A method for determining the enantiomeric purity of profens

Article abstract of DOI:10.1016/j.tetasy.2009.02.051

A simple method for determining the enantiomeric purity of profens (based on the carbon skeleton of 2-phenylpropionic acid) is discussed. The enantiomeric purity of a given profen can be determined by stereospecific DCC self-coupling to give a statistical diastereoisomeric mixture of racemic and meso- anhydrides. The relative ratio of diastereoisomers formed can be related to the enantiomeric excess of the original carboxylic acid.

Full text of DOI:10.1016/j.tetasy.2009.02.051

Tetrahedron: Asymmetry 20 (2009) 635–640
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A method for determining the enantiomeric purity of profens
*
Elliot Coulbeck, 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 26 January 2009
Accepted 26 February 2009
A simple method for determining the enantiomeric purity of profens (based on the carbon skeleton of
2-phenylpropionic acid) is discussed. The enantiomeric purity of a given profen can be determined by
stereospecific DCC self-coupling to give
a statistical diastereoisomeric mixture of racemic and
meso- anhydrides. The relative ratio of diastereoisomers formed can be related to the enantiomeric excess
of the original carboxylic acid.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
resolution.13 We now report a synthetic extension to this approach
by determining the enantiomeric purity of 2-phenylpropionic acid
Since 2004, we have been interested in the parallel kinetic res-
olution1 of profen-based active esters,2 such as pentafluorophenyl
2-phenylpropionate (rac)-23 [formed from the N,N0-dicyclohexyl-
carbodiimide (DCC) coupling of 2-phenylpropionic acid (rac)-1
and pentafluorophenol in 92% yield] using a combination of qua-
si-enantiomeric oxazolidin-2-ones (R)-3 and (S)-4 (Scheme 1).4
This process has been shown to be highly enantiomer selective
leading to two separable oxazolidin-2-one adducts (S,R)-syn-5 (in
53% yield with 96% de) and (R,S)-syn-6 (in 50% yield with 96%
de). Hydrolysis of both adducts (S,R)-syn-5 and (R,S)-syn-6 using
LiOH–H2O and H2O2 in THF/H2O (3:1), gave the corresponding
enantiomerically enriched 2-phenyl propionic acids (S)- and (R)-1
in good yield with >98% ee and 96% ee, respectively (Scheme 1).
There are a variety of methods available for determining the
enantiomeric purity of 2-phenylpropionic acid and related pro-
fens.5 Chemical methods6 have primarily been focussed on derivat-
isation7 (with an enantiomerically pure reagent, such as an
alcohol8) and thermodynamic salt formation (by the addition of
an enantiomerically pure chiral ammonium salt9). Non-chemical
methods, such as chiral HPLC10 and/or NMR chiral shift reagents,
have also been used extensively.11
1 and related profens using a stereospecific DCC coupling reaction
to give a statistical mixture of two diastereoisomeric chiral and
meso-anhydrides. The diastereoisomeric ratio of the anhydrides
can be related to the enantiomeric purity of the original carboxylic
acids. As the coupling is stereorandom there is no requirement for
the reaction to be driven to completion. This concept is well docu-
mented14 and has been used previously to enhance enantiomeric
purity15 and to determine the enantiomeric purity using chiral sys-
tems.16 There are a limited number of reports17 where a statistical
resolution has been used to determine enantiomeric excess of alco-
18,19
hols and thiols using PCl3
and (PhO)2PS2H.20
In an attempt to avoid this inherent rate difference, we became
interested in developing an efficient and reliable derivatisation
procedure for determining the enantiomeric excesses of 2-phenyl-
propionic acid (and related profens) which was independent of
percentage conversion. For a diastereoselective coupling to have
a minimal kinetic resolution, the stereochemical information [ste-
reocentre(s)] present within the coupling reagent must to be posi-
tioned away from its reaction site in order to have no
stereochemical discrimination. However, there is clearly a balance
needed as for two non-isotopic diastereoisomeric products to be
distinguishable (e.g., using traditional spectroscopic methods);
the stereocentres need to be positioned near enough to one an-
other in order for them to relay their stereochemical information.
