 min
⇑
Corresponding author. Tel.: +44 1482 466401; fax: +44 1482 466410.
E-mail address: j.eames@hull.ac.uk (J. Eames).
Scheme 2. Change in diastereoisomeric excess versus reaction time.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.109

N. Al Shaye, J. Eames / Tetrahedron Letters 51 (2010) 5892–5895
5893
O
O
O
appears to be a steric threshold as the most sterically demanding ac-
tive ester, (rac)-6, was unreactive under these reaction conditions
(À78 °C, 5 min). By comparison, the less stericallydemandingpenta-
fluorophenyl 2-phenylbutanoate (rac)-4 gave the corresponding
oxazolidin-2-one (R,S)-syn-5 in 43% yield with the highest level of
diastereocontrol (96% de) (Scheme 4, entry 2). The relatively and less
sterically demanding pentafluorophenyl 2-phenylpropanoate (rac)-
2, gave the corresponding oxazolidin-2-one (R,S)-syn-3 in 39% yield
with marginally lower levels of diastereocontrol (94% de). The
remaining pentafluorophenyl propanoates (rac)-8, (rac)-10 and
(rac)-14 were comparable to the parent pentafluorophenyl 2-phe-
nylpropanoate (rac)-2 (Scheme 4, entries 4, 5 and 7). However, the
active ester, pentafluorophenyl 4-chlorophenyl propanoate (rac)-
12, was notably less stereoselective presumably due to the elec-
tron-withdrawing 4-chlorophenyl group (Scheme 4, entry 6).11
The unreacted active esters, (S)-4, (S)-8, (S)-10, (S)-12 and (S)-14,
were recovered in good yields (20–43%) with moderate to good lev-
els of enantiomeric excesses (46–80% ee) (Scheme 4).9
O
O
1. n-BuLi,
THF, -78 oC
Ph
Me
Ph
HN
Ph
O
N
O
N
O
2. (rac)-2
(n equiv.)
5 min
H
H
Me
Ph
Ph
(S)-1
(R,S)-syn-3
(S,S)-anti-3
syn-3:anti-3
97:3 (7%) 97:3 (3%)
0.5 equiv. 0.25 equiv.
97:3 (57%)
2 equiv.
97:3 (39%)8
1 equiv.
(rac)-2 n equiv.
Scheme 3. Resolution of active ester (rac)-2 using oxazolidin-2-one (S)-1.
O
O
1. n-BuLi (1.1 equiv.)
THF, -78 oC
O
Ar
HN
Ph
O
N
O
2.
O
R
Ar
Ph
OC6F5
(rac)-2, 5 min
R
(S)-1
(1 equiv.)
(R,S)-syn-
(1 equiv.)
In an attempt to increase the levels of diastereoisomeric control,
we next chose to probe the use of other structurally related 4-aryl/
phenyl oxazolidin-2-ones, such as (S)-16, (R)-18 and (R,S)-20
(Scheme 5).12 Treatment of these 4-aryl/phenyl oxazolidin-2-ones
(S)-16, (R)-18 and (R,S)-20 in THF at À78 °C, with n-BuLi, followed
by the addition of our standard active ester, pentafluorophenyl 2-
phenylpropanoate (rac)-2, gave after 5 min the corresponding
oxazolidin-2-ones (R,S)-syn-17, (S,R)-syn-19 and (S,R,S)-syn-21 in
poor to good yields (12–43%), but with excellent levels of diaste-
d.e.
Yield
39%
Product
Entry
1
Active ester
O
O
N
Ph
CO2C6F5
Ph
94% d.e.
96% d.e.
O
O
O
Me
(rac)-2
Me
Ph
(R,S)-syn-3
O
O
Ph
CO2C6F5
Ph
Ph
2
43%
N
Et
Et
Ph
O
O
O
1. n-BuLi (1.1 equiv.)
THF, -78 oC
(rac)-4
(R,S)-syn-5
Ph
HN
R
O
N
O
O
2.
