Parallel kinetic resolution of D-labelled 2-aryl-propionic and butanoic acids using quasi-enantiomeric combinations of oxazolidin-2-ones

Article abstract of DOI:10.1002/chir.20727

The parallel kinetic resolution of racemic 2-aryl-2-deuterio-propionic and butanoic acids using an equimolar combination of quasi-enantiomeric oxazolidin-2-ones is discussed. The levels of diastereoselectivity were high leading to enantiomerically pure D-

Full text of DOI:10.1002/chir.20727

CHIRALITY 22:193–205 (2010)
Parallel Kinetic Resolution of D-Labelled 2-Aryl-Propionic and
Butanoic Acids Using Quasi-Enantiomeric Combinations of
Oxazolidin-2-Ones
ELLIOT COULBECK,1 MARCO DINGJAN,1,2 AND JASON EAMES
1
*
1Department of Chemistry, University of Hull, Hull HU6 7RX, United Kingdom
2Department of Chemistry, Queen Mary, University of London, London E1 4NS, United Kingdom
ABSTRACT
The parallel kinetic resolution of racemic 2-aryl-2-deuterio-propionic
and butanoic acids using an equimolar combination of quasi-enantiomeric oxazolidin-2-
ones is discussed. The levels of diastereoselectivity were high leading to enantiomeri-
C
VV
cally pure D-labeled products in good yield. Chirality 22:193–205, 2010.
2009 Wiley-
Liss, Inc.
KEY WORDS: parallel kinetic resolution; kinetic resolution; quasi-enantiomers; 2-
phenylpropionic acid; resolution; oxazolidin-2-ones
INTRODUCTION
size a series of D-labeled pentafluorophenyl active esters
The synthesis of enantiomerically pure profens1–7 such
as ibuprofen8–10 and naproxen11–14 is well documented.
Since 2005, we have been interested in the mutual and par-
allel kinetic resolutions15–21 of profen-based pentafluoro-
phenyl active esters (based on carbon skeleton of 2-phe-
nylpropionic acid) using a combination of oxazolidin-2-
ones as a strategy for the separation of their enantiomers.
For example, treatment of the active ester, pentafluoro-
phenyl 2-phenylpropionate (rac)-2, with an equimolar
amount of lithiated oxazolidin-2-ones {derived from the
deprotonation of an equimolar mixture of oxazolidin-2-
ones (R)-1 and (S)-1 [: (rac)-1] with n-BuLi}, gave the
corresponding adducts (S,R)-syn- and (R,S)-syn-3 [: (rac)-
syn-3] as the major diastereoisomer in 70% yield with
>94% d.e. (Scheme 1). The corresponding oxazolidin-2-one
anti-3 can be synthesised using Evans’ diasteeoselective
alkylation method; for further information see. Ref. 22–24
From this study, it was apparent that the (R)-enantiomer
of oxazolidin-2-one 1 recognized the (S)-enantiomer of the
active ester 2 to give oxazolidin-2-one (S,R)-syn-3, and the
complementary enantiomeric oxazolidin-2-one (S)-1 recog-
nized the remaining (R)-enantiomer of the active ester 2
to give the enantiomeric adduct (R,S)-syn-3 in an equal
and opposite stereochemical sense (Scheme 1). We have
also demonstrated that an isotopomeric mixture of quasi-
enantiomeric oxazolidin-2-ones (R)-1 and (S)-[D2]-1 can
be used to resolve this active ester (rac)-2 to give an
inseparable mixture of labeled and unlabeled oxazolidin-2-
ones (S,R)-syn-3 and (R,S)-[D2]-syn-3 in a combined 70%
yield with comparable diastereoselection to its unlabeled
variant (>94% d.e.) (Scheme 1).22
[D1]-2 and [D1]-8-10 (Scheme 2). Addition of DCC to a
stirred solution of D-labeled carboxylic acids [D1]-4-7 and
pentafluorophenol in dichloromethane, gave the corre-
sponding pentafluorophenyl active esters [D1]-2 and [D1]-
8-10 in good yields (>85%) with high levels of deuterium
incorporation (>95% D-incorporation) (Scheme 2).
With these active esters in hand, we next probed their
parallel kinetic resolution using an isotopomeric pair of
quasi-enantiomeric oxazolidin-2-ones (R)-1 and (S)-[D2]-1
(Scheme 3). Treatment of an equimolar amount of oxazoli-
din-2-ones (R)-1 and (S)-[D2]-1 with n-BuLi in THF at
2788C, followed by the addition of active esters [D1]-2
and [D1]-8-10, gave after 2 h, an inseparable isotopomeric
mixture of the corresponding oxazolidin-2-one adducts
(S,R)-syn- and (R,R)-anti-[D1]-3, [D1]-11, [D1]-12 and
[D1]-13, and (R,S)-syn- and (S,S)-anti-[D3]-3, [D3]-11,
[D3]-12 and [D3]-13, respectively in good yields (71%–
78%) with high levels of diastereoselectivity (94%–96% d.e.)
(Scheme 3). From this study, there appears to be no pri-
mary or secondary kinetic isotope effect as the levels of
deuterium incorporation remained unchanged during the
course of this reaction. The D-labeled moiety served pri-
marily as a stereochemical marker for enantiomeric recog-
nition.
We first chose to investigate the optical resolution of
these active esters [D1]-2 and [D1]-8-10 using a combina-
tion of separable oxazolidin-2-ones based on Evans’ and
Seebach’s oxazolidin-2-ones (R)-126 and (S)-1427,28, res-
pectively (Scheme 4). Treatment of an equimolar combina-
tion of oxazolidin-2-ones (R)-1 and (S)-14 with n-BuLi in
We now report an extension of this study to the parallel
kinetic resolution of a series of deuterium labeled 2-phe-
nyl/aryl propionic and butanoic acids [D1]-4-725 using a
quasi-enantiomeric combination of isotopomeric and de-
signer oxazolidin-2-ones. For this study, we had to synthe-
C
*Correspondence to: Jason Eames, Department of Chemistry, University
of Hull, Hull HU6 7RX, United Kingdom. E-mail: j.eames@hull.ac.uk
Received for publication 24 September 2008; Accepted 20 February 2009
DOI: 10.1002/chir.20727
Published online 30 April 2009 in Wiley InterScience
(www.interscience.wiley.com).
VV
2009 Wiley-Liss, Inc.

194
COULBECK ET AL.
Scheme 1. Mutual/parallel kinetic resolution of active ester (rac)-2 using (quasi-)enantiomeric oxazolidin-2-ones (R)-1/(S)-1 and (R)-1/(S)-[D2]-1.
THF at 2788C, followed by the addition of the D-labeled (for [D1]-10), respectively, in high yield with excellent lev-
active esters [D1]-2 and [D1]-8-10, gave after 2 h, a mix- els of diastereocontrol (Scheme 5).
ture of oxazolidin-2-one adducts (S,R)-[D1]-syn-3 (in 66%
With these adducts at hand, we next investigated the hy-
yield with 88% d.e.) and (R,S)-[D1]-syn-15 (in 54% yield drolysis of two pairs of quasi-enantiomeric combinations of
with 94% d.e.) (for [D1]-2), (S,R)-[D1]-syn-11 (in 69% yield oxazolidin-2-ones (S,R)-syn-[D1]-3 and (R,S)-syn-[D1]-15,
with 98% d.e.) and (R,S)-[D1]-syn-16 (in 63% yield with 98% and (S,R)-syn-[D1]-20 and (R,S)-syn-[D1]-3 using LiOH
d.e.) (for [D1]-8), (S,R)-[D1]-syn-12 (in 64% yield with 90% monohydrate (mediated by hydrogen peroxide) in THF/
d.e.) and (R,S)-[D1]-syn-17 (in 57% yield with 98% d.e.) (for H2O (3:1) (Scheme 6). Simple treatment of the oxazolidin-
[D1]-9), and (S,R)-[D1]-syn-13 (in 69% yield with 90% d.e.) 2-ones (S,R)-syn-[D1]-3, (R,S)-syn-[D1]-15, (S,R)-syn-[D1]-
and (R,S)-[D1]-syn-18 (in 64% yield with 94% d.e.) (for 20 and (R,S)-syn-[D1]-3 with LiOH/H2O2 in THF/H2O
[D1]-10) in high yields with excellent levels of diastereo- (3:1), and stirring the resulting solution for 12 h, gave the
control (Scheme 4). All products were easily separable by corresponding enantiomerically enriched 2-deuterio-2-phe-
column chromatography [eluting with light petroleum nylpropionic acids [D1]-4 in good yields (Scheme 6). The
ether (b.p. 40-608C)/diether ether (1:1)] {DRF [light petro- enantiomeric excess of 2-phenylpropionic acid 4 was
leum ether (b.p. 40-608C)/diether ether (1:1)] 5 ꢀ0.25} determined by derivatisation with enantiomerically pure 1-
with the exception of those [(R,S)-syn-[D1]- and (S,S)-anti- phenylethanol using a DCC/DMAP coupling procedure;
[D1]-15-18] derived from Seebach’s oxazolidin-2-one (S)- see experimental details for a representative procedure.
14 (Scheme 4).
The levels of deuterium incorporation for the carboxylic
In an attempt to improve separability, we next turned
our attention to probing the parallel kinetic resolution of
these D-labeled active esters [D1]-2 and [D1]-8-10 using a
combination of designer oxazolidin-2-ones based on
Fox’s29 and Evans’26 oxazolidin-2-ones (R)-19 and (S)-1,
respectively, which were known to lead to separable dia-
stereoisomeric adducts. Deprotonation of the oxazolidin-2-
ones (R)-19 and (S)-1 using n-BuLi in THF at 2788C, fol-
lowed by the addition of active esters [D1]-2 and [D1]-8-
10, gave after 2 h, the corresponding oxazolidin-2-ones
(S,R)-[D1]-syn-20 (in 78% with 94% d.e.) and (R,S)-[D1]-syn-
3 (in 69% yield with 94% d.e.) (for [D1]-2), (S,R)-[D1]-syn-
21 (in 67% yield with 98% d.e.) and (R,S)-[D1]-syn-11 (in
68% yield with 98% d.e.) (for [D1]-8), (S,R)-[D1]-syn-22 (in
71% with 90% d.e.) and (R,S)-[D1]-syn-12 (in 76% yield with
92% d.e.) (for [D1]-9), and (S,R)-[D1]-syn-23 (in 77% with
94% d.e.) and (R,S)-[D1]-syn-13 (in 76% yield with 94% d.e.)
Chirality DOI 10.1002/chir
Scheme 2. Synthesis of active esters [D1]-2, [D1]-8, [D1]-9 and [D1]-
10.

D-LABELLED 2-ARYL-PROPIONIC AND BUTANOIC ACIDS
195
Scheme 3. Parallel kinetic resolution of active esters (rac)-[D1]-2 and [D1]-8-10 using quasi-enantiomeric oxazolidin-2-ones (R)-1 and (S)-[D2]-1.
acids (e.g., [D1]-4) remained unchanged (62%) through- automatic AA-10 Optical Activity polarimeter. All isotopi-
out the resolution sequence.
cally labeled oxazolidin-2-one adducts have been given an
L superscript and unlabeled derivatives a U superscript.
EXPERIMENTAL
Pentafluorophenyl 2-deuterio-2-phenyl-propionate
(rac)-[D1]-2
General
All solvents were distilled before use. All reactions were
N,N0-Dicyclohexylcarbodiimide (DCC) (0.78 g, 3.82
carried out under nitrogen using oven-dried glassware. mmol) was slowly added to a stirred solution of 2-deuterio-
Flash column chromatography was carried out using 2-phenylpropionic acid (rac)-[D1]-2 (0.51 g, 3.38 mmol,
Merck Kieselgel 60 (230–400 mesh). Thin layer chroma- [D]:[H] 5 97:3) in dichloromethane (5 mL) at room tem-
tography (TLC) was carried out on commercially available perature. The resulting solution was stirred for 15
pre-coated plates (Merck Kieselgel 60F254 silica). Proton minutes. A solution of pentafluorophenol (0.62 g, 3.40
and carbon NMR spectra were recorded on a Bruker 400 mmol) in dichloromethane (5 mL) was added slowly and
MHz Fourier transform spectrometer using an internal the solution was stirred for a further 12 h. The resulting
deuterium lock. Chemical shifts are quoted in parts per white precipitate (dicyclohexylurea) was removed through
million downfield from tetramethylsilane. Carbon NMR filtration (using a sintered funnel). The reaction was
spectra were recorded with broad proton decoupling. quenched with water (20 mL) and extracted with dichloro-
Infrared spectra were recorded on a Shimadzu 8300 FTIR methane (3 3 10 mL). The combined organic layers were
spectrometer. Optical rotations were measured using an dried (over MgSO4) and evaporated under reduced pres-
Scheme 4. Parallel kinetic resolution of active esters (rac)-[D1]-2 and [D1]-8-10 using quasi-enantiomeric oxazolidin-2-ones (R)-1 and (S)-14.
Chirality DOI 10.1002/chir