For our method, we initially chose to investigate the self-cou-
pling of 2-(4-isobutylphenyl)propionic acid 7 to give the corre-
sponding anhydride 8 using a DCC coupling procedure as this
would not require the use of an additional chiral auxiliary (Scheme
2). Treatment of 2-(4-isobutylphenyl)propionic acid (rac)-7 with
DCC (0.6 equiv) in CH2Cl2, gave an equimolar mixture of two insep-
arable diastereoisomeric anhydrides (rac)-anti- and syn-meso-8 in
78% yield (Scheme 2). Formation of these anhydrides (RS,RS)-
(rac)-anti- and (SR,RS)-meso-syn-8 were stereo-unselective as both
diastereoisomers were formed in a statistical and equimolar
2. Results and discussion
We have previously measured the enantiomeric purity of
2-phenylpropionic acid 1 through chemical derivatisation using
enantiomerically pure 1-phenylethanol.12 This procedure though
successful has an obvious limitation in that the reaction needs to
be driven to completion to ensure complete removal of both
enantiomers of 2-phenylpropionic acid due to its inherent kinetic
* Corresponding author. Tel.: +44 01482 466401; fax: +44 01482 466410.
E-mail address: j.eames@hull.ac.uk (J. Eames).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.051

636
E. Coulbeck, J. Eames / Tetrahedron: Asymmetry 20 (2009) 635–640
DCC
C6F5OH
Ph
CO2H
Me
Ph
CO2C6F5
Me
rac-2; 92%
CH2Cl2
H
rac-1
H
O
O
O
LiOH-H2O
H2O2
Ph
Me
Ph
CO2H
N
O
HN
Ph
O
THF, H2O
H
Me
H
Ph
(S,R)- ; 53%; 96% d.e.
1. n-BuLi (2 equiv.)
THF, -78oC
(S)-1; 92%; >98% e.e.
5
3
(R)-
2. rac-2 (2 equiv.)
O
O
O
LiOH-H2O
H2O2
Ph
Ph
CO2H
Me
(R)-1; 58%; 96% e.e
HN
Ph
O
N
O
THF, H2O
Ph
H
Me
H
Ph
Ph
Ph
Ph
4
(R,S)-6; 50%; 96% d.e.
(S)-
Scheme 1. Parallel kinetic resolution of active ester (rac)-2 using quasi-enantiomeric oxazoldin-2-ones (R)-3 and (S)-4.
O
O
Ar
Ar
O
Me
H
H Me
(S,S)-anti-8
Ar
CO2H
H
Me
78%
DCC
O
O
7
(S)-
Ar
CO2H
Ar
Ar
O
CH2Cl2
Me
H
Ar
CO2H
Me
(R)-7
H
H
Me
Me
Ar = 4-isobutylphenyl
8
(R,R)-anti-
7
H
(rac)-
O
O
Ar
Ar
O
H
Me
H
Me
(S,R)-meso-8
8
8
(RS,RS)-anti- :(SR,RS)-meso- 50:50
Scheme 2. Formation of anhydride 8 by stereorandom coupling of 2-(4-isobutylphenyl)propionic acid (rac)-7.
amount. This coupling procedure was also shown to be stereospe-
cific as treatment of enantiomerically pure 2-(4-isobutyl-
phenyl)propionic acid (S)-7 under identical conditions gave a
single diastereoisomeric anhydride (S,S)-anti-8 in 89% yield with
>99% diastereoisomeric excess.22 The enantiomeric purity of this
anhydride was established through simple hydrolysis [using
LiOH–H2O and H2O2 in THF/H2O (3:1) to give (S)-7 in 96% yield]
and derivatisation of the resulting carboxylic acid with enantiome-
rically pure 1-phenylethanol (S)-9 using a DMAP-mediated DCC
coupling procedure to give the enantiomerically and diastereoiso-
merically pure ester (S,S)-anti-10 in 74% yield (Scheme 3).