O
O
Me
Ph
R
Ph
CO2C6F5
OC6F5
N
3
0%
Me
(1 equiv.)
(S)-
(rac)-2 , t
(R,S)-syn-
i-Pr
i-Pr
(1 equiv.)
Ph
Entry
t
Oxazolidin-2-one
O
Product
d.e.
Yield
(rac)-6
(R,S)-syn-7
O
O
O
O
N
Tol
CO2C6F5
Tol
Ph
Ph
94% d.e.
40% d.e.
39%
34%
1
2
5 min
2 h
HN
O
N
O
O
4
5
84% d.e.
82% d.e.
36%
44%
Me
Me
Me
Ph
(S)-1
Ph
Ph
(R,S)-syn-3
(rac)-8
(R,S)-syn-9
O
O
O
O
O
4-i-BuC6H4
CO2C6F5
4-i-BuC6H4
12%
30%
90% d.e.
82% d.e.
3
4
5 min
2 h
N
O
HN
Ph
O
N
O
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
(S)-16
(R,S)-syn-17
(rac)-10
(R,S)-syn-11
O
O
O
O
O
4-ClC6H4
CO2C6F5
4-ClC6H4
Ph
N
O
84% d.e.
38% d.e.
36%
53%
5
6
5 min
2 h
6
52% d.e.
80% d.e.
54%
43%
N
O
HN
O
Me
Me
Me
Ph
4-ROC6H4
4-ROC6H4
R = TBDMS
(R)-18
R = TBDMS
(S,R)-syn-19
(rac)-12
(R,S)-syn-13
O
O
O
O
O
Ar
CO2C6F5
Ar
Ph
N
O
90% d.e.
58% d.e.
43%
54%
5 min
2 h
7
8
HN
O
7
N
O
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ar = 6-methoxynaphthyl
(rac)-14
(R,S)-syn-15
(R,S)-20
(S,R,S)-syn-21
Scheme 4. Resolution of active esters (rac)-2, 4, 8, 10, 12 and 14 using oxazolidin-
2-one (S)-1.
Scheme 5. Resolution of active ester (rac)-2 using oxazolidin-2-ones (S)-1, (S)-16,
(R)-18 and (R,S)-20.

5894
N. Al Shaye, J. Eames / Tetrahedron Letters 51 (2010) 5892–5895
O
O
With this information at hand, we next investigated the struc-
tural nature of the oxazolidin-2-one by probing the resolution of
(rac)-2 using a series of 4-alkylsubstituted oxazolidin-2-ones, (S)-
22, (R,S)-24, (S)-26, (S)-28, (S)-30, (S)-32 and (S)-34 (Scheme 6).13
Under our standard reaction conditions (À78 °C, 5 min), the oxaz-
olidin-2-ones, (S)-22 and (S)-30, gave the corresponding oxazoli-
din-2-ones (S,S)-syn-23 and (R,S)-syn-31 in moderate yields, 27%
and 26%, respectively, with high levels of diastereocontrol, 56%
de and 72% de, respectively (Scheme 6, entries 1 and 9). From this
study, it appears that the less sterically demanding oxazolidin-2-
ones, (R,S)-24 and (S)-26, gave the corresponding oxazolidin-2-
ones (S,R,S)-syn-25 and (R,S)-syn-27 in good yields, 54% and 65%,
respectively, but with low levels of diastereocontrol, 28% de and
14% de, respectively (Scheme 6, entries 3 and 5). By comparison,
the more sterically demanding oxazolidin-2-ones (S)-28, (S)-32
and (S)-34 were unreactive under these reaction conditions
(À78 °C, 5 min) (Scheme 6, entries 7, 11 and 13).
O
1. n-BuLi (1.1 equiv.)
THF, -78 oC
Ph
HN
R
O
N
O
2.
O
Me
Ph
R
OC6F5
(S)-
Me
(rac)-2
(1 equiv.)