196
COULBECK ET AL.
Scheme 5. Parallel kinetic resolution of active esters (rac)-[D1]-2 and [D1]-8-10 using quasi-enantiomeric oxazolidin-2-ones (R)-19 and (S)-1.
sure. The residue was purified by flash column chroma- 1.01 (3 H, t, J 7.5, CH2CH3); dC (100 MHz; CDCl3) 170.1
1
tography on silica gel eluting with light petroleum ether (OC¼¼O), 141.1 (142.36 and 139.88, 2 C, ddtd, JC,F
5
2
3
4
(b.p. 40–608C):diethyl ether (9:1) to give pentafluoro- 251.3 Hz, JC,F 5 11.9 Hz, JC,F 5 3.4 Hz and JC,F 5 3.4
1
phenyl 2-deuterio-2-phenyl-propionate (rac)-[D1]-2 (0.91 g, Hz, C(2)-F), 139.4 (140.65 and 138.14, 1 C, dtt, JC,F
5
2
3
85%, [D]:[H] 5 97:3) as a colourless oil; RF [light petro- 252.8 Hz, JC,F 5 13.9 Hz and JC,1F 5 3.8 Hz, C(4)-F),
leum (40–608C):diethyl ether (1:1)] 0.88; mmax(CH2Cl2)cm21 137.8 (139.04 and 136.55, 2 C, dtdd, JC,F 5 254.3 Hz, JC,F
2
3
4
2397 (C-D) and 1781 (C¼¼O); dH (400 MHz; CDCl3) 7.41-7.25 5 14.2 Hz, JC,F 5 4.9 Hz and JC,F 5 2.6 Hz, C(3)-F),
(5 H, m, 5 3 CH; Ph), and 1.63 (3 H, s, CH3CD); dC (100 137.2 (i-C; Ph), 128.8,2 127.92 and 127.81 (5 3 CH; Ph),
2
4
3
MHz; CDCl3) 170.7 (C¼¼O), 141.4 (142.7 3 and 140.20, 2 C, 125.3 (1 C, tdt, JC,F 5 14.2 Hz, JC,F 5 4.4 Hz and JC,F
5
1
2
3
ddt, JC,F 5 251.3 Hz, JC,F 5 12.2 Hz and JC,F 5 3.8 Hz, 2.2 Hz, i-CO; OC6F5), 52.7 (unlabelled PhCH), 52.3 (1 C, t
C(2)-F), 139.7 (141.00 and 138.48, 1 C, dtt, 1JC,F 5 253.2 Hz, [1:1:1], JC,D 5 20.6 Hz, PhCD), 26.6 (CH2CH3) and 11.8
1
2JC,F 5 13.4 Hz and JC,F 5 4.2 Hz, C(4)-F), 139.0 (i-C; Ph), (CH2CH3) (Found M1, 331.0732; C16H10DF5O2 requires
3
138.1 (139.35 and 136.88, 2 C, dtdd, 1JC,F 5 249.1 Hz, 2JC,F
5
M1, 331.0736); negative isotopic shift at 52.3 ppm (PhCD)
14.5 Hz, JC,F 5 5.7 Hz and JC,F 5 3.1 Hz, C(3)-F), 129.0,2 was 0.3973 ppm (39.7 Hz at 100.6 MHz).
3
4
127.82 and 127.51 (5 3 CH; Ph), 125.4 (1 C, tdt, 2JC,F 5 14.5
4
3
Pentafluorophenyl 2-deuterio-2-
Hz, JC,F 5 4.2 Hz and JC,F 5 2.0 Hz, i-CO; OC6F5), 45.1
1
(4-methylphenyl)propionate (rac)-[D1]-9
(unlabelled PhCHCH3), 44.7 (1 C, t [1:1:1], JC,D 5 19.8 Hz,
PhCDCH3) and 18.5 (PhCDCH3) (Found M1, 317.0579;
C15H8DF5O2 requires M1, 317.0580); negative isotopic
shift at 44.7 ppm (PhCDCH3) was 0.3591 ppm (35.9 Hz at
100.6 MHz).
In the same way as the active ester (rac)-[D1]-2, 2-deu-
terio-2-(4-methylphenyl)propionic acid (rac)-[D1]-6 (0.72 g,
4.35 mmol, [D]:[H] 5 96:6), DCC (1.01 g, 4.91 mmol) and
pentafluorophenol (0.81 g, 4.42 mmol) in dichloromethane
(20 mL), gave after purification by flash column chroma-
tography on silica gel eluting with light petroleum ether
(b.p. 40–608C): diethyl ether (9:1), pentafluorophenyl 2-
Pentafluorophenyl 2-deuterio-2-phenylbutanoate
(rac)-[D1]-8
In the same way as the active ester (rac)-[D1]-2, deuterio-2-(4-methylphenyl)propionate (rac)-[D1]-9 (1.29
2-deuterio-2-phenylbutanoic acid (rac)-[D1]-5 (0.53 g, 3.18 g, 89%, [D]:[H] 5 96:4) as a colourless oil; RF [light petro-
mmol, [D]:[H] 5 96:4), DCC (0.73 g, 3.52 mmol) and pen- leum ether (b.p. 40–608C): diethyl ether (1:1)] 0.83;
tafluorophenol (0.59 g, 3.20 mmol) in dichloromethane (40
m
max(film)cm-1 2399 (C¼¼O) and 1780 (C¼¼O); dH (400
mL), gave after purification by flash column chromatogra- MHz; CDCl3) 7.25 (2 H, dd, J 8.2 and 1.8, 2 3 CH; Ar),
phy on silica gel eluting with light petroleum ether (b.p. 7.19 (2 H, dd, J 8.2 and 1.8, 2 3 CH; Ar), 2.35 (3 H, s, CH3;
40–608C): diethyl ether (9:1), pentafluorophenyl 2-deu- Ar) and 1.62 (3 H, s, CH3CD); dC (100 MHz; CDCl3) 170.8
1
terio-2-phenylbutanoate (rac)-[D1]-8 (0.91 g, 86%, [D]:[H] (C¼¼O), 141.2 (142.50 and 139.95, 2 C, ddt, JC,F 5 251.6
2
3
5 96:4) as a colourless liquid; RF [light petroleum ether Hz, JC,F 5 11.9 Hz and JC,F 5 4.6 Hz, C(2)-F), 139.5
(b.p. 40–608C):diethyl ether (1:1)] 0.80; mmax(CHCl3)cm21 (140.74 and 138.23, 1 C, dtt, JC,F 5 252.8 Hz, JC,F 5 13.4
1
2
3
2399 (C-D) and 1772 (C¼¼O); dH (400 MHz; CDCl3) 7.41- Hz and JC,F 5 3.8 Hz), C(4)-F), 137.9 (139.14 and 136.63,
1
2
3
7.27 (5 H, m, 5 3 CH; Ph), 2.27 (1 H, dq, 13.9 and 7.5, 2 C, dtdd, JC,F 5 252.8 Hz, JC,F 5 12.1 Hz, JC,F 5 5.3 Hz
4
CHAHBCH3), 1.97 (1 H, dq, 13.9 and 7.5, CHAHBCH3) and and JC,F 5 3.1 Hz, C(3)-F), 137.6 and 135.8 (2 3 i-C; Ar),
Chirality DOI 10.1002/chir

D-LABELLED 2-ARYL-PROPIONIC AND BUTANOIC ACIDS
197
Scheme 6. Synthesis of enantiomerically pure 2-deuterio-2-phenylpropionic acids (S)-[D1]- and (R)-[D1]-4.
2
129.72 and 127.42 (4 3 CH; Ar), 125.2 (1 C, tdt, JC,F
5
pentafluorophenol (0.59 g, 3.20 mmol) in dichloromethane
4
3
14.3 Hz, JC,F 5 4.6 Hz and JC,F 5 2.3 Hz, i-CO; OC6F5), (100 mL), gave after purification by flash column chroma-
1
44.8 (1 C, s, unlabelled ArCH), 44.4 (1 C, t [1:1:1], JC,D
5
tography on silica gel eluting with light petroleum ether
19.4 Hz, ArCD), 21.1 (CH3; Ar) and 18.6 (ArCDCH3) (b.p. 40–608C): diethyl ether (9:1), pentafluorophenyl 2-deu-
(Found M1, 331.0739; C16H10DF5O2 requires M1, terio-2-(4-isobutylphenyl)propionate (rac)-[D1]-10 (1.02 g,
331.0736); negative isotopic shift at 44.4 ppm (PhCD) was 87%, [D]:[H] 5 95:5) as a colourless liquid; RF [light petro-
0.3590 ppm (35.9 Hz at 100.6 MHz).
leum ether (b.p. 40–608C):diethyl ether (1:1)] 0.80;
m
MHz; CDCl3) 7.20 (2 H, dt, J 8.2 and 2.2, 2 3 CH; Ar), 7.07
(2 H, dt, J 8.2 and 2.2, 2 3 CH; Ar), 2.40 (2 H, d, J 7.2,
max(CHCl3)cm21 2399 (C-D) and 1781 (C¼¼O); dH(400
Pentafluorophenyl 2-deuterio-2-
(4-isobutylphenyl)propionate (rac)-[D1]-10
In the same way as the active ester (rac)-[D1]-2, 2-deu- CH2CH), 1.86-1.72 (1 H, m, CH(CH3)2), 1.55 (3 H, s,
terio-2-(4-isobutylphenyl)propionic acid (rac)-[D1]-7 (0.65 g, ArCDCH3) and 0.83 (6 H, d, J 6.7, (CH3)2CH); dC (100
3.13 mmol, [D]:[H] 5 95:5), DCC (0.71 g, 3.44 mmol) and MHz; CDCl3) 170.8 (C¼¼O), 141.4 (i-C; Ar), 141.2 (142.50
Chirality DOI 10.1002/chir

