Non-thiazolidinedione antihyperglycaemic agents. Part 4: Synthesis of (±)-, (R)-(+)- and (S)-(-)-enantiomers of 2-oxy-3-arylpropanoic acids

Article abstract of DOI:10.1016/S0957-4166(99)00104-4

The synthesis of a new series of potent 2-oxy-3-arylpropanoic acid antihyperglycaemic agents in both racemic and non-racemic form is described. Resolution of racemic acids 1 is accomplished via amide formation with either (S)-2-phenylglycinol or (S)-4-benzyloxazolidin-2-one as complementary resolving agents.

Full text of DOI:10.1016/S0957-4166(99)00104-4

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1335–1351
Non-thiazolidinedione antihyperglycaemic agents.
Part 4: Synthesis of (ꢀ)-, (R)-(+)- and (S)-(−)-enantiomers of
2-oxy-3-arylpropanoic acids †
David Haigh,a,∗ Helen C. Birrell,b Barrie C. C. Cantello,a Richard M. Hindley,a
Anantha Ramaswamy,b Harshad K. Rami a and Nicola C. Stevens b
aDepartment of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, The Pinnacles,
Harlow, Essex, CM19 5AW, UK
bDepartment of Analytical Sciences, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, The Pinnacles,
Harlow, Essex, CM19 5AW, UK
Received 5 March 1999; accepted 18 March 1999
Abstract
The synthesis of a new series of potent 2-oxy-3-arylpropanoic acid antihyperglycaemic agents in both racemic
and non-racemic form is described. Resolution of racemic acids 1 is accomplished via amide formation with either
(S)-2-phenylglycinolor (S)-4-benzyloxazolidin-2-oneas complementary resolving agents. © 1999 Elsevier Science
Ltd. All rights reserved.
1. Introduction
Non-insulin-dependent diabetes mellitus (NIDDM) is a complex metabolic disorder characterised
by insulin resistance in the liver and peripheral tissues.2 NIDDM affects up to 5% of the population
of most western industrialised nations. Improvement of glycaemic control via reduction of peripheral
tissue insulin resistance has long been recognised as pivotal to the development of an effective long-
term therapy for the disease.3 Thiazolidine-2,4-dione insulin sensitisers,4 such as Rezulin (troglitazone)5
and our own Phase-III clinical drug Avandia (rosiglitazone, BRL-49653),6 are members of a new family
of drugs used for the treatment of chronic NIDDM. Recent evidence suggests that compounds of this
class exert their antidiabetic activity via activation of a nuclear hormone receptor PPARγ (peroxisomal
proliferator-activated receptor γ).7
∗
†
Corresponding author. Tel: 44-1279-627814; fax 44-1279-627841; e-mail: david_haigh-1@sbphrd.com
For the previous paper in this series, see Haigh et al.1
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00104-4

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In the first paper of this series8 we reported on the preliminary results of additional structure–activity
studies on BRL 48482 (a compound equipotent to BRL 49653),6 in which the 5-benzylthiazolidine-
2,4-dione moiety of the former agent was replaced by a series of racemic 2-oxy-3-arylcarboxylic acids
1. In an initial examination of the enantioselectivity of PPARγ binding and antidiabetic potency of
these compounds,1 we recently described an enzymic resolution approach to the synthesis of the (R)-
(+)- and (S)-(−)-enantiomers of the 2-methoxy-acid 1f, together with an alternative preparation of the
enantiomers of the 2-benzyloxy-analogues 1d. In order to undertake a more thorough examination of
the impact of chirality in this area9 we subsequently required larger quantities of both enantiomers
of the key lead compounds for in vivo biological evaluation. This paper describes a new synthesis of
racemic 2-alkoxy(aryloxy)-3-arylpropanoic acids 1a–e and the preparation of their enantiomers by two
complementary resolution methodologies.
2. Results and discussion
2.1. Synthesis of racemic 2-oxy-3-arylpropanoic acids
The racemic acids 1a–e, chosen for the present resolution studies, were prepared according to
Scheme 1. The Wadsworth–Emmons reaction of the appropriate alkoxy(aryloxy)phosphonoacetate 3
(prepared from triethyl diazophosphonoacetate and the alcohol in the presence of rhodium acetate)10,11
with aldehyde 26 afforded mixtures of geometric isomers of 2-oxy-3-arylpropenoates 4. In agree-
ment with an earlier report11a the alkoxy compounds 4a–d were predominantly isolated as the Z-
isomer (Table 1), although the ratio varied according to the substituent.12,13 As expected,11b the m-
trifluoromethylphenoxy-analogue 4e was isolated as a 1:1 mixture of isomers. Reduction of 4 either
by catalytic hydrogenation over palladium charcoal (for 4a,b), or by dissolving magnesium metal in
methanol solution14 gave esters 5. In the latter reaction, products 5c–e were isolated as the methyl
esters following in situ transesterification. Hydrolysis of 5 subsequently afforded the desired acids 1a–e
(Table 1).
2.2. Chemical resolution of 2-oxy-3-arylpropanoic acids
Resolution of racemic α-functionalised carboxylic acids has classically been achieved via formation
and fractional crystallisation of salts of a chiral amine.15 However, in view of the unpredictability of
the method and difficulties we had previously encountered in the choice of a suitable amine to resolve
closely related thiazolidine-2,4-dione analogues,16 this approach was deemed unattractive. Alternative
approaches to the resolution of functionalised carboxylic acids have included kinetic17 and dynamic
kinetic18 resolution and the formation and chromatographic separation19 of diastereoisomeric esters by
reaction of the acid with a suitable chiral alcohol.20 Unfortunately, attempts to resolve racemic acids