, t
(R,S)-syn-
(1 equiv.)
Entry
t
Oxazolidin-2-one
O
Product
d.e.
Yield
O
O
Ph
Ph
1
2
5 min
2 h
56% d.e.
28% d.e.
27%
65%
HN
O
N
O
O
Me
EtO2C
(S)-22
EtO2C
(S,S)-syn-23
O
O
O
3
4
5 min
2 h
28% d.e.
8% d.e.
54%
68%
HN
Me
O
N
Increasing the reaction time, from 5 min to 2 h, unsurprisingly
lowered the diastereoselectivity for the oxazolidin-2-ones (S)-22,
(R,S)-24, (S)-26 and (S)-30 (Scheme 6, entries: 2, 4, 6 and 10). How-
ever, for the more sterically demanding oxazolidin-2-ones (S)-28
and (S)-32, the relative diastereoselection was reversed, favouring
formation of the anti-diastereoisomeric adducts14 (S,S)-anti-29 and
(S,S)-anti-33 in moderate yields, 26% and 22%, respectively (Scheme
6, entries 8 and 12). This is somewhat surprising as their less steri-
cally demanding counterparts, oxazolidin-2-ones (S)-26 and (S)-
30, preferred formation of the complementary syn-adducts, (R,S)-
syn-27 and (R,S)-syn-31 (Scheme 6, entries 5–12). For the remaining
sterically demanding oxazolidin-2-one, 4-tert-butyl-oxazolidin-2-
one (S)-34, this favoured formation of the syn-diastereoisomer
(R,S)-syn-35 in a low (14%) yield with moderate diastereoselectivity
(32% de) (Scheme 6, entry 14). Interestingly, Evans-type oxazolidin-
2-ones (S)-1, (S)-22, (R,S)-24, (S)-26, (S)-30 and (S)-34 preferred for-
mation of the syn-diastereoisomeric adducts (R,S)-3, (S,S)-23, (S,R,S)-
25, (R,S)-27, (R,S)-31 and (R,S)-35, whereas, Seebach-type oxazoli-
din-2-ones, (S)-28 and (S)-32, preferred formation of the comple-
mentary anti-diastereoisomeric adduct (S,S)-anti-29 and (S,S)-anti-
33 (Schemes 5 and 6). The only exception being the less sterically
demanding 4,5,5-triphenyloxazolidin-2-one (S)-16, which favoured
formation of the corresponding syn-adduct (R,S)-17 (Scheme 5, en-
tries 3 and 4). This addition process also occurred in a shorter reac-
tion time (5 min), whereas, for the more steric demanding Seebach
oxazolidin-2-ones, (S)-28 and (S)-32, no addition occurred (Scheme
5, entry 3 vs Scheme 6, entries 7 and 11).
Attempts at forming these syn-oxazolidin-2-one adducts, such as
(R,S)-syn-33, through stereospecific addition of oxazolidin-2-one
(S)-32 to pentafluorophenyl 2-phenylpropanoate (R)-2, were unsuc-
cessful. Addition of a solution of pentafluorophenyl 2-phenylpro-
panoate (R)-2 in THF, to a stirred solution of lithiated oxazolidin-2-
one (S)-32 in THF at À78 °C, gave after 2 h, an inseparable diastereo-
isomeric mixture of oxazolidin-2-ones (S,S)-anti- and (R,S)-syn-33
(ratio 66:34) in 20% yield. By comparison, stereospecific formation
of the complementary oxazolidin-2-one (S,S)-anti-33 [by addition
of oxazolidin-2-one (S)-32 to pentafluorophenyl 2-phenylpropano-
ate (S)-2] was more diastereoselective, leading to the required oxaz-
olidin-2-one (S,S)-anti-33 in 35% yield with 82% de. From this study,
it appears that addition of the sterically demanding oxazolidin-2-
Me
Me
Ph
Ph
(R,S)-24
(S,R,S)-syn-25
O
O
O
Ph
Ph
5
6
5 min
2 h
14% d.e.