198
COULBECK ET AL.
1
2
and 140.01, 2 C, ddt, JC,F 5 251.3 Hz, JC,F 5 11.9 Hz and 0.1681 ppm (16.81 Hz at 400 MHz) and at 43.4482 ppm
3JC,F 5 4.2 Hz, C(2)-F), 139.4 (140.74 and 138.23, 1 C, dtt, was 0.3590 ppm (35.90 Hz at 400 MHz). By mass spec-
2
3
1JC,F 5 253.2 Hz, JC,F 5 13.8 Hz and JC,1F 5 3.8 Hz, C(4)- trometry, this mixture of oxazolidin-2-ones (S,R)-syn-[D1]-3
F), 137.8 (139.14 and 136.64, 2 C, dtdd, JC,F 5 254.7 Hz, and (R,S)-syn-[D3]-3 gave a 52:48 ratio of (S,R)-syn-[D1]-3:
3
4
1
2JC,F 5 14.5 Hz, JC,F 5 5.3 and JC,F 5 3.0 Hz, C(3)-F), (R,S)-syn-[D3]-3. For (S,R)-syn-[D1]-3; found MNH4
,
135.9 (i-C; Ar), 129.72 and 127.22 (4 3 CH; Ar), 124.8 (1 C, 314.1607; C18H20DN2O3 requires MNH41, 314.1609, and
1
tdt, 2JC,F 5 14.2 Hz, 4JC,F 5 4.6 Hz and 3JC,F 5 2.3 Hz, i-CO; for
(R,S)-syn-[D3]-3;
found
MNH4
,
316.1733;
OC6F5), 45.1 (CH2; Ar), 44.7 (unlabelled ArCHCH3), 44.4 (1 C18H18D3N2O3 requires MNH41, 316.1735.
C, t [1:1:1], 1JC,D 5 19.8 Hz, ArCDCH3), 30.1 (CHCH2), 22.3
(CH(CH3)2) and 18.4 (ArCDCH3) (Found M1, 337.1203;
C19H16DF5O2 requires M1, 373.1206); negative isotopic
Parallel kinetic resolution of pentafluorophenyl
2-deuterio-2-phenylbutanoate (rac)-[D1]-8 using
4-phenyl-oxazolidin-2-one (R)-1 and 4-phenyl-5,5-
dideuterio-oxazolidin-2-one (S)-[D2]-1
shift at 44.39 ppm (ArCD) was 0.3629 ppm (36.2 Hz at 100.6
MHz).
Parallel kinetic resolution of pentafluorophenyl
2-deuterio-2-phenylpropionate (rac)-[D1]-2 using
4-phenyl-oxazolidin-2-one (R)-1 and 4-phenyl-
5,5-dideuterio-oxazolidin-2-one (S)-[D2]-1
In the same way as oxazolidin-2-one 3, n-butyl lithium
(0.19 mL, 2.5 M in hexane, 0.47 mmol), 4-phenyl-oxazoli-
din-2-one (R)-1 (33 mg, 0.20 mmol), 4-phenyl-5,5-dideu-
terio-oxazolidin-2-one (S)-[D2]-1 (34 mg, 0.20 mmol), and
n-BuLi (0.19 mL, 2.5 M in hexane, 0.47 mmol) was pentafluorophenyl 2-deuterio-2-phenylbutanoate (rac)-[D1]-
added to a stirred solution of 4-phenyl-oxazolidin-2-one 8 (0.161 g, 0.48 mmol, [D]:[H] 5 96:4), gave an insepara-
(R)-1 (32 mg, 0.20 mmol) and 4-phenyl-5,5-dideuterio-oxa- ble mixture of two diastereoisomeric oxazolidin-2-ones
zolidin-2-one (S)-[D2]-1 (33 mg, 0.20 mmol) in THF (5 (S,R)-[D1]-11 and (R,S)-[D3]-11 (ratio 98:2: syn-:anti-).
mL) at 2788C. After stirring for 1 h, a solution of penta- The crude residue was purified by flash chromatography
fluorophenyl 2-deuterio-2-phenylpropionate (rac)-[D1]-2 on silica gel eluting with light petroleum ether (b.p. 40–
(0.152 g, 0.48 mmol, [D]:[H] 5 97:3) in THF (1 mL) was 608C):diethyl ether (7:3) to give inseparable mixture of
added. The resulting mixture was stirred for 2 h at 2788C. (2S,4R)-3-[2-deuterio-2-phenylbutanoyl]-4-phenyl-oxazolidin-
The reaction was quenched with water (10 mL). The or- 2-one (S,R)-syn-[D1]-11 and (2R,4S)-3-[2-deuterio-2-phenyl-
ganic layer was extracted with diethyl ether (2 3 10 mL), butanoyl]-4-phenyl-5,5-dideuterio-oxazolidin-2-one (R,S)-
dried (over MgSO4) and evaporated under reduced pres- syn-[D3]-11 (97 mg, 78 %; ratio (S,R)-syn-[D1]-11: (R,S)-
sure to give a mixture of diastereoisomeric oxazolidin-2- syn-[D3]-11 5 53:47) as a white solid; RF [light petroleum
ones 3 [ratio 97:3: syn-:anti-]. The crude residue was puri- ether (b.p. 40–608C):diethyl ether (1:1)] 0.47; m.p. 70–
fied by flash chromatography on silica gel eluting with 728C; [a]2D0 5 12.88 (c 3.2, CHCl3); {Ref. 30 (S,R)-syn-11;
light petroleum ether (b.p. 40–608C):diethyl ether (7:3) to [a]2D0 5 177.4 (c 4.0, CHCl3)}; mmax(film)cm-1 2401 (C-D),
give an inseparable mixture of (2S,4R)-3-[2-deuterio-2- 1781 (OC¼¼O) and 1711 (NC¼¼O); dH(400 MHz; CDCl3)
phenylpropionyl]-4-phenyl-oxazolidin-2-one (S,R)-syn-[D1]- 7.22-7.10 (12 H, m, 12 3 CH; 2 3 PhU1L), 7.08-7.04 (4 H,
3
and (2R,4S)-3-[2-deuterio-2-phenylpropionyl]-4-phenyl- m, 4 3 CH; PhU1L), 6.82 (4 H, dt, J 7.2 and 1.5, 4 3 CH;
5,5-dideuterio-oxazolidin-2-one (R,S)-syn-[D3]-3 (84 mg, PhU1L), 5.39 (1 H, dd, J 8.9 and 5.0, CHNU), 5.39 (1 H, s,
71%; ratio (S,R)-syn-[D1]-3: (R,S)-syn-[D3]-3 5 52:48) as a CHNL), 4.55 (1 H, t, J 8.9, CHAHBOU), 3.99 (1 H, dd, J 8.9
white solid; RF [light petroleum ether (b.p. 40–608C): and 5.0, CHAHBOU), 1.97 (2 H, dq, 13.6 and 7.3,
diethyl ether: (1:1)] 0.33; m.p. 121–1238C; (Ref. 22 unla- CHAHBCH3U1L), 1.66 (2 H, dq, 13.6 and 7.3,
belled (rac)-syn-3; m.p. 124-125 8C; unlabelled (R,S)-3; CHAHBCH3U1L) and 0.82 (6 H, t, J 7.3, CH3CH2U1L); nega-
m.p. 128-1308C); [a]D20 5 13.90 (c 1.2, CHCl3) {Ref. 30 tive isotopic shift at 5.39 ppm was 0.0101 ppm (1.01 Hz at
(S,R)-syn-3; [a]D20
5
192.5 (c 4.9, CHCl3)}; vmax 400 MHz); dC(100 MHz; CDCl3) 173.0 (2 C; NC¼¼OU1L),
(CHCl3)cm-1 2400 (C-D), 1780 (OC¼¼O) and 1706 153.1 (2 C; OC¼¼OU1L), 138.2 (2 3 i-C; PhA), 137.9 (2 3 i-
(NC¼¼O); dH(400 MHz; CDCl3) 7.22-7.11 (12 H, m, 12 3 C; PhB), 128.8,4 128.6,4 128.4,6 127.12 and 125.64 (20 3
CH; 2 3 PhU1L), 7.06-7.01 (4 H, m, 4 3 CH; PhU1L), 6.87- CH; 2 3 PhU1L), 69.5 (CH2OU), 68.8 (1 C, quintet, JC,D
5
1
6.82 (4 H, m, 4 3 CH; PhU1L), 5.38 (1 H, dd J 9.0 and 5.1, 20.6, CD2OL), 57.6 (CHNU), 57.5 (CHNL), 51.1 (unlabelled
CHNU), 5.37 (1 H, s, CHNL), 4.57 (1 H, t, J 9.0, CHAH- PhCHCH3), 50.7 (2 C, t [1:1:1], JC,D 5 20.6 Hz,
1
U), 4.02 (1 H, dd, J 9.0 and 5.1, CHAHBOU) and 1.32 (6 PhCDCH3U1L), 26.1 (2 3 CH2CH3U1L) and 11.9 (2 3
BO
H, s, PhCDCH3U1L); negative isotopic shift at 5.37 ppm CH2CH3U1L); negative isotopic shift at 68.8 ppm was
was 0.0106 ppm (1.06 Hz at 400 MHz); dC(100 MHz; 0.6570 ppm (65.70 Hz at 100 MHz), 57.5 ppm was 0.1674
CDCl3) 173.7 (2 C; NC¼¼OU1L), 153.1 (2 C; OC¼¼OU1L), ppm (16.74 Hz at 100 MHz) and 50.7 ppm was 0.3973 ppm
139.7 and 138.2 (4 3 i-C; 2 3 PhU1L), 128.9,4 128.5,6 (39.73 Hz at 100 MHz). By mass spectrometry, this mix-
128.2,4 127.12 and 125.94 (20 3 CH; 2 3 PhU1L), 69.6 ture of oxazolidin-2-ones (S,R)-syn-[D1]-11 and (R,S)-syn-
(CH2OU), 68.9 (1 C, quintet, 1JC,D 5 21.4 Hz, CD2OL), 57.7 [D3]-11 gave a 53:47 ratio of (S,R)-syn-[D1]-11:(R,S)-syn-
(CHNU), 57.6 (CHNL), 43.8 (unlabelled PhCHCH3), 43.4 [D3]-11. For (S,R)-syn-[D1]-11; found MNH41, 328.1769;
1
(2 C, t [1:1:1], JC,D 5 21.4 Hz, PhCDCH3U1L) and 18.5 (2 C19H22DN2O3 requires MNH41, 328.1766, and for (R,S)-
1
3 PhCDCH3U1L); negative isotopic shifts at 68.9405 ppm syn-[D3]-11; found MNH4
was 0.6188 ppm (61.88 Hz at 100 MHz), 57.6039 ppm was requires MNH41, 330.1891.
Chirality DOI 10.1002/chir
, 330.1890; C19H20D3N2O3

D-LABELLED 2-ARYL-PROPIONIC AND BUTANOIC ACIDS
199
Parallel kinetic resolution of pentafluorophenyl
2-deuterio-2-(4-methylphenyl)propionate (rac)-[D1]-9
using 4-phenyl-oxazolidin-2-one (R)-1 and 4-phenyl-
5,5-dideuterio-oxazolidin-2-one (S)-[D2]-1
terio-oxazolidin-2-one (S)-[D2]-1 (21 mg, 0.13 mmol), and
pentafluorophenyl 2-deuterio-2-(4-isobutylphenyl)propio-
nate (rac)-[D1]-10 (0.119 g, 0.32 mmol, [D]:[H] 5 95:5),
gave an inseparable mixture of two diastereoisomeric oxa-
zolidin-2-ones (S,R)-13 and (R,S)-[D2]-13 (ratio 97:3: syn-
:anti-). The crude residue was purified by flash chromatog-
raphy on silica gel eluting with light petroleum ether (b.p.
40–608C):diethyl ether (7:3) to give an inseparable mixture
of (2S,4R)-3-[2-deuterio-2-(4-isobutylphenyl)propionate]-4-
phenyl-oxazolidin-2-one (S,R)-syn-[D1]-13 and (2R,4S)-3-
[2-deuterio-2-(4-isobutylphenyl)propionate]-4-phenyl-5,5-
dideuterio-oxazolidin-2-one (R,S)-syn-[D3]-13 (67 mg, 73%;
ratio (S,R)-syn-[D1]-13: (R,S)-syn-[D3]-13 5 53:47) as a
white solid; RF [light petroleum ether (b.p. 40–608C):dieth-
yl ether (1:1) 0.40; m.p. 69–718C (Ref. 22 unlabelled (rac)-
13; m.p. 69–718C; Ref. 22 (S,R)-syn-13; m.p. 97–998C};
[a]D20 5 112.1 (c 3.0, CHCl3) {Ref. 30 (S,R)-syn-13; [a]D20
5 1118.7 (c 6.0, CHCl3)}; mmax(CHCl3)cm-1 2401 (C-D),
1779 (OC¼¼O) and 1706 (NC¼¼O); dH(400 MHz; CDCl3)
7.20-7.08 (6 H, m, 6 3 CH; Ph and/or ArU1L), 6.96-6.91 (8
H, m, 8 3 CH, Ph and ArU1L), 6.83 (4 H, dt, J 7.9 and 1.9,
4 3 CH; ArU1L), 5.37 (1 H, dd J 9.1 and 5.1, CHNU), 5.36
(1 H, s, CHNL), 4.54 (1 H, t, J 9.1, CHAHBOU), 3.98 (1 H,
dd, J 9.1 and 5.1, CHAHBOU), 2.37 (4 H, dd, J 7.4 and 2.2,
CH2U1L), 1.89-1.79 (2 H, appears as a nonet, J 6.7,
(CH(CH3)2U1L), 1.31 (6 H, s, ArCDCH3U1L), 0.84 (6 H, d,
In the same way as oxazolidin-2-one 3, n-butyl lithium
(0.24 mL, 2.5 M in hexane, 0.60 mmol), 4-phenyl-oxazoli-
din-2-one (R)-1 (39 mg, 0.24 mmol), 4-phenyl-5,5-dideu-
terio-oxazolidin-2-one (S)-[D2]-1 (40 mg, 0.24 mmol), and
pentafluorophenyl 2-deuterio-2-(4-methylphenyl)propionate
(rac)-[D1]-9 (0.20 g, 0.60 mmol, [D]:[H] 5 96:4), gave an
inseparable mixture of two diastereoisomeric oxazolidin-2-
ones (S,R)-[D1]-12 and (R,S)-[D3]-12 (ratio 98:2: syn-:anti-).
The crude residue was purified by flash chromatography
on silica gel eluting with light petroleum ether (b.p. 40–
608C):diethyl ether (7:3) to give an inseparable mixture of
(2S,4R)-3-[2-deuterio-2-(4-methylphenyl)propionate]-4-phenyl-
oxazolidin-2-one (S,R)-syn-[D1]-12 and (2R,4S)-3-[2-deu-
terio-2-(4-methylphenyl)propionate]-4-phenyl-5,5-dideuterio-
oxazolidin-2-one (R,S)-syn-[D3]-12 (0.109 g, 73%; ratio
(S,R)-syn-[D1]-12: (R,S)-syn-[D3]-12 5 51:49) as a white
solid; RF [light petroleum ether (b.p. 40–608C):diethyl
ether (1:1)] 0.40; m.p. 117–1198C {Ref. 22 unlabelled (rac)-
12; m.p. 102–1048C; Ref. 22 (S,R)-syn-12; m.p. 107–1098C};
[a]D20 5 15.6 (c 3.2, CHCl3) {Ref. 30 (S,R)-syn-12; [a]D20
5
1121.6 (c 0.6, CHCl3) mmax(CHCl3)cm-1 2401 (C-D), 1781
(OC¼¼O) and 1713 (NC¼¼O); dH(400 MHz; CDCl3) 7.31-
7.21 (6 H, m, 6 3 CH; PhU1L), 7.06 (4 H, br d, J 7.9, 4 3
CH, ArU1L), 7.08 (4 H, dt, J 7.9 and 2.0, 4 3 CH; ArU1L),
6.96 (4 H, dt, J 7.6 and 1.8, 4 3 CH; PhU1L), 5.46 (1 H, dd J
8.9 and 5.0, CHNU), 5.45 (1 H, s, CDNL), 4.62 (1 H, t, J 8.9,
CHAHBOU), 4.08 (1 H, dd, J 8.9 and 5.2, CHAHBOU), 2.34
(6 H, s, 2 3 CH3; ArU1L) and 1.39 (6 H, s, ArCDCH3U1L);
negative isotopic shift at 5.45 ppm was 0.01025 ppm (1.25
Hz at 400 MHz); dC(100.6 MHz; CDCl3) 173.8 (2 C;
NC¼¼OU1L), 153.0 (2 C; OC¼¼OU1L), 138.2 (2 3 i-C;
ArU1L), 136.7 (2 3 i-C; ArU1L), 136.6 (2 3 i-C; PhU1L),
129.04 and 127.94 (8 3 CH; ArU1L), 128.74, 128.32 and
125.74 (10 3 CH; PhU1L), 69.5 (CH2OU), 68.8 (1 C, quintet,
1JC,D 5 22.9 Hz, CD2OL), 57.7 (CHNU), 57.5 (CHNL), 43.3
(unlabelled ArCHCH3), 43.0 (2 C, t [1:1:1], 1JC,D 5 19.8 Hz,
ArCDCH3U1L), 22.5 (2 C; CH3; ArU1L) and 18.5 (2 C;
ArCDCH3U1L) negative isotopic shifts at 68.8259 was
0.6494 ppm (64.94 Hz at 100 MHz), 57.4969ppm was
0.1680 ppm (16.80 Hz at 100 MHz) and at 43.6039 ppm was
0.3667 ppm (36.67 Hz at 400 MHz). By mass spectrometry,
this mixture of oxazolidin-2-ones (S,R)-syn-[D1]-12 and
J
6.7, CH3ACH BCH3) and 0.82 (6 H, d,
J 6.7,
CH3ACHBCH3U1L); negative isotopic shift at 5.36 ppm was
0.01025 ppm (1.025 Hz at 400 MHz); dC(100.6 MHz;
CDCl3) 173.8 (2 C; NC¼¼OU1L), 153.1 (2 C; OC¼¼OU1L),
140.5 (2 3 i-C; ArU1L), 138.2 (2 3 i-C; ArU1L), 136.8 (2 3
i-C; PhU1L), 129.14 and 127.84 (8 3 CH; ArU1L), 128.8,2
128.44 and 125.64 (10 3 CH; Ph), 69.5 (CH2OU), 68.8 (1 C,
quintet, JC,D 5 23.7 Hz, CD2OL), 57.6 (CHNU), 57.5
1
(CHNL), 45.1 (2 C; CH(CH3)2U1L), 43.2 (unlabelled
1
ArCHCH3), 42.8 (2 C, t [1:1:1], JC,D
5 19.8 Hz,
ArCDCH3U1L), 30.1 (2 C; CH2U1L), 22.3 (2 C, s, CH3ACH
BCH3U1L), 22.2 (2 C, s, CH3ACH BCH3U1L) and 18.3 (2 C,
ArCDCH3U1L); negative isotopic shifts at 68.9 was 0.6341
ppm (63.41 Hz at 100 MHz), 57.4892 ppm was 0.1757 ppm
(17.57 Hz at 100 MHz) and at 42.8752 ppm was 0.3667
ppm (36.67 Hz at 400 MHz). By mass spectrometry, this
mixture of oxazolidin-2-ones (S,R)-syn-[D1]-13 and (R,S)-
syn-[D3]-13 gave a 53:47 ratio of (S,R)-syn-[D1]-13:(R,S)-
1
syn-[D3]-13. For (S,R)-syn-[D1]-13; found MNH4
,
370.2234; C22H28DN2O3 requires MNH41, 370.2235, and
1
for
(R,S)-syn-[D3]-13;
found
MNH4
,
372.2357;
(R,S)-syn-[D3]-12 gave a 51:49 ratio of (S,R)-syn-[D1]-12:
C22H26D3N2O3 requires MNH41, 372.2361.
1
(R,S)-syn-[D3]-12. For (S,R)-syn-[D1]-12; found MNH4
,
328.1766; C19H22DN2O3 requires MNH41, 328.1766, and
1
for
(R,S)-syn-[D3]-12;
found
MNH4
,
330.1892;
Parallel kinetic resolution of pentafluorophenyl
2-deuterio-2-phenylpropionate (rac)-[D1]-1 using a
quasi-enantiomeric combination of oxazolidin-2-one
(R)-1 and oxazolidin-2-one (S)-14
C19H20D3N2O3 requires MNH41, 330.1891.
Parallel kinetic resolution of pentafluorophenyl
2-deuterio-2-(4-isobutylphenyl)propionate (rac)-[D1]-10
using 4-phenyl-oxazolidin-2-one (R)-1 and 4-phenyl-
5,5-dideuterio-oxazolidin-2-one (S)-[D2]-1
In the same way as oxazolidin-2-one 3, n-butyl lithium
(0.48 mL, 2.5 M in hexane, 1.20 mmol), 4-phenyl-oxazoli-
din-2-one (R)-1 (79 mg, 0.49 mmol), 4,5,5-triphenyl-oxazoli-
In the same way as oxazolidin-2-one 3, n-butyl lithium din-2-one (S)-14 (0.157 g, 0.49 mmol) and pentafluoro-
(0.13 mL, 2.5 M in hexane, 0.325 mmol), 4-phenyl-oxazoli- phenyl 2-deuterio-2-phenylpropionate (rac)-[D1]-2 (0.38 g,
din-2-one (R)-1 (21 mg, 0.13 mmol), 4-phenyl-5,5-dideu- 1.21 mmol, [D]:[H] 5 97:3), gave a mixture of two diaster-
Chirality DOI 10.1002/chir