With this information at hand, we next investigated the accu-
racy and reliability of this method for determining enantiomeric
purity for a series of scalemic mixtures of 2-(4-isobutylphenyl)pro-
pionic acid (S)-7 (Table 1). DCC coupling of enantiomerically im-
pure samples of 2-(4-isobutylphenyl)propionic acid (S)-7 with
10% ee, 50% ee and 90% ee, gave inseparable mixtures of anhy-
drides (S*,S*)-anti-21 and meso-8 as the major stereoisomers with
2%, 26% and 82% diastereoisomeric excesses. These statistical levels
of diastereoselectivity were found to be identical to their theoret-
ical values. This procedure does appear to be reliable for determin-
ing the enantiomeric excesses of samples with moderate to high
levels of enantiomeric purity (Tables 1 and 2). However, for sam-
ples with lower levels of enantiomeric purity (ca. 10% ee), the sta-
tistical levels of diastereoselectivity were near indistinguishable
from a racemic sample by NMR spectroscopy (Tables 1 and 2).
We next probed the generality of this DCC coupling method for
determining enantiomeric purity by screening a series of structur-
ally related 2-aryl/phenyl-propionic acids (R)-1, (S)-11, (S)-12 and
(S)-13, and 2-phenylbutanoic acids (S)-14 and (R)-15 (Scheme 4).
Under our standard conditions, the racemic carboxylic acids
(rac)-1 and (rac)-11–15 were shown to give a stereo-unselective
equimolar mixture of corresponding diastereoisomeric anhydrides
(rac)-anti- and meso-16–21 (Table 3). In comparison, the enantio-
merically pure carboxylic acids (R)-1, (S)-11–14 and (R)-15, gave
stereospecifically the diastereoisomerically pure anhydrides

E. Coulbeck, J. Eames / Tetrahedron: Asymmetry 20 (2009) 635–640
637
O
O
89%
Ar
CO2H
Ar
Ar
Me
DCC
O
CH2Cl2
Me
H
Me
H
H
Ar = 4-isobutylphenyl
(S,S)-anti-8; >99% e.e.; >99% d.e.
(S)-7
HO
Ph
(S)-
DCC, DMAP
CH2Cl2
H
O
Ph
O
H
96%
Me
9
LiOH-H2O
Ar
CO2H
Ar
Me
(S,S)-anti-10; >99% e.e.; 98.6% d.e.
Me
Me
H
THF, H2O
H
Ar = 4-isobutylphenyl
74%
(S)-7
Scheme 3. Stereospecific formation of anhydride (S,S)-anti-8 and ester (S,S)-anti-10.
Table 1
O
O
Statistical self-coupling of enantiomerically pure, scalemic and racemic 2-(4-isobu-
tylphenyl)propionic acids
Ph
CO2H
Me
(R)-1
Ph
Ph
Tol
Ar
DCC
CH2Cl2
O
Carboxylic acid (S)-7; ee
100%
100:0 91:9
100%
89%
90%
50%
63:37
26%
10%
51:49
2%
0%
50:50
0%
H
Me
H
Me H
Anhydride (S*,S*)-821:meso-8
(R,R)-16; 83%
de
Yield
82%
89%
89%
85%
78%
O
O
Theoretical (statistical) ratio 100:0 90.5:9.5
62.5:37.5 50.5:49.5 50:50
DCC
CH2Cl2
Tol
Me
Tol
Me
(S)-11
CO2H
O
H
H
H
Me
Table 2
(S,S)-17; 94%
Theoretical (statistical) ratio of diastereoisomeric anhydrides formed through self-
coupling of scalemic carboxylic acids
O
O
(S)-ee (%)
(S*,S*)-21
meso-
de (%)
Ar
Me
CO2H
DCC
CH2Cl2
Ar
98
96
94
92
90
88
86
84
82
80
78
76
74
72
70
60
50
40
32
26
20
14
10
6
98.02
96.08
94.18
92.32
90.50
88.72
86.98
85.28
83.63
82.00
80.42
78.88
77.38
75.92
74.50
68.00
62.50
58.00
55.12
53.18
52.00
50.98
50.50
50.18
50.02
50.00
1.98
3.92
5.82
7.68
96.04
92.16
88.36
84.64
81.00
77.44
73.96
70.56
67.26
64.00
60.84
57.76
54.76
51.84
49.00
36.00
25.00
16.00
10.24
7.06
O
H
Me
H
H Me
Ar = 6-Methoxy-naphthalene-2-yl
12
18
(S,S)- ; 47%