D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1335–1351
1337
Scheme 1. For definition of substituents R1 and R2 see Table 1. Reagents: (i) NaH, THF then 2. (ii) Either (A) H2, 10% Pd–C,
EtOH, or (B) Mg, MeOH. (iii) NaOH, MeOH
Table 1
Synthesis of racemic acids
1 via formation of diastereoisomeric esters of (S)-1-phenylethanol or of (R)-pantolactone20d afforded
chromatographically inseparable mixtures.
In an extension of this concept, the formation and separation of diastereoisomeric amides has also
been used for the resolution of racemic acids21 and Helmchen22 has shown 2-phenylglycinol to be a
particularly useful amine in this context. Reaction of the acid chlorides derived from 1a–c with (S)-
2-phenylglycinol afforded amides which were easily separated by silica gel chromatography to give
the individual[2R,N(1S)]-diastereoisomers 6a–c (faster eluting isomer) and [2S,N(1S)]-diastereoisomers
7a–c (slower eluting isomer), respectively, in excellent diastereoisomeric excess (often >98%; Scheme 2;
Table 2). Subsequent acid hydrolysis afforded the corresponding (R)- and (S)-enantiomers 8a–c and 9a–c,
respectively, in good enantiomeric excess (88–96%), although in only modest chemical yield (Table 2).
However, the diastereoisomeric amides derived from acids 1d or 1e and either (S)-2-phenylglycinol or
(S)-alaninol were inseparable by chromatography.
The use of various chiral oxazolidin-2-ones in the formation and separation of diastereoisomeric imide
derivatives of racemic carboxylic acids has recently been reported.23 However, to our knowledge, only a
single example of the resolution of an α-oxyacid in this manner has been recorded.23a Consequently, we
decided to examine the suitability of the Evans chiral auxiliary (S)-4-benzyloxazolidin-2-one 10 for the
resolution of the racemic acids 1d and 1e. Auxiliary 10 was acylated by the acid chlorides derived from

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Scheme 2. Resolution of (ꢀ)-1 via (S)-2-phenylglycinol. Reagents: (i) (COCl)2, benzene. (ii) (S)-2-Phenylglycinol, NEt3,
CH2Cl2. (iii) 1 M H2SO4, aq. dioxan
Table 2
Resolution of (ꢀ)-1 via (S)-2-phenylglycinol
1d and 1e in a standard manner.24 The resulting diastereoisomeric acyloxazolidinones 11d,e and 12d,e
(faster and slower eluting isomers, respectively) were readily separable by chromatography (Scheme 3;
Table 3). Subsequent cleavage of the auxiliary by treatment with sodium methoxide,25 followed by acid
hydrolysis of the resulting esters 13 and 14 afforded the desired enantiomeric acids 8d,e and 9d,e. It
is of note that diastereoisomer separation was not possible when acids 1a and 1b were employed in
this sequence; hence it would appear that (S)-2-phenylglycinol and (S)-4-benzyloxazolidin-2-one are
complementary in their suitability for the resolution of 2-oxycarboxylic acids of this type.
2.3. Determination of absolute configuration
Following Helmchen’s proposal of a conformational model for the determination of chromatographic
elution order21a and determination of absolute stereochemistry21a,b,d of the pair of diastereoisomeric