2% d.e.
65%
68%
HN
O
N
O
Me
Bn
(S)-26
Bn
(R,S)-syn-27
O
O
O
7
8
5 min
2 h
0%
HN
Bn
O
N
O
66% d.e.
26%
Me
Ph
Ph
Ph
Bn
Ph
(S)-28
(S,S)-anti-29
O
O
O
Ph
Ph
9
5 min
2 h
72% d.e.
20% d.e.
26%
33%
HN
i-Pr
O
N
O
10
Me
i-Pr
(S)-30
(R,S)-syn-31
O
O
O
11
12
5 min
2 h
0%
HN
O
N
O
66% d.e.
32% d.e.
22%
Me
Ph
Ph
Ph
i-Pr
(S)-32
i-Pr
Ph
(S,S)-anti-33
O
O
O
Ph
13
14
5 min
2 h
0%
HN
O
N
O
14%
Me
t-Bu
t-Bu
(S)-34
(R,S)-syn-35
Scheme 6. Resolution of active ester (rac)-2 using oxazolidin-2-ones (S)-22, (R,S)-
24, (S)-26, (S)-28, (S)-30, (S)-32 and (S)-34.
reocontrol (80–90% de) (Scheme 5, entries 3, 5 and 7).12 Under
these reaction conditions (À78 °C, 5 min), the oxazolidin-2-one
(R,S)-20 gave the optimum levels of yield and diastereoselectivity
(43%; 90% de) (Scheme 5). As expected from our previous study,
a longer reaction time (2 h), gave lower levels of diastereocontrol
(Scheme 5, entries 2, 4, 6 and 8). However, for less reactive oxazoli-
din-2-ones, such as (S)-16, the levels of diastereocontrol still
remained high (82% de) primarily due to their lower percentage
conversion (Scheme 5, entries 3 vs 4).
O
O
O
1.
2.
n
-BuLi (1.1 equiv.)
O
THF, -78 o
C
Ph
HN
Ph
O
N
O
HN
Ph
O
O
Et
Ph
Ph
OC6F5
5 min
Et
(
(
R
)-1
(
rac)-1
( , )-syn-5
S S
78%; 26% e.e.
(1 equiv.)
22%; 92%
d.e.
R
)-4
(1 equiv.)
Scheme 7. Resolution of oxazolidin-2-one (rac)-1 using active ester (R)-4.

N. Al Shaye, J. Eames / Tetrahedron Letters 51 (2010) 5892–5895
5895
O
O
O
References and notes
O
LiOH, H2O2
H2O, THF
Ph
Ph
Ph
OH
N
O
HN
Ph
O
1. (a) Sonawane, H. R.; Bellur, N. S.; Ahuja, J. R.; Kulkarni, D. G. Tetrahedron:
Asymmetry 1992, 3, 163; (b) Fuji, K.; Node, M.; Tanaka, F.; Hosoi, S. Tetrahedron
Lett. 1989, 30, 2825; (c) Larsen, R. D.; Corley, E. G.; Davis, P.; Reider, P. J.;
Grabowski, E. J. J. J. Am. Chem. Soc. 1989, 111, 7650; (d) Alper, H.; Hamel, N. J.
Am. Chem. Soc. 1990, 112, 2803; (e) Piccolo, O.; Spreafico, F.; Visentin, G.; Valoti,
E. J. Org. Chem. 1985, 50, 3945; (f) Piccolo, O.; Azzena, U.; Melloni, G.; Delogu,
G.; Valoti, E. J. Org. Chem. 1991, 56, 183; (g) Ohta, T.; Takaya, H.; Kitamura, M.;
Nagai, K.; Noyori, R. J. Org. Chem. 1987, 52, 3174.