(S)-
9.50
11.28
13.02
14.72
16.38
18.00
19.58
21.12
22.62
24.08
25.50
32.00
37.50
42.00
44.88
46.12
48.00
49.02
49.50
49.82
49.98
50.00
O
O
DCC
PhO
CO2H
PhO
H
OPh
O
CH2Cl2
H
Me
Me
Me
H
13
19
(S,S)- ; 93%
(S)-
O
O
DCC
Ph
Et
(S)-14
CO2H
Ph
Et
Ph
O
CH2Cl2
H
H
H
Et
(S,S)-20; 85%
4.00
1.96
1.00
0.36
0.04
0.00
O
O
Ph
CO2H
i-Pr
(R)-15
DCC
CH2Cl2
Ph
H
Ph
O
2
0
H
i-Pr
i-Pr
H
(R,R)-21; 53%
Scheme 4. Stereospecific formation of anti-anhydrides (R,R)-16, (S,S)-17, (S,S)-18,
(S,S)-19, (S,S)-20 and (R,R)-21 using DCC coupling.
(R,R)-16, (S,S)-17–20 and (R,R)-21 in excellent yield with high lev-
els of enantiomeric and diastereoisomeric purity (Scheme 4). As
this coupling procedure was found to be stereospecific and ste-
reo-unselective; the relative amounts of both diastereoisomeric
anti- and meso-anhydrides could be related to the enantiomeric
purity of the parent carboxylic acid. To test this concept, we
screened a series of scalemic samples of carboxylic acids (R)-1,
(S)-11–14 and (R)-15 with 50% enantiomeric excess under our
standard conditions, which gave predictably an inseparable diaste-
reoisomeric mixture of anhydrides (R*,R*)-16, (S*,S*)-17–20 and
(R*,R*)-21 in good yields with ꢀ26% diastereoisomeric excesses,
which were in close agreement with their theoretical value (25%
de) (Table 2).21
More interestingly, as this coupling procedure was stereoran-
dom, the diastereoselectivity was independent of the percentage
conversion and the amount of (unreacted) carboxylic acid remain-
ing. In order to test this, we chose to add a sub-stoichiometric
amount of DCC (ꢀ0.1 equiv) to
a solution of 2-(4-isobutyl-
phenyl)propionic acid (S)-7 with 90% ee in CDCl3, which gave a

638
E. Coulbeck, J. Eames / Tetrahedron: Asymmetry 20 (2009) 635–640
Table 3
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 deute-
rium lock. Chemical shifts are quoted in parts per million down-
field from tetramethylsilane. Carbon NMR spectra were recorded
with broad proton decoupling. Infrared spectra were recorded on
a Shimadzu 8300 FTIR spectrometer. Optical rotation was mea-
sured using an automatic AA-10 Optical Activity Ltd polAArimeter.
Statistical self-coupling of enantiomerically pure, scalemic and racemic carboxylic
acids 1 and 11–15
Carboxylic acid
ee?
Anhydrides anti-:meso-
100%
50%
0%
(R)-1
(R,R)-16
100:0
83%
(S,S)-17
100:0
94%
(S,S)-18
100:0
47%
(S,S)-19
100:0
93%
(S,S)-20
100:0
85%
(R,R)-21
100:0
53%
(R*,R*)-1621
63:37
rac-16
50:50
79%
rac-17
50:50
100%
rac-18
50:50
41%
rac-19
50:50
97%
rac-20
50:50
67%
99%
(S)-11
(S)-12
(S)-13
(S)-14
(R)-15
(S*,S*)-1721
64:36
100%
(S*,S*)-1821
63:37
4.1.1. 2-(4-Isopropylphenyl)propionic anhydride (S,S)-8
N,N0-Dicyclohexylcarbodiimide (DCC) (60 mg, 0.29 mmol) was
added to a solution of 2-(4-isopropylphenyl)propionic acid (S)-7
(0.10 g, 0.48 mmol) in CH2Cl2 (5 mL) at room temperature. The
solution was stirred for 2 h, and filtered (using CH2Cl2 as the elu-
ent) to remove the N,N0-dicyclohexylurea, DCU). Water (10 mL)
was added and the resulting mixture was extracted with CH2Cl2
(3 ꢁ 20 mL). The organic layers were combined, dried (over
MgSO4) and evaporated under reduced pressure to give a residue.