D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1335–1351
1339
Scheme 3. Resolution of (ꢀ)-1 via (S)-4-benzyloxazolidin-2-one. Reagents: (i) 1, (COCl)2, benzene. (ii) 10, n-BuLi, THF, then
add acid chloride. (iii) 1.1 equiv. NaOMe, MeOH. (iv) 2 M HCl, dioxan
Table 3
Resolution of (ꢀ)-1 via (S)-4-benzyloxazolidin-2-one
amides formed by the reaction of a racemic carboxylic acid with a chiral amine (or vice versa), the
generality of this model for predicting stereochemistry has been firmly established.26 Thus, inspection
of the conformational models and ‘extended Newman projections’ (arrowed) for (R,S)- and (S,S)-
diastereoisomers 6 and 7, Figs. 1 and 2, respectively, suggested that the methylene protons of the ArCH2−
group in 7 should be shielded relative to 6 by the phenyl ring of the auxiliary.21a Comparison of the 1H
NMR spectra for 6a–c and 7a–c showed a consistent upfield shift of these protons in 7 (−0.05≤∆δ≤−0.15
ppm). However, the protons directly attached to the stereogenic centre of the acid moiety showed no 1H
NMR diastereoisomeric shifts. Figs. 1 and 2 also predicted that the (R,S)-diastereoisomer 6 should be the
chromatographically earlier eluting isomer, since the bulky phenyl and aryl groups occupy opposite sides
of the plane of the amide group.21a In each case, diastereoisomer 6 was indeed the chromatographically
earlier eluting isomer. Together, these data thus supported the assignment of the stereochemistry of 6

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Figure 1. (R,S)-Diastereoisomer 6
Figure 2. (S,S)-Diastereoisomer 7
and 7 and hence of the corresponding enantiomeric acids 8a–c and 9a–c. Independent proof of absolute
stereochemistry was subsequently provided by correlation of 8a–c and 9a–c with the enantiomers of 1d
and 1f, whose stereochemistry had been unambiguously determined by X-ray crystallography.1
Similar observations were also noted with the diastereoisomers 11d,e and 12d,e. In each case, (R,S)-
diastereoisomer 11 was the faster eluting. The protons attached to the two stereogenic centres in 11 and
1
12 were also found to show diagnostic shift differences in the H NMR spectra. Diastereoisomer 11
consistently showed an upfield shift for the proton on the stereogenic centre in the acid moiety‡ and a
downfield shift for the proton on the stereogenic centre in the auxiliary, relative to 12.
3. Conclusion
Synthesis of a new series of potent, racemic, 2-oxy-3-arylpropanoic acid antihyperglycaemic agents 1
has been reported. Resolution of acids 1 was achieved by the complementary utilisation of either (S)-2-
phenylglycinol or (S)-4-benzyloxazolidin-2-one as resolving agents. Use of the latter auxiliary represents
an extension to the versatility of this oxazolidin-2-one in synthesis. The absolute stereochemistry of acids
8 and 9 was inferred by literature analogy based on chromatographic elution order and 1H NMR chemical
shift differences between the diastereoisomeric amide intermediates and was substantiated by correlation
to earlier X-ray studies.
Biological evaluation of the enantiomeric acids 8 and 9 demonstrated the greater potency of the (S)-
enantiomer 9 and will be reported elsewhere. However, a de novo enantioselective aldol synthesis of 9a–e
is the subject of the following paper.27
4. Experimental
4.1. General experimental details
Mass spectroscopy was conducted using electron impact (EI), chemical ionisation (CI), with ammo-
nia as the reagent gas, or fast atom bombardment (FAB) in a 3-nitrobenzyl alcohol–sodium acetate
(NOBA–Na) matrix. Compounds characterised by high resolution mass measurement were homogeneous
by TLC. 1H NMR spectra were recorded at 270 or 400 MHz in CDCl3 solution. Chemical shifts are given
‡
The 1H NMR signal for the proton on the stereogenic centre in the acid moiety is particularly diagnostic. ∆δ (δ11–δ12) for
CHOR1 is −0.12 ppm and −0.16 ppm for 11d/12d (R1=CH2Ph) and 11e/12e (R1=m-C6H4CF3), respectively. Similar shifts were
observed for the (inseparable) diastereoisomers corresponding to 11a/12a (R1=Et, ∆δ=−0.14 ppm) and 11b/12b (R1=CH2CF3,
∆δ=−0.12 ppm).