200
COULBECK ET AL.
eoisomeric oxazolidin-2-ones (S,R)-syn-3 (ratio 94:6: syn- 52:48. The crude residue was purified by flash chromatog-
:anti-) and (R,S)-syn-15 (ratio 97:3: syn-:anti-) in a ratio of raphy on silica gel eluting with light petroleum ether (b.p.
55:45. The crude residue was purified by flash chromatog- 40–608C):diethyl ether (7:3) to give (2S,4R)-3-(2-deuterio-2-
raphy on silica gel eluting with light petroleum ether (b.p. phenylbutanoyl)-4-phenyl-oxazolidin-2-one (S,R)-syn-[D1]-
40–608C):diethyl ether (7:3) to give the (2S,4R)-3-(2-deu- 11 (81 mg, 69%) as a white solid; RF [light petroleum
terio-2-phenylpropionyl)-4-phenyl-oxazolidin-2-one
(S,R)- ether (b.p. 40–608C):diethyl ether (1:1)] 0.29; m.p. 80–
32
syn-[D1]-3 (96 mg, 66%) as a white solid; m.p. 121–1238C 828C {Ref. unlabelled (S,R)-syn-11; m.p. 82–848C}; [a]D20
(Ref. 31 unlabelled (R,S)-syn-3; m.p. 124–1268C); RF [light 5 153.2 (c 4.6, CHCl3) {Ref. 30 (S,R)-syn-11; [a]D20
petroleum ether (b.p. 40–608C):diethyl ether (1:1)] 0.42; 177.4 (c 4.0, CHCl3); Ref. 22 (R,S)-syn-[D2]-11; [a]D20
5
5
m
max(CHCl3)cm-1 2397 (C-D), 1780 (OC¼¼O) and 1701 255.2 (c 4.6, CHCl3)}; mmax(CH2Cl2)cm-1 2399 (C-D), 1772
(NC¼¼O); [a]2D0 5 171.6 (c 6.4, CHCl3) {unlabelled (S,R)- (OC¼¼O) and 1700 (NC¼¼O); dH (400 MHz; CDCl3) 7.19-
syn-3; [a]2D0 5 192.5 (c 4.9, CHCl3)} {Ref. 30 unlabelled 7.09 (6 H, m, 6 3 CH; Ph), 7.04-7.02 (2 H, m, 2 3 CH;
(S,R)-syn-3; [a]D20 5 192.5 (c 4.9, CHCl3)}; dH(400 MHz; Ph), 6.81 (2 H, dt, J 8.4 and 1.8, 2 3 CH; Ph), 5.38 (1 H,
CDCl3) 7.29-7.21 (6 H, m, 6 3 CH; 2 3 Ph), 7.14-7.10 (2 dd, J 8.9 and 5.0, CHN), 4.53 (1 H, t, J 8.9, CHAHBO), 3.98
H, m, 2 3 CH; Ph), 6.96-6.92 (2 H, m, 2 3 CH; Ph), 5.45 (1 H, dd, J 8.9 and 5.0, CHAHBO), 1.95 (1 H, dq, J 13.5 and
(1 H, dd J 9.0 and 5.1, CHN), 4.63 (1 H, t, J 9.0, CHAHBO), 7.4, CHAHBCH3), 1.63 (1 H, dq,
J 13.5 and 7.4,
4.08 (1 H, dd, J 9.0 and 5.1, CHAHBO) and 1.40 (3 H, s, CHAHBCH3) and 0.79 (3 H, t, J 7.4, CH3CH2); dC(100
PhCDCH3); dC (100 MHz; CDCl3) 174.1 (NC¼¼O), 153.6 MHz; CDCl3) 173.0 (NC¼¼O), 153.1 (OC¼¼O), 138.2 and
(OC¼¼O), 140.2 and 138.7 (2 3 i-C; 2 3 Ph), 129.3,2 138.0 (2 3 i-C; 2 3 Ph), 128.8,2 128.6,2 128.3,3 127.11 and
128.9,3 128.6,2 127.51 and 126.32 (10 3 CH; 2 3 Ph), 70.0 125.62 (10 3 CH; 2 3 Ph), 69.4 (CH2O), 57.7 (CHN), 50.7
1
(CH2O), 58.2 (CHN), 44.2 (unlabelled PhCHCH3), 43.8 (1 (1 C, t [1:1:1], JC,D 5 21.3 Hz, PhCDEt), 26.2 (CH2CH3)
1
1
C, t [1:1:1], JC,D 20.3, PhCDCH3) and 19.0 (PhCDCH3) and 11.9 (CH2CH3) (Found MNH4
,
328.1766;
(Found MH1, 297.1346; C18H17DNO3 requires MH1, C19H22DN2O3 requires MNH41, 328.1766); negative iso-
297.1344); negative isotopic shift at 43.8 ppm (PhCD) was topic shift at 50.7 ppm (PhCD) was 0.3973 ppm (39.7 Hz at
0.366 ppm (36.6 Hz at 100.6 MHz) and (2R,4S)-3-(2-deu- 100.6 MHz); and (2R,4S)-3-(2-deuterio-2-phenylbutanoyl)-
terio-2-phenylpropionyl)-4,5,5-triphenyl-oxazolidin-2-one (R,S)- 4,5,5-triphenyl-oxazolidin-2-one (R,S)-syn-[D1]-16 (0.11 g,
syn-[D1]-15 (0.12 g, 54 %) as a white powder; RF [light pe- 63 %) as a white powder; RF [light petroleum ether (b.p.
32
troleum ether (b.p. 40-608C):diethyl ether (1:1)] 0.58; m.p. 40-608C): diethyl ether (1:1)] 0.52; m.p. 121-1228C {Ref.
156-1588C {Ref. 32 unlabelled m.p. 154-1568C}; [a]D20
5
unlabelled (R,S)-syn-16; m.p. 150–1538C}; [a]2D0 5 2231.4
2226.4 (c 4.2, CHCl3) {Ref. 32 unlabelled (R,S)-syn-15; (c 5.6, CHCl3) {Ref. 32 unlabelled (R,S)-syn-16; [a]D20
5
[a]D20 5 2255.1 (c 3.4, CHCl3)}; mmax(CHCl3)cm-1 2389 (C- 2195.2 (c 3.4, CHCl3)}; mmax(CHCl3)cm-1 2399 (C-D), 1779
D), 1779 (OC¼¼O) and 1704 (NC¼¼O); dH(400 MHz; (OC¼¼O) and 1707 (NC¼¼O); dH(400 MHz; CDCl3) 7.55 (2
CDCl3) 7.66 (2 H, br d, J 7.7, 2 3 CH; Ph), 7.50-7.36 (4 H, H, br d, J 7.5, 2 3 CH; Ph), 7.39-7.29 (3 H, m, 3 3 CH;
m, 4 3 CH; Ph), 7.18-7.11 (2 H, m, 2 3 CH; Ph), 7.11-7.07 Ph), 7.16-7.07 (5 H, m, 5 3 CH; 2 3 Ph), 6.90-6.80 (8 H,
(2 H, m, 2 3 CH; Ph), 7.01-6.89 (8 H, m, 8 3 CH; Ph), m, 8 3 CH; 3 3 Ph), 6.57-6.55 (2 H, d, J 7.5, 2 3 CH; Ph),
6.67 (2 H, br d, J 7.7, 2 3 CH; Ph), 6.30 (1 H, s, CHN) and 6.20 (1 H, s, CHN), 1.90 (1 H, dq, J 13.5 and 7.3,
1.37 (3 H, s, PhCDCH3); dC(100 MHz; CDCl3) 173.2 CHAHBCH3), 1.63 (1 H, dq, J 13.5 and 7.3, CHAHBCH3)
(NC¼¼O), 152.0 (OC¼¼O), 141.8, 137.9 and 134.9 (3 3 i-C; and 0.68 (3 H, t, J 7.3, CH3CH2); dC(100 MHz; CDCl3)
3 3 Ph – oxazolidin-2-one), 139.4 (i-C; Ph), 128.9,2 128.8,1 172.8 (NC¼¼O), 152.1 (OC¼¼O), 141.7, 137.9 and 135.0 (3
128.4,2 128.2,2 127.9,4 127.5,2 127.4,1 127.3,1 126.9,1 126.12 3 i-C; 3 3 Ph), 137.6 (i-C; PhCHEt), 128.9,3 128.8,2 128.3,2
and 126.02 (20 3 CH; 4 3 Ph), 88.5 (CPh2O), 65.9 (CHN), 127.9,2 127.8,1 127.5,2 127.4,1 127.3,2 127.1,1 126.32 and
1
43.9 (unlabelled PhCHCH3), 43.5 (1 C, t [1:1:1], JC,D
5
126.22 (20 3 CH; 4 3 Ph), 88.6 (CPh2O), 65.9 (CHN), 50.7
1
20.6
Hz,
PhCDCH3)
(Found
MH1,
449.1968; (1 C, t [1:1:1], JC,D 5 19.9 Hz, ArCDEt), 26.6 (CH2CH3)
1
1
1
C30H25DNO3 requires 449.1970; and found MNH4
,
and 11.8 (CH2CH3) (Found MNH4
,
480.2386;
465.2155; C30H28DN2O3 requires MNH41, 465.2157); C31H30DN2O3 requires MNH41, 480.2392); negative iso-
1
negative isotopic shift at 43.5 ppm (PhCD) was 0.3743 topic shift at 50.7 ppm (PhCD) was 0.4125 ppm (41.2 Hz at
ppm (37.4 Hz at 100.6 MHz).
100.6 MHz).
Parallel kinetic resolution of pentafluorophenyl
2-deuterio-2-phenylbutanoate (rac)-[D1]-8 using a
quasi-enantiomeric combination of oxazolidin-2-one
(R)-1 and oxazolidin-2-one (S)-14
Parallel kinetic resolution of pentafluorophenyl
2-deuterio-2-(4-methylphenyl)propionate (rac)-[D1]-9
using a quasi-enantiomeric combination of oxazolidin-2-
one (R)-1 and oxazolidin-2-one (S)-14
In the same way as oxazolidin-2-one 3, n-butyl lithium
In the same way as oxazolidin-2-one 3, n-butyl lithium
(0.36 mL, 2.5 M in hexane, 0.90 mmol), 4-phenyl-oxazoli- (0.37 mL, 2.5 M in hexane, 0.92 mmol), 4-phenyl-oxazoli-
din-2-one (R)-1 (62 mg, 0.38 mmol), 4,5,5-triphenyl-oxazoli- din-2-one (R)-1 (62 mg, 0.38 mmol), 4,5,5-triphenyl-oxazoli-
din-2-one (S)-14 (0.12 g, 0.38 mmol) and pentafluoro- din-2-one (S)-14 (0.12 g, 0.38 mmol) and pentafluoro-
phenyl 2-deuterio-2-phenylbutanoate (rac)-[D1]-8 (0.30 g, phenyl 2-deuterio-2-(4-methylphenyl)propionate (rac)-[D1]-
0.91 mmol, [D]:[H] 5 96:4), gave a mixture of two diaster- 9 (0.307 g, 0.92 mmol, [D]:[H] 5 96:4), gave a mixture of
eoisomeric oxazolidin-2-ones (S,R)-syn-11 (ratio 99:1: syn- two diastereoisomeric oxazolidin-2-ones (S,R)-syn-12 (ratio
:anti-) and (R,S)-syn-16 (ratio 99:1: syn-:anti-) in a ratio of 95:5: syn-:anti-) and (R,S)-syn-17 (ratio 99:1: syn-:anti-) in a
Chirality DOI 10.1002/chir