Pentane (10 mL) was added, and the resulting organic solution
was filtered and evaporated under reduced pressure to give the
2-(4-isopropylphenyl)propionic anhydride (S,S)-8 (85 mg, 89%) as
51%
(S*,S*)-1921
63:37
84%
(S*,S*)-2021
63:37
73%
(R*,R*)-2121
62:38
rac-21
50:50
45%
63%
diastereoisomeric mixture of anhydrides (S*,S*)-21 and meso-8 in
18% conversion with 78% de (theoretical: ꢀ20% conversion with
81% de) (determined by 400 MHz 1H NMR spectroscopy). From this
diastereoselectivity, the original enantiomeric excess of the parent
2-(4-isobutylphenyl)propionic acid (S)-7 was found to be 89% ee
Using 1H NMR spectroscopy, this approach has also been shown
to be useful for determining the enantiomeric purity of isotopically
labelled carboxylic acids, such as (R)-[D3]-1 (Scheme 5).
a colourless oil; ½a D20
ꢂ
¼ þ60:8 (c 3.6, CHCl3); mmax (film) cmꢃ1
1811 (C@O, asymm) and 1742 (C@O, symm); dH (400 MHz; CDCl3)
7.08–7.02 (8H, m, 8 ꢁ CH; 2 ꢁ Ar), 3.66 (2H, q, J 7.2, 2 ꢁ ArCHCH3),
2.45 (4H, d, J 7.3, 2 ꢁ CH2Ar), 1.85 (2H, septet, J 6.7, 2 ꢁ CH(CH3)2),
1.41 (6H, d,
J
7.2, 2 ꢁ ArCHCH3) and 0.89 (12H, d,
J 6.7,
2 ꢁ CH(CH3)2); dC (100 MHz; CDCl3) 170.02 (2 ꢁ C@O), 141.02
(2 ꢁ i-C; 2 ꢁ Ar), 135.82 (2 ꢁ i-CCH3; 2 ꢁ Ar), 129.54 and 127.34
(8 ꢁ CH; 2 ꢁ Ar), 46.02 (2 ꢁ ArCHCH3), 45.02 (2 ꢁ CH2Ar), 30.22
(2 ꢁ CH(CH3)2), 22.42 (2 ꢁ CH(CH3)2) and 17.72 (2 ꢁ ArCHCH3);
3. Conclusion
m/z: 206 (50%, ArCHCO2H+) and 161 (100, ArCHCH3þ). (Found
þ
MNH4
,
412.2851; C26H38NO3 required 412.2846; found
In conclusion, we have shown that the enantiomeric purity of 2-
aryl/phenyl-propionic acids and 2-phenylbutanoic acids can be
determined efficiently using a DCC-mediated self-condensation
reaction. This procedure was shown to be stereospecific leading
to the formation of an inseparable diastereoisomeric mixture of
statistical chiral and meso-anhydrides. The enantiomeric purity of
the parent carboxylic acid can be related to the relative ratio of dia-
stereoisomers formed,23 and re-isolated through base-mediated
hydrolysis.
ArCHCO2HNH4þ, 224.1645; C13H22NO2 þ required 224.1645, and
þ
found isoureaH+, 413.3160; C26H41N2O2 required 413.3165).