D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1335–1351
1341
in δ (ppm) relative to TMS and coupling constants J are given in hertz. [α]D25 values are given in deg cm2
g−1. Dry solvents refer to the use of Aldrich Sure-Seal™ dried solvents. All organic solutions obtained
from aqueous extractions were dried over MgSO4. Chromatography refers to flash chromatography on
silica gel.
4.2. HPLC conditions
Diastereoisomeric amides 6a,c and 7a,c were resolved on a Zorbax Octyl column using MeOH:0.05
M NH4OAc (pH 4.5, 70:30 v/v) as eluent. Amides 6b and 7b were resolved on the same column using
MeOH:0.1 M NH4OAc (pH 4.5, 65:35 v/v). Diastereoisomeric imides 11 and 12 were separated on a
Lichrosorb Si60 column using hexane:ethyl acetate (70:30 v/v) as eluent. Chiral esters 13d and 14d were
resolved on a Chiralcel OD column using hexane:PriOH (95:5 v/v) and for esters 13e and 14e, a Chiralpak
AD column using hexane:EtOH (90:10 v/v) as eluent was employed. Chiral acids 8a,d and 9a,d were
separated on a Chiralpak AD column using hexane:PriOH (92:8 v/v) containing CF3CO2H (0.05% v/v)
as eluent; for acids 8b and 9b, hexane:EtOH (96.5:3.5 v/v) containing CF3CO2H (0.05% v/v) was used
and for acids 8c and 9c, hexane:EtOH (90:10 v/v) containing CF3CO2H (0.05% v/v) was used. Acids 8e
and 9e were resolved on a Chiralcel OJ column using hexane:EtOH (85:15 v/v) containing CF3CO2H
(0.05% v/v) as eluent. Solvent flow rate was 1 mL min−1 throughout and detection wavelength was either
220, 245 or 250 nm.
4.3. General procedure for preparation of 2-alkoxy(aryloxy)phosphonoacetates 3
4.3.1. Ethyl 2-(2,2,2-trifluoroethoxy)-2-diethylphosphonoacetate 3b
A mixture of ethyl 2-diazo-2-diethylphosphonoacetate (3.75 g, 0.015 mol), 2,2,2-trifluoroethanol (2.19
mL, 0.03 mol) and rhodium(II) acetate dimer (66 mg, 1 mol%) in benzene (40 mL) was heated at
reflux for 18 h. After removal of solvent under reduced pressure, the residual oil was chromatographed
with ethyl acetate:diethyl ether (2.5:97.5) as eluent to give the product as a clear oil (3.66 g, 76%);
(found M+ (EI) 322.0795. C10H18F3PO6 requires M 322.0793); νmax (film)/cm−1 1745 (CO) and 1260
[PO(OEt)2]; δH (270 MHz, CDCl3) 1.30–1.40 (9H, m, 3×CH3), 3.95 (1H, m, OCHHCF3), 4.10–4.40
(7H, m, OCHHCF3 and 3×CH2) and 4.51 (1H, d, 2JPH 18.7, POCH); m/z (CI) 340 [(M+NH4)+, 100%],
323 [(M+H)+, 12] and 258 (9).
4.3.2. Ethyl 2-(2-methoxyethoxy)-2-diethylphosphonoacetate 3c
Similarly prepared. An oil, 66%; (found M+ (EI) 298.1181. C11H23PO7 requires M 298.1181); δH
(270 MHz, CDCl3) 1.32 (9H, m, 3×CH2CH3), 3.35 (3H, s, OMe), 3.59 (2H, t, J 4.5, CH2OMe), 3.80
(2H, m, OCH2CH2OMe), 4.20 (6H, m, 3×CH2CH3) and 4.47 (1H, d, 2JPH 18.9, POCH).
4.3.3. Ethyl 2-benzyloxy-2-diethylphosphonoacetate 3d
Similarly prepared. An oil, 56%; (found (M+H)+ (CI) 331.1308. C15H23PO6 requires M 331.1311);
2
δH (270 MHz, CDCl3) 1.30 (9H, m, 3×OCH2CH3), 4.20 (6H, 3×OCH2CH3), 4.35 (1H, d, JPH 18.9,
POCH), 4.58 (1H, d, J 11.8, OCHHPh), 4.82 (1H, d, J 11.8, OCHHPh) and 7.28 (5H, m, Ph).