2. (a) Coumbarides, G. S.; Eames, J.; Flinn, A.; Northen, J.; Yohannes, Y. Tetrahedron
Lett. 2005, 46, 849; (b) Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.;
Motevalli, M.; Northen, J.; Yohannes, Y. Synlett 2006, 101; (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; (d) Coulbeck, E.; Coumbarides, G. S.; Dingjan, M.;
Eames, J.; Ghilagaber, S.; Yohannes, Y. Tetrahedron: Asymmetry 2006, 17, 3386;
(e) Boyd, E.; Chavda, S.; Eames, J.; Yohannes, Y. Tetrahedron: Asymmetry 2007,
18, 476; (f) Coulbeck, E.; Eames, J. Tetrahedron: Asymmetry 2007, 18, 2313; (g)
Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.; Northen, J. Chirality 2007,
19, 321; (h) Chavda, S.; Coulbeck, E.; Eames, J.; Motevalli, M. Tetrahedron:
Asymmetry 2008, 19, 1274.
Me
Me
Ph
Ph
Ph
(R,S)-20; 94%
(S)-36; 82%; 98% e.e.
(S,R,S)-syn-21
O
O
O
O
Ph
LiOH, H2O2
H2O, THF
OH
N
O
HN
O
Et
Et
Ph
Ph
R)-1; 85%
(S)-37; 89%; >98% e.e.
(
(S,R)-syn-5
Scheme 8. Formation of enantiomerically pure 2-phenyl-propanoic acid (S)-36 and
butanoic acid (S)-37.
one 32 to the active ester 2 is not stereospecific and probably pro-
ceeds via a deprotonation/deprotonation ketene mechanism.
In an attempt to probe the complementarity of this resolution, we
next investigated the resolution of 4-phenyl-oxazolidin-2-ones
(rac)-1 using an enantiomerically pure active ester, pentafluorophe-
nyl 2-phenylbutanoate (R)-4 (Scheme 7). Treatment of the oxazoli-
din-2-one (rac)-1 in THF at À78 °C, with n-BuLi, followed by the
addition of pentafluorophenyl 2-phenylbutanoate (R)-4 in THF,
and stirring the resulting solution for 5 min, gave the oxazolidin-2-
one (S,S)-syn-5 in 22% yield with 92% de (Scheme 7). The remaining
oxazolidin-2-one (R)-1 was recovered with 26% ee (Scheme 7).
Simple hydrolysis of these enantiomerically pure oxazolidin-2-
one adducts, such as (S,R,S)-syn-21 and (S,R)-syn-5, using a combina-
tion of LiOH and H2O2 in THF/H2O (3:1), gives access to the resolved
2-phenylpropanoic acid (S)-36 and 2-phenylbutanoic acid (S)-37 in
good yields with excellent enantiomeric excesses (Scheme 8).6
In conclusion, we have reported the kinetic resolution of a series
of pentafluorophenyl active esters, such as (rac)-2, using 4-aryl/
phenyl-substituted oxazolidin-2-ones, such as (R,S)-20, to give
the corresponding oxazolidin-2-one adduct (S,R,S)-syn-21 in good
yield (43%) with high levels of diastereocontrol (90% de). The levels
of diastereocontrol were found to be highly dependent on the
structural nature of the 4-substituted oxazolidin-2-one. Those
oxazolidin-2-ones that contained a 4-aryl/phenyl-substituted ring
gave higher levels of diastereoselectivity than those contained a
simple 4-alkyl substituent. Increasing the steric demand of these
oxazolidin-2-ones, by using 5,5-diphenyl substitution15 [in the
case of oxazolidin-2-ones (S)-28 and (S)-32] increased the likeli-
hood of non-stereospecific addition pathways. The recovered ac-
tive esters were isolated in good yield (9–90%) and were found
to be enantiomerically enriched with up to 80% ee.
3. (a) Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.; Northen, J.; Yohannes,
Y. Tetrahedron Lett. 2005, 46, 2897; (b) Yohannes, Y. Ph.D. Thesis, University of
London, 2004.