4.1.2. 2-Phenylpropionic anhydride (R,R)-16
In the same way as anhydride (S,S)-8, 2-phenylpropionic acid
(R)-1 (0.10 g, 0.67 mmol) and DCC (82 mg, 32 mmol) in CH2Cl2
(5 mL), gave after selective extraction with pentane, 2-phenylpro-
pionic anhydride (R,R)-16 (78 mg, 83%) as
a colourless oil;
½
a 2D0
ꢂ
¼ ꢃ101:0 (c 3.2, CHCl3);
m
max (film) cmꢃ1 1812 (C@O, asymm)
A typical NMR sample to determine enantiomeric excess. The
and 1742 (C@O, symm); dH (400 MHz; CDCl3) 7.30–7.24 (6H, m,
6 ꢁ CH; 2 ꢁ Ph), 7.15–7.11 (4H, m, 4 ꢁ CH; 2 ꢁ Ph), 3.66 (2H, q, J
7.2, 2 ꢁ PhCHCH3) and 1.43 (6H, d, J 7.2, 2 ꢁ PhCHCH3); dC
(100 MHz; CDCl3) 169.72 (2 ꢁ C@O), 138.62 (2 ꢁ i-C; 2 ꢁ Ph),
128.8,4 127.64 and 127.52 (10 ꢁ CH; 2 ꢁ Ph), 46.42 (2 ꢁ PhCHCH3)
and 17.82 (2 ꢁ PhCHCH3); m/z: 150 (20%, ArCHCO2H+) and 105
appropriate carboxylic acid [e.g., (S)-7; 90% ee (20 mg, 97.1
was added to CDCl3 (0.7 mL) and transferred to an NMR tube
lmol)
(100 mm). DCC (2 mg, 9.7 lmol) was added and the solution was
allowed to stir for 2 min. The sample was analysed by 1H NMR
spectroscopy to give the anhydride (S*,S*)-21 and meso-8 in a rela-
tive 89:11 ratio. The percentage conversion for anhydride forma-
tion was 18%.
(100, ArCHCH3
)
(Found MH+, 283.2498; C18H19O3 required
þ
þ
283.1328, and found isoureaH+, 357.2544; C22H33N2O2 required
357.2536).
þ
4. Experimental
4.1. General
4.1.3. 2-(4-Methylphenyl)propionic anhydride (S,S)-17
In the same way as anhydride (S,S)-8, 2-(4-methylphenyl)propi-
onic acid (S)-11 (9 mg, 55 lmol) and DCC (7 mg, 33 lmol) in
CH2Cl2 (2 mL), gave after selective extraction with pentane, 2-(4-
All solvents were distilled before use. All reactions were carried
out under nitrogen using oven-dried glassware. Flash column chro-
methylphenyl)propionic anhydride (S,S)-17 (8 mg, 94%) as a col-
ourless oil; ½a 2D0
ꢂ
¼ þ83:8 (c 1.6, CHCl3); mmax (film) cmꢃ1 1812
(C@O, asymm) and 1743 (C@O, symm); dH (400 MHz; CDCl3) 7.06
(4H, dABq, J 7.9, 4 ꢁ CH; 2 ꢁ Ar), 7.01 (4H, dABq, J 7.9, 4 ꢁ CH;
2 ꢁ Ar), 3.63 (2H, q, J 7.2, 2 ꢁ ArCHCH3), 2.31 (6H, s, 2 ꢁ CH3Ar)
and 1.41 (6H, d, J 7.2, 2 ꢁ ArCHCH3); dC (100 MHz; CDCl3) 169.92
(2 ꢁ C@O), 137.12 (2 ꢁ i-C; 2 ꢁ Ar), 135.62 (2 ꢁ i-CCH3; 2 ꢁ Ar),
129.44 and 127.54 (8 ꢁ CH; 2 ꢁ Ar), 45.94 (2 ꢁ ArCHCH3 and
2 ꢁ CH3Ar) and 17.82 (2 ꢁ ArCHCH3); m/z: 164 (40%, ArCHCO2H+)
Ph
CO2H
CD3
H
(R)-[D3]-1
Scheme 5. 2-Phenyl-2-trideuteriomethylacetic acid (R)-[D3]-1.