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4.4. General procedure for olefination of aldehyde 2
4.4.1. Ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroeth-
oxy)propenoate 4b
Sodium hydride (60% dispersion in oil, 250 mg, 6.2×10−3 mol, 1.1 equiv.) was added to a solution of
phosphonate 3b (1.819 g, 5.6×10−3 mol) in dry THF (5 mL) at 0°C under an atmosphere of argon. After
stirring at 0°C for 10 min, a solution of aldehyde 2 (1.670 g, 1 equiv.) in dry THF (5 mL) was added and
the mixture allowed to warm to ambient temperature and stirred for 3.5 h. Water (30 mL) was added,
the mixture was extracted with ethyl acetate (×3) and the combined extracts washed with brine then
dried and evaporated to dryness to afford an oil. This was chromatographed using ethyl acetate:hexane
(gradient, 10:90 to 50:50) as eluent to afford a 43:57 E:Z mixture of geometric isomers of the title
compound as a wax (2.278 g, 88%); (found (M+H)+ (FAB) 465. C23H23F3N2O5 requires M 465); νmax
(film)/cm−1 1712 (CO); δH (270 MHz, CDCl3) geometric isomerism causes doubling of most peaks,
1.17, 1.36 (combined, 3H, t, J 7.1, isomers of OCH2CH3), 3.35, 3.36 (combined, 3H, s, NMe), 3.95 (2H,
m, OCH2CH2N), 4.10–4.40 (6H, m, 3×OCH2), 6.48 (0.43H, s, E-olefinic H) and 6.80–7.70 (8.57H, m,
Z-olefinic H and ArH); m/z (FAB) 487 [(M+Na)+, 10%], 465 [(M+H)+, 100], 419 (4), 316 (16) and 175
(61).
4.4.2. Ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxypropenoate 4a
Similarly prepared. A gum, 71%; 38:62 E:Z mixture of geometric isomers; (found M+ (EI) 410.1840.
C23H26N2O5 requires M 410.1842); δH (270 MHz, CDCl3) geometric isomerism causes doubling of
most peaks, 1.13 (0.38×3H, t, J 7.1, CO2CH2CH3, E-isomer), 1.25–1.45 (3H+0.62×3H, m, OCH2CH3
and CO2CH2CH3, Z-isomer), 3.34 (3H, s, NMe), 3.95–4.40 (8H, m, 3×OCH2 and NCH2), 6.06 (0.32H,
s, E-olefinic H) and 6.80–7.80 (8.62H, m, Z-olefinic H and aryl-H).
4.4.3. Ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyethoxy)-
propenoate 4c
Similarly prepared. A gum, 60%; 24:76 E:Z mixture of geometric isomers; (found M+ (EI) 440.1948.
C24H28N2O6 requires M 440.1948); δH (270 MHz, CDCl3) geometric isomerism causes doubling of
most peaks, 1.12, 1.35 (combined, 3H, t, J 7.1, isomers of OCH2CH3), 3.35–3.45 (combined, 6H, m,
isomeric NMe and OMe), 3.67, 3.72 (combined, 2H, m, OCH2CH2OMe), 3.90–4.35 (8H, m, 3×OCH2
and NCH2), 6.15 (0.24H, s, E-olefinic H) and 6.80–7.80 (8.76H, m, Z-olefinic H and ArH).
4.4.4. Ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-benzyloxypropenoate
4d
Similarly prepared. A gum, 68%; 41:59 E:Z mixture of geometric isomers. These were partially
resolved by silica gel chromatography using ethyl acetate:dichloromethane (2:98) as an eluent to afford
initially the Z-isomer Z-4d: (found M+ (EI) 472.1996. C28H28N2O5 requires M 472.1996); δH (270
MHz, CDCl3) 1.34 (3H, t, J 7.1, OCH2CH3), 3.34 (3H, s, NMe), 3.95 (2H, t, J 5.2, NCH2), 4.30 (4H,
m, 2×OCH2), 4.93 (2H, s, CH2Ph), 6.83 (2H, d, J 8.9, aryl 3-H and 5-H) and 6.95–7.75 (12H, m, aryl-H
and Z-olefinic H); followed by the E-isomer E-4d: δH (270 MHz, CDCl3) 1.15 (3H, t, J 7.2, OCH2CH3),
3.34 (3H, s, NMe), 3.94 (2H, t, J 5.3, NCH2), 4.16 (2H, q, J 7.2 OCH2CH3), 4.25 (2H, t, J 5.3 OCH2),
4.94 (2H, s, CH2Ph), 6.19 (1H, s, E-olefinic H) and 6.78–7.45 (13H, m, aryl-H).