4. Al Shaye, N.; Broughton, T. W.; Coulbeck, E.; Eames, J. Synlett 2009, 960.
5. The level of diastereocontrol was found to be excellent [measured by 1H NMR
(400 MHz) spectroscopy]. For oxazolidin-2-one (S,S)-anti-3, the PhCHN double
doublet is at 5.32 ppm (1H, dd, J = 8.8 and 3.2). Whereas, for oxazolidin-2-one
(R,S)-syn-3, the PhCHN double doublet is 5.45 ppm (1H, dd, J = 9.0 and 5.1).
6. The enantiomeric excess was determined through hydrolysis of the active ester
to give the corresponding carboxylic acid. The enantiomeric excess of this
carboxylic acid was determined through statistical anhydride formation by
treatment with DCC. For further information, see: Coulbeck, E.; Eames, J.
Tetrahedron: Asymmetry 2009, 20, 635.
7. After 1 min—the active ester (S)-2 was recovered in 30% yield with 90% ee. The
enantiomeric excess was confirmed by specific rotation and self-coupling; see
Ref. 6.
8. For 1 equiv—the active ester (S)-2 was recovered in 35% yield with 44% ee. The
enantiomeric excess was confirmed by specific rotation and self-coupling; see
Ref. 6.
9. The following enantiomerically enriched active esters were isolated; Scheme 4,
entry 1—(S)-2; 35%; 46% ee; entry 2—(S)-4; 43%; 80% ee; entry 3—(rac)-6; 90%;
entry 4—(S)-8; 42%; 55% ee; entry 5—(S)-10; 42%; 74% ee; entry 6—(S)-12; 20%;
65% ee; entry 7—(S)-14; 37%; 63% ee.
10. The% ee of the recovered active esters were comparable (within experimental
error) to the theoretical value based on the %yield ( 10%) and %de of the
oxazolidin-2-one adduct.
11. Addition of the lithiated oxazolidin-2-one (S)-1 to the active ester (rac)-12 is
stereospecific as addition to the enantiomerically pure active ester (R)-12 gave
exclusively the major diastereoisomeric oxazolidin-2-one (R,S)-syn-13 in 54%
yield with >98% de.
12. The enantiomerically enriched active ester 2 was isolated; Scheme 5, entry
1—35%; (S)-54% ee; entry 2—14%; (S)-23% ee; entry 3—59%; (S)-17% ee; entry 4—
32%; (S)-53% ee; entry 5—24%; (R)-56% ee; entry 6—15%; (R)-54% ee; entry
7—37%; (R)-66% ee; entry 8—17%; (R)-64% ee.
13. The enantiomerically enriched active ester 2 was isolated; Scheme 6, entry
1—25%; (R)-32% ee; entry 2—17%; (R)-68% ee; entry 3—32%; (R)-37% ee; entry
4—15%; (R)-19% ee; entry 5—14%; (S)-44% ee; 4%; (S)-4% ee; entry 8—31%; (R)-
36% ee; entry 9—37%; (S)-36% ee; entry 10—9%; (S)-16% ee; entry 12—19%; (R)-
33% ee; entry 14—50%; 6% ee.
14. The stereochemistry of the Seebach adducts, (R,S)-syn-17, (S,S)-anti-29 and
(S,S)-anti-33, were confirmed by stereospecific synthesis.
Acknowledgements
15. (a) Bull, S. D.; Davies, S. G.; Garner, A. C.; Kruchinin, D.; Key, M. S.; Roberts, P.
M.; Savory, A. D.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2006, 4, 2945;
(b) Gaul, C.; Schweizer, B. W.; Seiler, P.; Seebach, D. Helv. Chim. Acta 2002, 85,
1546; (c) Hintermann, T.; Seebach, D. Helv. Chim. Acta 1998, 81, 2093.
We are grateful to the Saudi Government for financial support
(to N.A.S), and the EPSRC National Mass Spectrometry Service
(Swansea) for accurate mass determinations.