E. Coulbeck, J. Eames / Tetrahedron: Asymmetry 20 (2009) 635–640
639
and 119 (100, ArCHCH3þ). (Found M++NH3, 327.0083; C20H25NO3
7.26–7.21 (6H, m, 6 ꢁ CH; 2 ꢁ Ph), 7.15–7.11 (4H, m, 4 ꢁ CH;
2 ꢁ Ph), 3.10 (2H, d, J 10.2, 2 ꢁ PhCHCH), 2.28 (2H, double septet,
J 10.2 and 6.5, 2 ꢁ CH(CH3)2), 0.94 (6H, d, J 6.5, 2 ꢁ CHACHCHB)
þ
required 327.1829; found isoureaH+, 371.2694; C23H35N2O2 re-
þ
quired 371.2693).
3
3
and 0.60 (6H, d, J 6.5, 2 ꢁ CHACHCHB); dC (100 MHz; CDCl3)
3
3
4.1.4. 2-(6-Methoxy-naphthalene-2-yl)propionic anhydride
(S,S)-18
168.92 (2 ꢁ C@O), 136.42 (2 ꢁ i-C; 2 ꢁ Ph), 128.7,4 128.64 and
127.62
(10 ꢁ CH;
2 ꢁ Ph),
60.52
(2 ꢁ PhCHCH),
31.22
In the same way as anhydride (S,S)-8, 2-(6-methoxy-naphtha-
lene-2-yl)propionic acid (S)-12 (0.10 g, 0.43 mmol) and DCC
(54 mg, 26 mmol) in CH2Cl2 (5 mL), gave after selective extraction
with diethyl ether, 2-(6-methoxy-naphthalene-2-yl)propionic
(2 ꢁ CH(CH3)2), 21.32 and 19.42 (4 ꢁ CH3); m/z: 133 (100%, ArCH-
CO2H+) and 91 (60, PhCH2
)
(Found PhCH(i-Pr)CONH2–H+,
þ
178.1228; C11H16NO+ required 178.1226; found isoureaH+,
þ
385.2857; C24H37N2O2 required 385.2849).
anhydride (S,S)-18 (45 mg, 47%) as a colourless oil; ½a D20
¼ þ18:1
ꢂ
(c 3.5, CHCl3); mmax (film) cmꢃ1 1812 (C@O, asymm) and 1743
(C@O, symm); dH (400 MHz; CDCl3) 7.42 (2H, d, J 8.4, CH;
2 ꢁ Ar), 7.41 (2H, d, J 8.8, CH; 2 ꢁ Ar), 7.32 (2H, br s, CH; 2 ꢁ Ar),
7.06 (2H, dd, J 8.5 and 1.8, CH; 2 ꢁ Ar), 7.02 (2H, dd, J 8.8 and
2.5, CH; 2 ꢁ Ar), 6.95 (2H, d, J 2.5, CH; 2 ꢁ Ar), 3.85 (6H, s,
2 ꢁ OCH3), 3.71 (2H, q, J 7.2, 2 ꢁ ArCHCH3) and 1.41 (6H, d, J 7.2,
2 ꢁ ArCHCH3); dC (100.6 MHz; CDCl3) 170.02 (2 ꢁ C@O), 157.72
(2 ꢁ i-CO; 2 ꢁ Ar), 133.72, 133.62 and 128.82 (6 ꢁ i-C; 2 ꢁ Ar),
129.22, 127.32, 126.32, 125.82, 119.02 and 105.52 (12 ꢁ CH;
2 ꢁ Ar), 55.32 (2 ꢁ OCH3), 46.32 (2 ꢁ ArCHCH3) and 17.82
(2 ꢁ ArCHCH3); (Found ArCH+, 185.0963; C13H13O+ required
4.1.8. 1H NMR assignment of configurations21
For (S*,S*)-anti-8, methyl doublet appears at 1.4344 ppm, for
meso-8, Me doublet appears at 1.4198 ppm;
Dd = +0.0147 ppm
(5.88 Hz at 400 MHz).
For (R*,R*)-anti-16, methyl doublet appears at 1.4399 ppm, for
meso-16, Me doublet appears at 1.4303 ppm;
Dd = +0.0097 ppm
(3.88 Hz at 400 MHz).