D-LABELLED 2-ARYL-PROPIONIC AND BUTANOIC ACIDS
201
ratio of 53:47. The crude residue was purified by flash matography on silica gel eluting with light petroleum ether
chromatography on silica gel eluting with light petroleum (b.p. 40–608C):diethyl ether (7:3) to give (2S,4R)-3-[2-deu-
ether (b.p. 40–608C):diethyl ether (7:3) to give (2S,4R)-3- terio-2-(4-isobutylphenyl)propionyl]-4-phenyl-oxazolidin-2-
[2-deuterio-2-(4-methylphenyl)propionyl]-4-phenyl-oxazoli-
one (S,R)-syn-[D1]-13 (95 mg, 69%) as a white solid; m.p.
din-2-one (S,R)-syn-[D1]-12 (75 mg, 64%) as a white solid; 78–808C (Ref. 32 unlabelled (S,R)-syn-13; m.p. 86–888C); RF
RF [light petroleum ether (b.p. 40-60 8C):diethyl ether [light petroleum ether (b.p. 40–608C):diethyl ether (1:1)]
(1:1)] 0.30; m.p. 110–1128C {Ref. 32 unlabelled (S,R)-syn- 0.37; [a]2D5 5 198.9 (c 4.6, CHCl3) {Ref. 32 (S,R)-syn-13;
12; m.p. 105-110 8C; for unlabelled (R,S)-syn-12; m.p. 105– [a]2D5 5 1118.7 (c 6.0, CHCl3)} {for unlabelled (R,S)-syn-13;
1108C}; mmax(CHCl3)cm-1 2397 (C-D), 1772 (OC¼¼O) and lit. [a]2D5 5 2114.6 (c 4.2, CHCl3)}; mmax(CHCl3)cm-1 2399
1700 (NC¼¼O); [a]D20 5 190.4 (c 4.6, CHCl3) {Ref. 30 (C-D), 1780 (OC¼¼O) and 1705 (NC¼¼O); dH(400 MHz;
(S,R)-syn-12; [a]D20 5 1121.6 (c 0.6, CHCl3)} {for unla- CDCl3) 7.15-7.07 (3 H, m, 3 3 CH; Ph), 7.00 (4 H, m, 4 3
belled (R,S)-syn-12; [a]2D0 5 2116.5 (c 0.8, CHCl3)}; dH CH, Ph and Ar), 6.80 (2 H, dt, J 7.9 and 1.9, 2 3 CH; Ar),
(400 MHz, CDCl3) 7.28-7.21 (3 H, m, 3 3 CH; Ph), 7.06 (2 5.36 (1 H, dd J 9.0 and 5.2, CHN), 4.53 (1 H, t, J 9.0,
H, br d, J 8.1, 2 3 CH; Ar), 7.01 (2 H, dt, J 8.1 and 2.2, 2 3 CHAHBO), 3.97 (1 H, dd, J 9.0 and 5.2, CHAHBO), 2.43 (2 H,
CH; Ar), 6.96 (2 H, dt, J 7.7 and 1.8, 2 3 CH; Ph), 5.47 (1 dd, J 7.3 and 2.2, CH2Ar), 1.82-1.74 (1 H, m, (CH(CH3)2),
B
H, dd, J 9.1 and 5.1, CHN), 4.64 (1 H, t, J 9.1, CHAHBO), 1.32 (3 H, s, ArCDCH3), 0.82 (3 H, d, J 6.6, CH3ACHCH3
)
4.06 (1 H, dd, J 9.1 and 5.1, CHAHBO), 2.34 (3 H, s, CH3; and 0.80 (3 H, d, J 6.6, CH3ACHCH3B); dC(100.6 MHz;
Ar) and 1.39 (3 H, s, ArCDCH3); dC (100 MHz, CDCl3) CDCl3) 173.8 (NC¼¼O), 153.1 (OC¼¼O), 140.5 (i-C; Ar),
173.5 (NC¼¼O), 152.7 (OC¼¼O), 137.9 (i-CMe; Ar), 136.4 138.2 (i-C; Ar), 136.8 (i-C; Ph), 129.32 and 128.72 (4 3 CH;
(i-C; Ar), 136.2 (i-C; Ph), 129.8,2 128.4,2 128.0,1 127.62 and Ar), 128.4,1 127.82 and 125.72 (5 3 CH; Ph), 69.5 (CH2O),
1
125.52 (9 3 CH; Ph and Ar), 69.1 (CH2O), 57.3 (CHN), 57.6 (CHN), 44.9 (CH(CH3)2), 42.8 (1 C, t [1:1:1], JC,D
5
42.6 (1 C, t [1:1:1], 1JC,D 5 20.2 Hz, ArCDCH3), 20.7 (CH3; 20.6 Hz, ArCDCH3), 30.1 (CH2Ar), 22.52 (CH3)2CH) and
Ar) and 18.1 (ArCDCH3) (Found MNH41, 328.1768; 18.4 (ArCDCH3) (Found MNH41, 370.2232; C22H28DN2O3
C19H22DN2O3 requires MNH41, 328.1766); negative iso- requires MNH41, 370.2235); negative isotopic shift at 42.8
1
topic shift at 42.6 ppm (ArCD) was 0.3666 ppm (36.6 Hz at ppm (ArCD) was 0.3665 ppm (36.6 Hz at 100.6 MHz); and
100.6 MHz); and (2R,4S)-3-[2-deuterio-2-(4-methylphenyl)- (2R,4S)-3-[2-deuterio-2-(4-isobutylphenyl)propionyl]-4,5,5-tri-
propionyl]-4,5,5-triphenyl-oxazolidin-2-one (R,S)-syn-[D1]- phenyl-oxazolidin-2-one (R,S)-syn-[D1]-18 (0.126 g, 64 %) as
17 (0.101 g, 57 %) as a white powder; RF [light petroleum a white powder; RF [light petroleum ether (b.p. 40-608C):
ether (b.p. 40-608C): diethyl ether (1:1)] 0.57; m.p. 87– diethyl ether (1:1)] 0.63; m.p. 57–598C {Ref. 32 unlabelled
898C {Ref. 32 unlabelled (R,S)-syn-17; m.p. 119-1218C}; m.p. 5 62-648C}; [a]2D0 5 2228.7 (c 5.0, CHCl3) {Ref. 32
[a]2D0 5 2213.2 (c 5.4, CHCl3) {Ref. 32 unlabelled (R,S)- unlabelled (R,S)-syn-18; [a]D20 5 2306.7 (c 4.4, CHCl3)};
syn-17; [a]D20 5 2258.6 (c 2.4, CHCl3)}; mmax(CHCl3)cm-1
m
max(CHCl3)cm-1 2399 (C-D), 1780 (OC¼¼O) and 1704
2399 (C-D), 1780 (OC¼¼O) and 1703 (NC¼¼O); dH(400 (NC¼¼O); dH(400 MHz; CDCl3) 7.66 (2 H, br d, J 7.3, 2 3
MHz; CDCl3) 7.65 (2 H, br d, J 7.5, 2 3 CH; Ph), 7.48-7.38 CH; Ph), 7.49-7.37 (3 H, m, 3 3 CH; Ph), 7.28 (2 H, br d, J
(3 H, m, 3 3 CH; Ph), 7.04-6.89 (12 H, m, 12 3 CH; Ph 8.1, 2 3 CH; Ar), 7.16 (2 H, br d, J 8.1, 2 3 CH; Ar), 7.07-
and Ar), 6.69 (2 H, br d, J 7.5, Ph), 6.29 (1 H, s, CHN), 6.85 (8 H, m, 8 3 CH; 3 3 Ph), 6.66 (2 H, br d, J 7.3, 2 3
2.32 (3 H, s, CH3Ar) and 1.36 (3 H, s, ArCDCH3); dC(100 CH; Ph), 6.29 (1 H, s, CHN), 2.44 (2 H, dd, J 7.2 and 1.6,
MHz; CDCl3) 173.5 (NC¼¼O), 151.9 (OC¼¼O), 141.8, 138.0 CH2Ar), 1.91-1.80 (1 H, appears as a septet, J 6.8,
and 135.0 (3 3 i-C; 3 3 Ph), 136.7 and 136.5 (2 3 i-C; Ar), (CH3)2CH), 1.36 (3 H, s, ArCDCH3), 0.92 (3 H, d, J 6.6,
129.1,2 128.9,2 128.8,1 128.2,2 127.8,3 127.5,2 127.4,2 127.3,1 CH3ACHCH3B) and 0.91 (3 H, d, J 6.6, CH3ACHCH3B);
126.22 and 126.12 (19 3 CH; 3 3 Ph and Ar), 88.5 dC(100 MHz; CDCl3) 173.5 (NC¼¼O), 152.1 (OC¼¼O), 141.8,
1
(CPh2O), 65.9 (CHN), 44.6 (1 C, t [1:1:1], JC,D 5 20.6 Hz, 138.1 and 135.0 (3 3 i-C; 3 3 Ph), 140.5 (i-CCH2; Ar), 136.6
ArCDCH3), 21.0 (CH3Ar) and 19.0 (ArCHCH3) (Found (i-C; Ar), 129.2,2 128.9,3 128.9,1 128.1,2 127.9,1 127.9,2
MH1, 463.2124; C31H27DNO3 requires MH1, 463.2126); 127.6,2 127.4,1 127.3,1 126.32 and 126.22 (19 3 CH; 19 3 Ph
negative isotopic shift at 44.6 ppm (ArCD) was 0.3629 ppm and Ar), 88.6 (CPh2O), 66.0 (CHN), 45.0 (CH3)2CH), 43.1
1
(36.3 Hz at 100.6 MHz).
(1 C, t [1:1:1], JC,D 5 19.1 Hz, ArCDCH3), 30.2 (CH2Ar),
22.5 (CH3ACHCH3B), 22.4 (CH3ACHCH3
) and 18.9
B
1
Parallel kinetic resolution of pentafluorophenyl
2-deuterio-2-(4-isobutylphenyl)propionate (rac)-[D1]-10
using a quasi-enantiomeric combination of oxazolidin-2-
ones (R)-1 and oxazolidin-2-one (S)-14
(ArCDCH3) (Found MNH4
, 522.2859; C34H36DN2O3
requires MNH41, 522.2861); negative isotopic shift at 43.1
ppm (ArCD) was 0.3781 ppm (37.8 Hz at 100.6 MHz).
Parallel kinetic resolution of pentafluorophenyl
2-deuterio-2-phenylpropionate (rac)-[D1]-2 using
4-[4-(tert-butyldimethylsilyloxy)phenyl]-oxazolidin-2-one
(R)-19 and 4-phenyl-oxazolidin-2-one (S)-1
In the same way as oxazolidin-2-one 3, n-butyl lithium
(0.37 mL, 2.5 M in hexane, 0.925 mmol), 4-phenyl-oxazoli-
din-2-one (R)-1 (64 mg, 0.39 mmol), 4,5,5-triphenyl-oxazoli-
din-2-one (S)-14 (0.122 g, 0.39 mmol) and pentafluoro-
phenyl 2-deuterio-2-(4-isobutylphenyl)propionate (rac)-[D1]-
In the same way as oxazolidin-2-one 3, n-butyl lithium
10 (0.346 g, 0.92 mmol, [D]:[H] 5 95:5), gave a mixture of (0.38 mL, 2.5 M in hexane, 0.95 mmol), 4-[4-(tert-butyldi-
two diastereoisomeric oxazolidin-2-ones (S,R)-syn-13 (ratio methylsilyloxy)phenyl]-oxazolidin-2-one (R)-19 (0.117 g,
95:5: syn-:anti-) and (R,S)-syn-18 (ratio 97:3: syn-:anti-) in a 0.40 mmol), 4-phenyl-oxazolidin-2-one (S)-1 (65 mg, 0.40
ratio of 52:48. The crude residue was purified by flash chro- mmol), and pentafluorophenyl 2-deuterio-2-phenylpropio-
Chirality DOI 10.1002/chir

202
COULBECK ET AL.
nate (rac)-[D1]-2 (0.303 g, 0.95 mmol, [D]:[H] 5 97:3), noate (rac)-[D1]-8 (0.30 g, 0.91 mmol, [D]:[H] 5 96:4),
gave a mixture of two diastereoisomeric oxazolidin-2-ones gave a mixture of two diastereoisomeric oxazolidin-2-ones
(S,R)-syn-20 (ratio 97:3: syn-:anti-) and (R,S)-syn-2 (ratio (S,R)-syn-21 (ratio 99:1: syn-:anti-) and (R,S)-syn-11 (ratio
97:3: syn-:anti-) in a ratio of 53:47. The crude residue was 99:1: syn-:anti-) in a ratio of 53:47. The crude residue was
purified by flash chromatography on silica gel eluting with purified by flash chromatography on silica gel eluting with
light petroleum ether (b.p. 40–608C):diethyl ether (7:3) light petroleum ether (b.p. 40–608C):diethyl ether (7:3)
to give (2S,4R)-3-[2-deuterio-2-phenylpropionyl]-4-[4-(tert- to give (2S,4R)-3-[2-deuterio-2-phenylbutanoyl]-4-[4-(tert-
butyldimethylsilyloxy)phenyl]-oxazolidin-2-one (S,R)-syn- butyldimethylsilyloxy)phenyl]-oxazolidin-2-one (S,R)-syn-
[D1]-20 (0.133 g, 78%) as a white solid; RF [light petro- [D1]-21 (0.11 g, 67%) as a colourless oil; RF [light petro-
leum ether (b.p. 40–608C): diethyl ether (1:1)] 0.50; m.p. leum ether (b.p. 40–608C):diethyl ether (1:1)] 0.57; [a]D20
80–818C (Ref. 30 for unlabelled (S,R)-syn-20; m.p. 96– 5 187.6 (c 4.0, CHCl3) {Ref. 30 unlabelled (R,S)-syn-21;
988C); [a]2D0 5 197.2 (c 5.0, CHCl3); {Ref. 30 (R,S)-20; [a]D20 5 289.4 (c 4.4, CHCl3)}; mmax(CH2Cl2)cm-1 2401 (C-
[a]2D0 5 295.2 (c 2.0, CHCl3)}; mmax(CHCl3)cm-1 2400 (C- D), 1778 (OC¼¼O) and 1702 (NC¼¼O); dH(400 MHz;
D), 1776 (OC¼¼O) and 1706 (NC¼¼O); dH(400 MHz; CDCl3) 7.19-7.16 (3 H, m, 3 3 CH; Ph), 7.07-7.04 (2 H, m,
CDCl3) 7.19-7.15 (3 H, m, 3 3 CH; Ph), 7.05-7.00 (2 H, m, 2 3 CH; Ph), 6.75 (2 H, dt, J 8.5 and 2.5, 2 3 CH; Ar), 6.61
2 3 CH; Ph), 6.87 (2 H, dt, J 8.4 and 2.4, 2 3 CH; Ar), 6.63 (2 H, dt, J 8.5 and 2.5, 2 3 CH; Ar), 5.37 (1 H, dd, J 9.0 and
(2 H, dt, J 8.4 and 2.4, 2 3 CH; Ar), 5.35 (1 H, dd, J 9.0 and 5.0, CHN), 4.56 (1 H, t, J 9.0, CHAHBO), 4.03 (1H, dd, J 9.0
5.0, CHN), 4.54 (1 H, t, J 9.0, CHAHBO), 4.04 (1 H, dd, J and 5.0, CHAHBO), 2.00 (1 H, dq, J 13.8 and 7.3,
9.0 and 5.0, CHAHBO), 1.34 (3H, s, PhCDCH3), 0.94 (9 H, CHAHBCH3), 1.66 (1 H, dq, J 13.8 and 7.3, CHAHBCH3),
s, 3 3 CH3C; t-Bu) and 0.14 (6 H, s, 2 3 CH3Si); dC(100 0.94 (9 H, s, 3 3 CH3; t-Bu), 0.83 (3 H, t, J 7.3, CH3CH2),
MHz; CDCl3) 173.6 (NC¼¼O), 155.7 (i-C; Ar), 153.0 0.14 (6 H, s, 2 3 SiCH3); dC (100 MHz; CDCl3) 173.0
(OC¼¼O), 139.8 (i-C; Ph), 130.9 (i-C; Ar), 128.42, 128.02 (NC¼¼O), 155.7 (OC¼¼O), 153.2 (i-CO; Ar), 138.1 (i-C; Ph)
and 127.01 (5 3 CH; Ph), 127.32 and 120.22 (4 3 CH; Ar), 130.9 (i-C; Ar), 128.6,2 128.4,2 127.1,2 127.01 and 120.22 (9
69.7 (CH2O), 57.3 (CHN), 43.8 (unlabelled PhCHCH3), 3 CH; Ph and Ar), 69.6 (CH2O), 57.3 (CHN), 51.1 (unla-
43.4 (1 C, t [1:1:1], 1JC,D 5 19.8 Hz, PhCDCH3), 25.63 (3 3 belled PhCH), 50.7 (1 C, t [1:1:1], 1JC,D 5 19.8 Hz, PhCD),
CH3C; t-Bu), 18.4 (PhCHCH3), 18.1 (CH3C; t-Bu), 24.5 26.2 (CH2CH3), 25.63 (3 3 CH3C; t-Bu), 18.1 (CH3C; t-Bu),
(CH3ASiCH3B) and 24.5 (CH3ASiCH3B); negative isotopic 11.9 (CH2CH3) and 24.52 (2 3 SiCH3); negative isotopic
shift at 43.4405 ppm was 0.3367 ppm (33.67 Hz at 100 shift at 50.7742 ppm was 0.3972 ppm (39.72 Hz at 100
MHz) (Found MH1, 427.2157; C24H31DNO4Si requires MHz) (Found MH1, 441.2312; C25H33DNO4Si requires
MH1, 427.2158); and (2R,4S)-3-[2-deuterio-2-phenylpro- MH1, 441.2314); and (2R,4S)-3-[2-deuterio-2-phenylbuta-
pionyl]-4-phenyl-oxazolidin-2-one (R,S)-syn-[D1]-3 (82 mg, noyl]-4-phenyl-oxazolidin-2-one (R,S)-syn-[D1]-11 (80 mg,
69 %) as a white solid; RF [light petroleum ether (b.p. 40– 68 %) as a white solid; RF [light petroleum ether (b.p. 40–
608C):diethyl ether (1:1)] 0.33; m.p. 121–1238C (Ref. 31 608C):diethyl ether (1:1)] 0.43; m.p. 80–828C (Ref. 32 unla-
(R,S)-syn-3; m.p. 124–1268C); [a]2D35 279.1 (c 5.6, CHCl3) belled (S,R)-syn-11; m.p. 82–848C); [a]2D0 5 259.4 (c 3.2,
{for unlabelled (R,S)-syn-3; [a]2D3 5 291.9 (c 4.9, CHCl3); CHCl3); {Ref. 30 (S,R)-syn-11; [a]2D0 5 177.4 (c 4.0,
{Ref. 30 unlabelled (S,R)-syn-3, [a]2D0 5 192.5 (c 4.9, CHCl3); Ref. 22 (R,S)-syn-[D2]-11; [a]2D0 5 254.2 (c 4.6,
CHCl3)}; mmax(CHCl3)cm-1 2401 (C-D), 1781 (OC¼¼O) and CHCl3)}; mmax(CH2Cl2)cm-1 2401 (C-D), 1782 (OC¼¼O) and
1713 (NC¼¼O); dH(400 MHz; CDCl3) 7.20-7.11 (6 H, m, 6 1708 (NC¼¼O); dH (400 MHz; CDCl3) 7.18-7.08 (6 H, m, 6
3 CH; 2 3 Ph), 7.04-7.00 (2 H, m, 2 3 CH; Ph), 6.86-6.82 3 CH; Ph), 7.06-7.01 (2 H, m, 2 3 CH; Ph), 6.82-6.78 (2 H,
(2 H, m, 2 3 CH; Ph), 5.37 (1 H, dd J 9.0 and 5.1, CHN), m, 2 3 CH; Ph), 5.38 (1 H, dd, J 8.9 and 5.0, CHN), 4.57 (1
4.53 (1 H, t, J 9.0, CHAHBO), 3.99 (1 H, dd, J 9.0 and 5.1, H, t, J 8.9, CHAHBO), 3.98 (1 H, dd, J 8.9 and 5.0,
CHAHBO) and 1.31 (3 H, s, PhCDCH3); dC(100 MHz; CHAHBO), 2.00-1.90 (1 H, dq, J 13.5 and 7.3, CHAHBCH3),
CDCl3) 173.6 (C¼¼O), 153.0 (C¼¼O), 139.7 and 138.2 (2 3 1.68-1.58 (1 H, dq, J 13.5 and 7.3, CHAHBCH3) and 0.79 (3
i-C; 2 3 Ph), 128.8,2 128.6,3 128.0,2 127.01 and 125.82 (10 H, t, J 7.5, CH3CH2); dC(100 MHz; CDCl3) 173.1 (NC¼¼O),
3 CH; 2 3 Ph), 69.5 (CH2O), 57.7 (NCH), 43.7 (unlabelled 153.1 (OC¼¼O), 138.2 and 137.9 (2 3 i-C; 2 3 Ph), 128.8,2
1
PhCHCH3), 43.4 (1 C, t [1:1:1], JC,D 5 20.6 Hz, 128.7,2 128.4,1 128.3,2 127.1,1 and 125.62 (10 3 CH; 2 3
PhCDCH3) and 18.4 (PhCHCH3); negative isotopic shift at Ph), 69.4 (CH2O), 57.7 (CHN), 51.1 (unlabelled PhCH),
1
43.3871 ppm was 0.3666 ppm (36.66 Hz at 100 MHz) 50.7 (1 C, t [1:1:1], JC,D 5 19.8 Hz, PhCD), 26.1
1
(Found MNH4
,
314.1608; C18H20DN2O3 requires (CH2CH3) and 11.9 (CH2CH3); negative isotopic shift at
MNH41, 314.1609).
50.7055 ppm was 0.4049 ppm (40.49 Hz at 100 MHz)
1
(Found MNH4
,
328.1765; C19H22DN2O3 requires
MNH41, 328.1766).
Parallel kinetic resolution of pentafluorophenyl
2-deuterio-2-phenylbutanoate (rac)-[D1]-8 using
4-[4-(tert-butyldimethylsilyloxy)phenyl]-oxazolidin-2-one
(R)-19 and 4-phenyl-oxazolidin-2-one (S)-1
Parallel kinetic resolution of pentafluorophenyl
2-deuterio-2-(4-methylphenyl)propionate (rac)-[D1]-9
using 4-[4-(tert-butyldimethylsilyloxy)phenyl]-oxazolidin-
2-one (R)-19 and 4-phenyl-oxazolidin-2-one (S)-1
In the same way as oxazolidin-2-one 3, n-butyl lithium
(0.37 mL, 2.5 M in hexane, 0.92 mmol), 4-[4-(tert-butyldi-
methylsilyloxy)phenyl]-oxazolidin-2-one (R)-19 (0.11 g,
In the same way as oxazolidin-2-one 3, n-butyl lithium
0.38 mmol), 4-phenyl-oxazolidin-2-one (S)-1 (62 mg, 0.38 (0.53 mL, 2.5 M in hexane, 1.325 mmol), 4-[4-(tert-butyldi-
mmol), and pentafluorophenyl 2-deuterio-2-phenylbuta- methylsilyloxy)phenyl]-oxazolidin-2-one (R)-19 (0.162 g,
Chirality DOI 10.1002/chir