For (R*,R*)-anti-17, methyl doublet appears at 1.4170 ppm, for
meso-17, Me doublet appears at 1.4115 ppm;
Dd = +0.0055 ppm
(2.2 Hz at 400 MHz).
For (R*,R*)-anti-18, methyl doublet appears at 1.4180 ppm, for
185.09609; found ArCHCONH2–H+, 230.1180; C14H16NO2 þ re-
meso-18, Me doublet appears at 1.4004 ppm; Dd = +0.0176 ppm
þ
quired 230.1175; found isoureaH+, 437.2803; C27H37N2O3 re-
quired 437.2798).
(7.0 Hz at 400 MHz).
For (R*,R*)-anti-19, methyl doublet appears at 1.5460 ppm, for
meso-19, Me doublet appears at 1.5197 ppm;
Dd = +0.0263 ppm
4.1.5. 2-Phenoxypropionic anhydride (S,S)-19
(10.5 Hz at 400 MHz).
In the same way as anhydride (S,S)-8, 2-phenoxypropionic acid
(S)-13 (34 mg, 0.20 mmol) and DCC (25 mg, 12 mmol) in CH2Cl2
(3 mL), gave after selective extraction with pentane, 2-phenoxy-
propionic anhydride (S,S)-19 (30 mg, 93%) as a colourless oil;
For (R*,R*)-anti-20, methyl triplet appears at 0.8186 ppm, for
meso-20, Me triplet appears at 0.8218 ppm;
D
d = ꢃ0.0032 ppm
(1.3 Hz at 400 MHz). For (R*,R*)-anti-20, the PhCH triplet appears
at 3.4133 ppm, for meso-20, the PhCH triplet appears at
½
a 2D0
ꢂ
¼ ꢃ50:0 (c 6.0, CHCl3); mmax (film) cmꢃ1 1833 (C@O, asymm)
3.4316 ppm;
D
d = ꢃ0.0183 ppm (7.32 Hz at 400 MHz).
and 1758 (C@O, symm); dH (400 MHz; CDCl3) 7.18 (4H, t, J 7.6,
4 ꢁ CH; 2 ꢁ Ph), 6.93 (2H, t, J 7.6, 2 ꢁ CH; 2 ꢁ Ph), 6.75 (4H, d, J
7.6, 4 ꢁ CH; 2 ꢁ Ph), 4.71 (2H, q, J 7.0, 2 ꢁ PhCHCH3) and 1.55
(6H, d, J 7.0, 2 ꢁ PhCHCH3); dC (100 MHz; CDCl3) 167.62 (2 ꢁ C@O),
157.02 (2 ꢁ i-CO; 2 ꢁ OPh), 129.6,4 122.12 and 115.14 (10 ꢁ CH;
2 ꢁ Ph), 72.62 (2 ꢁ PhOCHCH3) and 17.92 (2 ꢁ PhOCHCH3); m/z:
166 (50%, PhOCHCH3CO2H+), 121 (90, PhOCHMe+) and 94 (100,
For (R*,R*)-anti-21, the PhCH doublet appears at 3.0632 ppm, for
meso-21, the PhCH doublet appears at 3.0854 ppm;
ꢃ0.0222 ppm (8.9 Hz at 400 MHz).
Dd =
Acknowledgements
PhOH+). (Found PhOCHCO2H–NH4
,
184.0968; C9H14NO3 re-
þ
þ
We are grateful to the EPSRC for a studentship (to E.C.) and to
the EPSRC National Mass Spectrometry Service (Swansea) for accu-
rate mass determinations.
quired 184.0968; isoureaH+, 373.2491; C22H33N2O3 required
373.2485).
þ
4.1.6. 2-Phenylbutanoic anhydride (S,S)-20
In the same way as anhydride (S,S)-8, 2-phenylbutanoic acid
(S)-14 (0.10 g, 0.61 mmol) and DCC (75 mg, 0.37 mmol) in CH2Cl2
(5 mL), gave after selective extraction with pentane, 2-phenylbuta-
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ꢂ
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