D-LABELLED 2-ARYL-PROPIONIC AND BUTANOIC ACIDS
203
0.55 mmol), 4-phenyl-oxazolidin-2-one (S)-1 (90 mg, 0.55 methylsilyloxy)phenyl]-oxazolidin-2-one (R)-19 (0.146 g,
mmol), and pentafluorophenyl 2-deuterio-2-(4-methylphe- 0.50 mmol), 4-phenyl-oxazolidin-2-one (S)-1 (82 mg, 0.50
nyl)propionate (rac)-[D1]-9 (0.438 g, 1.32 mmol, [D]:[H] mmol), and pentafluorophenyl 2-deuterio-2-(4-isobutylphe-
5 96:4), gave a mixture of two diastereoisomeric oxazoli- nyl)propionate (rac)-[D1]-10 (0.45 g, 1.21 mmol, [D]:[H]
din-2-ones (S,R)-syn-[D1]-22 (ratio 95:5: syn-:anti-) and 5 95:5), gave a mixture of two diastereoisomeric oxazoli-
(R,S)-syn-[D1]-12 (ratio 96:4: syn-:anti-) in a ratio of 53:47. din-2-ones (S,R)-syn-23 (ratio 97:3: syn-:anti-) and (R,S)-syn-
The crude residue was purified by flash chromatography 13 (ratio 97:3: syn-:anti-) in a ratio of 53:47. The crude resi-
on silica gel eluting with light petroleum ether (b.p. 40– due was purified by flash chromatography on silica gel
608C):diethyl ether (7:3) to give (2S,4R)-3-[2-deuterio-2-(4- eluting with light petroleum ether (b.p. 40–608C):diethyl
methylphenyl)propionate]-4-[4-(tert-butyldimethylsilyloxy)- ether (7:3) to give (2S,4R)-3-[2-deuterio-2-(4-isobutylphe-
phenyl]-oxazolidin-2-one (S,R)-syn-[D1]-22 (0.172 g, 71 %) nyl)propionate]-4-[4-(tert-butyldimethylsilyloxy)phenyl]-ox-
as a colourless oil; RF [light petroleum ether (b.p. 40– azolidin-2-one (S,R)-syn-[D1]-23 (0.185 g, 77%) as a colour-
608C):diethyl ether (1:1)] 0.53; [a]2D0 5 1121.1 (c 4.2, less oil; RF [light petroleum ether (b.p. 40–608C):diethyl
CHCl3) {Ref. 30 (R,S)-syn-22; [a]2D0 5 2120.3 (c 6.0, ether (1:1)] 0.50; (Ref. 30 unlabelled (R,S)-syn-23; m.p.
CHCl3)}; mmax(CH2Cl2)cm-1 2401 (C-D), 1777 (OC¼¼O) and 68–708C); [a]D20 5 1134.5 (c 6.2, CHCl3) {Ref. 30 (R,S)-syn-
1702 (NC¼¼O); dH(400 MHz; CDCl3) 6.95 (2 H, br d, J 8.0, 23; [a]2D0 5 2129.6 (c 3.4, CHCl3)}; mmax(CH2Cl2)cm-1
2 3 CH; ArA), 6.91 (2 H, dt, J 8.0 and 1.8, 2 3 CH; ArA), 2400 (C-D), 1776 (OC¼¼O) and 1702 (NC¼¼O); dH (400
6.78 (2 H, dt, J 8.5 and 2.5, 2 3 CH; ArB), 6.62 (2 H, dt, J MHz; CDCl3) 6.96 (4 H, br s, 4 3 CH; ArA), 6.73 (2 H, dt,
8.5 and 2.5, 2 3 CH; ArB), 5.35 (1 H, dd, J 9.0 and 5.0, J 8.4 and 2.4, 2 3 CH; ArB), 6.60 (2 H, dt, J 8.4 and 2.4, 2
CHN), 4.56 (1 H, t, J 9.0, CHAHBO), 4.05 (1H, dd, J 9.0 and 3 CH; ArB), 5.37 (1 H, dd, J 9.0 and 5.1, CHN), 4.56 (1 H,
5.0, CHAHBO), 2.27 (3 H, s, CH3; Ar), 1.32 (3 H, s, t, J 9.0, CHAHBO), 4.03 (1H, dd, J 9.0 and 5.1, CHAHBO),
ArCDCH3), 0.93 (9 H, s, 3 3 CH3; t-Bu) and 0.15 (6 H, s, 2 2.40 (2 H, d, J 6.9, CH2Ar), 1.83 (1 H, appears as a nonet, J
3 SiCH3); dC (100 MHz; CDCl3) 173.8 (NC¼¼O), 155.8 6.8, (CH3)2CH), 1.34 (3 H, s, ArCDCH3), 0.95 (9 H, s, 3 3
(OC¼¼O), 153.1 (i-CO; ArB), 136.9, 136.6 and 130.9 (3 3 i- CH3; t-Bu), 0.91 (3 H, d, J 6.8, CH3ACHCH3B), 0.89 (3 H, d,
C; ArA and ArB), 129.1, 128.0, 127.3 and 120.2 (4 3 CH; J 6.8 , CH3ACHCH3B) and 0.15 (6 H, s, 2 3 SiCH3); dC
ArA and ArB), 69.7 (CH2O), 57.3 (CHN), 43.4 (unlabelled (100 MHz; CDCl3) 173.8 (NC¼¼O), 155.6 (OC¼¼O), 153.1
1
ArCHCH3), 43.0 (1 C,
t
[1:1:1], JC,D 5 19.8 Hz, (i-CO; ArA), 140.4, 136.9 and 130.9 (3 3 i-C; ArA and ArB),
ArCDCH3), 25.63 (3 3 CH3; t-Bu), 21.0 (CH3; Ar), 18.5 129.1, 127.8, 127.1 and 120.2 (4 3 CH; ArA and ArB), 69.6
(ArCDCH3), 18.2 (CH3C; t-Bu) and 24.52 (2 3 SiCH3); (CH2O), 57.2 (CHN), 45.0 (CH2Ar), 43.3 (ArCHCH3), 42.8
1
negative isotopic shift at 43.0433 ppm was 0.3667 ppm (1 C, t [1:1:1], JC,D
5 19.8 Hz, ArCDCH3), 30.1
(36.67 Hz at 100 MHz) (Found MH1, 441.2315; (CH3)2CH), 25.53 (3 3 CH3C; t-Bu), 22.3 and 22.2 (2 3
C25H33DNO4Si requires MH1, 441.2314); and (2R,4S)-3-[2- CH3; i-Bu), 18.2 (ArCHCH3), 18.1 (CH3C; t-Bu) and 24.52
deuterio-2-(4-methylphenyl)propionyl]-4-phenyl-oxazolidin-
(2 3 SiCH3); negative isotopic shift at 42.8523 ppm was
2-one (R,S)-syn-[D1]-12 (0.129 g, 76 %) as a white solid; RF 0.3743 ppm (37.43 Hz at 100 MHz) (Found MH1,
[light petroleum ether (b.p. 40-60 8C):diethyl ether (1:1)] 483.2788; C28H39DNO4Si requires MH1, 483.2784); and
32
0.31; m.p. 118–1208C; {Ref.
(R,S)-syn-12; m.p. 105- (2R,4S)-3-[2-deuterio-(4-isobutylphenyl)propionyl]-4-phenyl-
1108C}; mmax (CHCl3) cm-1 2400 (C-D), 1781 (OC¼¼O) and oxazolidin-2-one (R,S)-syn-[D1]-13 (0.134 g, 76 %) as a col-
1706 (NC¼¼O); [a]2D0 5 2101.4 (c 2.6, CHCl3) {Ref. 32 ourless oil; RF [light petroleum ether (b.p. 40–608C):dieth-
(S,R)-syn-12; [a]D20 5 1121.6 (c 0.6, CHCl3)}; dH (400 yl ether (1:1)] 0.34; {Ref. 32 (S,R)-syn-13; m.p. 86–888C};
MHz, CDCl3) 7.22-7.12 (3 H, m, 3 3 CH; Ph), 6.97 (2 H, [a]2D5 5 2113.2 (c 3.8, CHCl3) {Ref. 32 (S,R)-syn-13; [a]2D5
br d, J 8.2, 2 3 CH; Ar), 6.91 (2 H, dt, J 8.2 and 2.2, 2 3 5 1118.7 (c 6.0, CHCl3); for unlabelled (R,S)-syn-13; [a]D25
CH; Ar), 6.86 (2 H, dt, J 6.9 and 1.8, 2 3 CH; Ph), 5.36 (1 5 2114.6 (c 4.2, CHCl3)}; mmax(CHCl3)cm-1 2400 (C-D),
H, dd, J 9.0 and 5.1, CHN), 4.54 (1 H, t, J 9.0, CHAHBO), 1780 (OC¼¼O) and 1707 (NC¼¼O); dH(400 MHz; CDCl3)
3.99 (1 H, dd, J 9.0 and 5.1, CHAHBO), 2.25 (3 H, s, CH3; 7.20-7.08 (3 H, m, 3 3 CH; Ph), 6.97-6.90 (4 H, m, 4 3 CH,
Ar) and 1.32 (3 H, s, ArCDCH3); dC (100 MHz, CDCl3) Ph and Ar), 6.82 (2 H, dt, J 7.8 and 2.0, 2 3 CH; Ar), 5.37
173.9 (NC¼¼O), 153.1 (OC¼¼O), 138.3 (i-CMe; Ar), 136.8 (1 H, dd J 9.1 and 5.1, CHN), 4.54 (1 H, t, J 9.1, CHAHBO),
(i-C; Ar), 136.7 (i-C; Ph), 129.1,2 128.8,2 128.5,1 128.02 and 3.96 (1 H, dd, J 9.1 and 5.1, CHAHBO), 2.35 (2 H, dd, J 7.4
125.82 (9 3 CH; Ph and Ar), 69.6 (CH2O), 57.8 (CHN), and 2.2, CH2Ar), 1.83-1.71 (1 H, appears as a nonet, J 6.8,
1
43.4 (unlabelled ArCHCH3), 43.0 (1 C, t [1:1:1], JC,D
5
(CH(CH3)2), 1.31 (3 H, s, ArCDCH3), 0.84 (3 H, d, J 6.6,
20.6 Hz, ArCDCH3), 21.0 (CH3; Ar) and 18.6 (ArCHCH3); CH3ACHCH3B) and 0.82 (3 H, d, J 6.6, CH3ACHCH3B);
negative isotopic shift at 43.0815 ppm was 0.3667 ppm dC(100.6 MHz; CDCl3) 173.8 (NC¼¼O), 153.1 (OC¼¼O),
(36.67 Hz at 100 MHz). (Found MNH41, 328.1766; 140.5 (i-C; Ar), 138.2 (i-C; Ar), 136.8 (i-C; Ph), 129.22 and
C19H22DN2O31 requires MNH41, 328.1766).
128.72 (4 3 CH; Ar), 128.4,1 127.82 and 125.72 (5 3 CH;
Ph), 69.5 (CH2O), 57.6 (CHN), 45.0 (CH(CH3)2), 43.2
1
Parallel kinetic resolution of pentafluorophenyl
2-deuterio-2-(4-isobutylphenyl)propionate (rac)-[D1]-10
using 4-[4-(tert-butyldimethylsilyloxy)phenyl]-oxazolidin-
2-one (R)-19 and 4-phenyl-oxazolidin-2-one (S)-1
(unlabelled ArCHCH3), 42.8 (1 C, t [1:1:1], JC,D 5 19.8
Hz, ArCDCH3), 30.2 (CH2Ar), 22.4 (CH3ACHCH3B), 22.3
(CH3ACHCH3B) and 18.2 (ArCDCH3); negative isotopic
shift at 42.8829 ppm was 0.3590 ppm (35.90 Hz at 100
MHz) (Found MH1, 353.1970; C22H25DNO3 requires
MH1, 353.1971).
In the same way as oxazolidin-2-one 3, n-butyl lithium
(0.49 mL, 2.5 M in hexane, 1.225 mmol), 4-[4-(tert-butyldi-
Chirality DOI 10.1002/chir

204
COULBECK ET AL.
Hydrolysis of oxazolidin-2-one (S,R)-syn-[D1]-3;
synthesis of 2-deuterio-2-phenylpropionic acid
(S)-[D1]-4
and evaporated under reduced pressure and purified by
column chromatography to give the oxazolidin-2-one (R)-
19 (44 mg, 88%) as a white solid.
Lithium hydroxide monohydrate (32 mg, 0.76 mmol)
was slowly added to a stirred solution of oxazolidin-2-one
(S,R)-syn-[D1]-3 (0.18 g, 0.60 mmol) and hydrogen perox-
ide (0.22 mL, 3.53 M in H2O, 0.79 mmol) in THF/water
(1:1; 5 mL). The reaction mixture was stirred at room tem-
perature for 12 h. The reaction was quenched with water
(10 mL) and extracted with dichloromethane (3 3 10 mL).
The combined organic layers were dried (over MgSO4)
and evaporated under reduced pressure to give the oxazo-
lidin-2-one (R)-1 (0.116 g, 96 %) as a white solid. After
acidic extraction of the aqueous layer using HCl (1 M, 10
mL) and dichloromethane (3 3 10 mL), gave 2-deuterio-2-
phenylpropionic acid (S)-4 (75 mg, 82%) ([D]:[H] 5 97:3)
as a colourless liquid; >98% e.e., [a]2D4 5 1 71.8 (c 0.15,
CHCl3); {unlabelled (S)-4; Ref. 31 [a]2D0 5 171.2 (c 0.66,
CHCl3)}; mmax (film)cm-1 2306 (CD) and 1704 (C¼¼O); dH
(270 MHz; CDCl3) 7.35-7.20 (5 H, m, 5 3 CH; Ph) and
1.50 (3 H, s, CH3); dC (100 MHz; CDCl3) 180.6 (C¼¼O),
140.0 (i-C; Ph), 129.0,2 128.02 and 127.71 (5 3 CH; Ph),
45.7 (1 C, s, unlabelled PhCHCH3), 45.3 (1 C, t [1:1:1],
1JC,D 5 20.1 Hz, PhCDCH3) and 18.3 (CDCH3); (Found
MNH41, 169.1081; C9H13DNO2 requires 169.1082). Iso-
tope shift at C(2) was 0.27 ppm (27.1 Hz at 100.613 MHz).
Hydrolysis of oxazolidin-2-one (R,S)-syn-[D1]-3;
synthesis of 2-deuterio-2-phenylpropionic acid
(R)-[D1]-4
In the same way as 2-deuterio-2-phenylpropionic acid
(S)-[D1]-4, oxazolidin-2-one (R,S)-syn-[D1]-3 (44 mg, 0.15
mmol), lithium hydroxide monohydrate (12 mg, 0.30
mmol) and hydrogen peroxide (80 lL, 3.53 M in H2O, 0.30
mmol) in THF/water (1:1; 5 mL), gave after purification
by aqueous extraction as 2-deuterio-2-phenylpropionic acid
(R)-[D1]-4 (15 mg, 67%) ([D]:[H] 5 95:5) as a colourless
liquid; >98% e.e., [a]D22 5 263.6 (c 3.0, CHCl3); which was
spectroscopically identical to those previously obtained.
The combined organic layers were dried (over MgSO4)
and evaporated under reduced pressure and purified by
column chromatography to give the oxazolidin-2-one (S)-1
(23 mg, 95%) as a white solid.
Representative procedure for determining the
enantiomeric excess of 2-deuterio-2-phenylpropionic
acid 4
(S)-1-Phenyl-ethanol (12 mg, 99 lmol) was added to a
stirred solution of 2-deuterio-2-phenyl-propionic acid (S)-
[D1]-4 (15 mg, 99 lmol) {derived from the hydrolysis of
oxazolidin-2-one (S,R)-syn-[D1]-20}, DMAP (3 mg, 20
lmol) and DCC (23 mg, 0.11 mmol) in CH2Cl2 (5 ml) at
room temperature. The solution was stirred for 12 h. The
resulting DCU was filtered off, and the remaining CH2Cl2
layer was washed with brine (10 mL), dried (over MgSO4)
and evaporated under reduced pressure. By 1H NMR spec-
troscopy (400 MHz) a single diastereoisomeric ester
[(S,S)-anti-]34 was detected. The enantiomeric excess of
the original 2-deuterio-2-phenyl-propionic acid (S)-[D1]-4
was >98% e.e.
Hydrolysis of oxazolidin-2-one (R,S)-syn-[D1]-15;
synthesis of 2-deuterio-2-phenylpropionic acid
(R)-[D1]-4
In the same way as 2-deuterio-2-phenylpropionic acid
(S)-[D1]-4, oxazolidin-2-one (R,S)-syn-[D1]-15 (61 mg, 0.14
mmol), lithium hydroxide monohydrate (11 mg, 0.27
mmol) and hydrogen peroxide (80 lL, 3.53 M in H2O, 0.27
mmol,) in THF/water (1:1; 5 mL), gave after purification
by aqueous extraction as 2-deuterio-2-phenylpropionic acid
(R)-[D1]-433 (19 mg, 92%) ([D]:[H] 5 99:1) as a colourless
liquid; >95% e.e., [a]2D2 5 264.9 (c 3.6, CHCl3) {unlabelled
(R)-4; Ref. 30 [a]2D2 5 271.4 (c 0.7, CHCl3)} which was
spectroscopically identical to those previously obtained.
The combined organic layers were dried (over MgSO4)
and evaporated under reduced pressure and purified by
column chromatography to give the 4,5,5-triphenyloxazoli-
din-2-one (S)-14 (41 mg, 95%) as a white solid.
In the same way as above, (R)-1-phenyl-ethanol (33 mg,
0.27 mmol) was added to a stirred solution of 2-deuterio-2-
phenyl-propionic acid (R)-[D1]-4 (41 mg, 0.27 mmol)
{derived from the hydrolysis of oxazolidin-2-one (R,S)-syn-
[D1]-15}, DMAP (7 mg, 50 lmol) and DCC (62 mg, 0.30
mmol) in CH2Cl2 (5 ml) at room temperature. The solution
was stirred for 12 h. The resulting DCU was filtered off,
and the remaining CH2Cl2 layer was washed with brine
(10 mL), dried (over MgSO4) and evaporated under
1
Hydrolysis of oxazolidin-2-one (S,R)-syn-[D1]-20;
synthesis of 2-deuterio-2-phenylpropionic acid
(S)-[D1]-4
reduced pressure. By H NMR spectroscopy (400 MHz) a
single diastereoisomeric ester [(R,R)-anti-]34-] was
detected. The enantiomeric excess of the original 2-deu-
terio-2-phenyl-propionic acid (R)-[D1]-4 was >98% e.e.
In the same way as 2-deuterio-2-phenylpropionic acid
(S)-[D1]-4, oxazolidin-2-one (S,R)-syn-[D1]-20 (73 mg, 0.17
mmol), lithium hydroxide monohydrate (7 mg, 0.17 mmol)
and hydrogen peroxide (50 lL, 3.53 M in H2O, 0.17 mmol)
in THF/water (1:1; 5 mL), gave after purification by aque-
CONCLUSIONS
In conclusion, we have reported the efficient parallel ki-
ous extraction as 2-deuterio-2-phenylpropionic acid (S)- netic resolution of a series of structurally related penta-
[D1]-4 (20 mg, 77%) ([D]:[H] 5 95:5) as a colourless liq- fluorophenyl active esters {e.g., (rac)-[D1]-2} using three
uid; >98% e.e., [a]2D2 5 168.0 (c 1.7, CHCl3) {unlabelled combinations of designer oxazolidin-2-ones (R)-1 and (S)-
(S)-4; Ref. 31 [a]D22 5 171.2 (c 0.66, CHCl3)} which was [D2]-1, (R)-1 and (S)-14, and (S)-1 and (R)-19. The levels
spectroscopically identical to those previously obtained. of diastereocontrol were found to be excellent favoring the
The combined organic layers were dried (over MgSO4) formation of the corresponding syn-oxazolidin-2-one
Chirality DOI 10.1002/chir

D-LABELLED 2-ARYL-PROPIONIC AND BUTANOIC ACIDS
205
15. Coumbarides GS, Eames J, Flinn A, Northen J, Yohannes Y. Probing
the resolution of 2-phenylpropanoyl chloride using quasi-enantiomeric
Evans’ oxazolidinones. Tetrahedron Lett 2005;46:849–853.
adducts 3, 15 and 20 in high yields with excellent levels
of diastereoselectivity. The preferred combination of quasi-
enantiomeric oxazolidin-2-ones for the efficient resolution
of pentafluorophenyl 2-deuterio-2-phenylpropionate (rac)-
[D1]-2 was found to involve the oxazolidin-2-ones (S)-1
and (R)-19. These oxazolidin-2-ones were shown to be effi-
cient quasi-enantiomers for the parallel kinetic resolution
and separation of a variety of 2-deuterio-2-aryl-propionic
and butanoic acids in good yield with high levels of deute-
rium incorporation.
16. Coumbarides GS, Dingjan M, Eames J, Flinn A, Northen J, Yohannes
Y. Efficient parallel resolution of an active ester of 2-phenylpropionic
acid using quasi-enantiomeric Evans’ oxazolidinones. Tetrahedron
Lett 2005;46:2897–2902.
17. Coumbarides GS, Dingjan M, Eames J, Flinn A, Motevalli M, Northen
J, Yohannes Y. Efficient parallel resolution of racemic Evans’ oxazoli-
dinones using quasi-enantiomeric profens. Synlett 2006;101–105.
18. Boyd E, Chavda S, Eames J, Yohannes Y. Parallel kinetic resolution of
2-methoxy and 2-phenoxy-substituted carboxylic acids using a combi-
nation of quasi-enantiomeric oxazolidinones. Tetrahedron: Asymmetry
2007;18:476–482.
ACKNOWLEDGMENTS
The authors are grateful to the EPSRC for a studentship
(to E.C.) and The University of Hull for their financial sup-
port (to J.E.), and the EPSRC National Mass Spectrometry
Service (Swansea) for accurate mass determinations. The
authors also thank Onyx Scientific Limited (Drs. Tony
Flinn and Julian Northen) for their interest in this project.
19. Coumbarides GS, Dingjan M, Eames J, Flinn A, Northen J. Parallel ki-
netic resolution of an oxazolidinone using a quasi-enantiomeric combi-
nation of [D,13C]-isotopomers of pentafluorophenyl 2-phenyl propio-
nate. Chirality 2007;19:321–328.
20. Chavda S, Coumbarides GS, Dingjan M, Eames J, Flinn A, Northen J.
Mutual kinetic separation of isotopomers of pentafluorophenyl 2-phe-
nyl propionate using quasi-enantiomeric oxazolidinones. Chirality
2007;19:313–320.
LITERATURE CITED
21. Coulbeck E, Eames J. Probing the parallel kinetic resolution of 1-phe-
nylethanol using quasi-enantiomeric oxazolidinone adducts. Tetrahe-
dron: Asymmetry 2007;18:2313–2325.
1. Sonawane HR, Bellur NS, Ahuja JR, Kulkarni DG. Recent develop-
ments in the synthesis of optically active a-arylpropanoic acids: an im-
portant class of non-steroidal anti-inflammatory agents. Tetrahedron:
Asymmetry 1992;3:163–192.
22. Boyd E, Chavda S, Coulbeck E, Coumbarides GS, Dingjan M, Eames
J, Flinn A, Krishnamurthy AK, Namutebi M, Northen J, Yohannes Y.
Synthesis, characterisation and application of enantiomeric isotopom-
ers of Evans’ oxazolidinones. Tetrahedron: Asymmetry 2006;17:3406–
3422.
2. Fuji K, Node M, Tanaka F, Hosoi S. Binaphthol as a chiral auxiliary.
Asymmetrical alkylation of arylacetic acid. Tetrahedron Lett 1989;30:
2825–2828.
23. Evans DA, Ennis MD, Mathrp DJ. Asymmetric alkylation reactions of
chiral imide enolates. A practical approach to the enantioselective syn-
thesis of a-substituted carboxylic acid derivatives. J Am Chem Soc
1982;104:1737–1739.
3. Corriu JP, Masse JP. Activation of Grignard reagents by transition-
metal complexes. A new and simple synthesis of trans-stilbenes and
polyphenyls. J Chem Soc Chem Commun 1972;144–144.
4. Tamao K, Sumitani K, Kumada M. Selective carbon-carbon bond for-
mation by cross-coupling of Grignard reagents with organic halides.
Catalysis by nickel-phosphine complexes. J Am Chem Soc 1972;94:
4374–4379.
24. Evans DA. Studies in asymmetric synthesis. The development of prac-
tical chiral enolate synthons. Aldrichim Acta 1982;15:23–32.
25. Coumbarides GS, Dingjan M, Eames J, Flinn A, Northen J. An effi-
cient laboratory synthesis of a-deuteriated profens. J Label Compd
Radiopharm 2006;78:903–914.
5. Hayashi T, Konishi M, Fukushima M, Kanehira K, Hioki T, Kumada
M. Chiral (b-aminoalkyl)phosphines. Highly efficient phosphine
ligands for catalytic asymmetric Grignard cross-coupling. J Org Chem
1983;48:2195–2202.
26. Evans DA, Sjogren EB. The asymmetric synthesis of b-lactam antibiot-
ics- I. application of chiral oxazolidones in the staudinger reaction. Tet-
rahedron Lett 1985;26:3783–3786.
6. Larsen RD, Corley EG, Davis P, Reider PJ, Grabowski EJJ. a-Hydroxy
esters as chiral reagents: asymmetric synthesis of 2-arylpropionic
acids. J Am Chem Soc 1989;111:7650–7651.
27. Hintermann T, Seebach D. A useful modification of the Evans auxil-
iary: 4-isopropyl-5,5-diphenyloxazolidin-2-one. Hel Chim Acta 1998;81:
2093–2126.
7. Fadel A. Optical active arylpropionic acids from the stereoselective al-
kylation of chiral imide enolates. Synlett 1992;48–50.
28. Gaul C, Schweizer BW, Seiler P, Seebach D. Crystal structures—a
manifesto for the superiority of the valine-derived 5,5-diphenyloxazoli-
dinone as an auxiliary in enantioselective organic synthesis. Hel Chim
Acta 2002;85:1546–1566.
8. Alper H, Hamel N. Asymmetric synthesis of acids by the palladium-
catalyzed hydrocarboxylation of olefins in the presence of (R)-(2)- or
(S)-(1)-1,10-binaphthyl-2,20-diyl hydrogen phosphate. J Am Chem Soc
1990;112:2803–2804.
29. Liao L, Zhang F, Dmitrenko O, Bach RD, Fox JM. A reactivity/affinity
switch for parallel kinetic resolution: a-amino acid quasienantiomers
and the resolution of cyclopropene carboxylic acids. J Am Chem Soc
2004;126:4490–4491.
9. Piccolo O, Spreafico F, Visentin G, Valoti E. Alkylation of aromatic
compounds with optically active lactic acid derivatives: synthesis of
optically pure 2-arylpropionic acid and esters. J Org Chem 1985;50:
3945–3946.
30. Chavda S, Coulbeck E, Dingjan M, Eames J, Flinn A, Northen J. Parallel
kinetic resolution of active esters using designer oxazolidin-2-ones derived
from phenylglycine. Tetrahedron: Asymmetry 2008;19:1536–1548.
10. Piccolo O, Azzena U, Melloni G, Delogu G, Valoti E. Stereospecific
Friedel-Crafts alkylation of aromatic compounds: synthesis of optically
active 2- and 3-arylalkanoic esters. J Org Chem 1991;56:183–187.
31. Boyd E, Chavda S, Coulbeck E, Coumbarides GS, Dingjan M, Eames
J, Flinn A, Motevalli M, Northen J, Yohannes Y. Parallel kinetic reso-
lution of racemic oxazolidinones using quasi-enantiomeric active
esters. Tetrahedron: Asymmetry 2007;18:2515–2530.
11. Ohta T, Takaya H, Kitamura M, Nagai K, Noyori R. Asymmetric hy-
drogenation of unsaturated carboxylic acids catalyzed by BINAP-ruth-
enium(II) complexes. J Org Chem 1987;52:3174–3176.
32. Coulbeck E, Eames J. Parallel kinetic resolution of active esters using
a quasi-enantiomeric combination of (R)-4-phenyl-oxazolidin-2-one and
(S)-4,5,5-triphenyl-oxazolidin-2-one. Tetrahedron: Asymmetry 2008;19:
2223–2233.
12. Stille JK, Parrinello G. Asymmetric hydroformylation of styrene by
polymer-supported catalysts: platinum-tin chloride supported on poly-
mer-bound chiral phosphines. J Mol Cat 1993;21:203–210.
13. Kumar A, Salunkhe RV, Rane RA, Dike SY. Novel catalytic enantiose-
lective protonation (proton transfer) in Michael addition of benzene-
thiol to a-acrylacrylates: synthesis of (S)-naproxen and a-arylpropionic
acids or esters. J Chem Soc Chem Commun 1991;485–486.
33. Kato D-I, Mitsuda S, Ohta H. Microbial deracemization of a-substi-
tuted carboxylic acids: substrate specificity and mechanistic investiga-
tion. J Org Chem 2003;68:7234–7242.
34. Coulbeck E, Eames J. Parallel kinetic resolution of 1-phenylethanol
using quasi-enantiomeric active esters. Synlett 2008;333–336.
14. Franck A, Ruchardt C. Optically active naproxen by kinetic resolution.
Chem Lett 1984;1431–1434.
Chirality DOI 10.1002/chir