D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1335–1351
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4.4.5. Ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(3-trifluoromethyl-
phenoxy)propenoate 4e
Similarly prepared. A gum, 94%; 50:50 E:Z mixture of geometric isomers; (found M+ (EI) 526.1712.
C28H25N2O5 requires M 526.1716); δH (270 MHz, CDCl3) geometric isomerism causes doubling of
most peaks, 1.05, 1.18 (combined, 3H, t, J 7.1, isomers of OCH2CH3), 3.32, 3.35 (combined, 3H, s,
NMe), 3.96 (2H, m, NCH2), 4.05–4.35 (4H, m, 2×OCH2) and 6.80–7.70 (13H, m, aryl-H and olefinic
H).
4.5. Reduction of alkene 4, Method A
4.5.1. Ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)-
propanoate 5b (R2=Et)
A mixture of alkene 4b (2.240 g, 4.83×10−3 mol), 10% palladium on charcoal (220 mg) and ethanol
(30 mL) was shaken under an atmosphere of hydrogen at 30 p.s.i. and ambient temperature. After 5 h,
the catalyst was removed by filtration and solvent removed in vacuo to give the product as an oil (2.201
g, 98%), which was used without further purification; (found M+ (EI) 466.1715. C23H25F3N2O5 requires
M 466.1716); νmax (film)/cm−1 1744 (CO); δH (270 MHz, CDCl3) 1.24 (3H, t, J 7.2, OCH2CH3), 3.00
(2H, m, ArCH2CH), 3.34 (3H, s, NMe), 3.65 (1H, m, OCHHCF3), 3.94 (2H, t, J 5.2, NCH2), 3.97 (1H,
m, OCHHCF3), 4.10–4.30 (5H, m, 2×OCH2 and ArCH2CH), 6.80 (2H, d, J 8.8, phenyl-3H and 5H) and
6.95–7.40 (6H, m, ArH); m/z (FAB) 489 [(M+Na)+, 17%], 467 [(M+H)+, 100], 175 (52) 161 (18) and
148 (58).
4.5.2. Ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxypropanoate 5a
(R2=Et)
Similarly prepared. A gum, 73%; (found (M+H)+ (CI) 413.2070. C23H28N2O5 requires M 413.2077);
δH (270 MHz, CDCl3) 1.15 (3H, t, J 6.9, OCH2CH3), 1.22 (3H, t, J 7.1, CO2CH2CH3), 2.95 (2H, m,
ArCH2CH), 3.30 (1H, m, OCHHCH3), 3.34 (3H, s, NMe), 3.60 (1H, m, OCHHCH3), 3.93 (3H, m,
ArCH2CH and NCH2), 4.17 (2H, q, J 7.1, CO2CH2CH3), 4.24 (2H, t, J 5.2, OCH2), 6.80 (2H, d, J 8.8,
aryl 3-H and 5-H) and 6.95–7.40 (6H, m, aryl H).
4.6. Reduction of alkene 4, Method B
4.6.1. Methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyethoxy)-
propanoate 5c (R2=Me)
A mixture of alkene 4c (1.36 g, 3 mmol), magnesium (0.5 g, 20 mmol) iodine (ca. 10 mg) and
methanol (80 mL) was warmed gently (hairdryer) with stirring until evolution of hydrogen commenced.
An additional portion of magnesium (3.5 g, 140 mmol) was added and the mixture stirred at room
temperature (temperature regulated by immersion in a cold water bath) for 23 h then concentrated. The
residue was suspended in water (500 mL) and concentrated hydrochloric acid was added to give a final
pH of 2, once all the solid had dissolved. The mixture was extracted with ethyl acetate (3×500 mL)
and the combined organic solutions washed with brine (500 mL), dried and evaporated. The residue
was chromatographed using ethyl acetate:dichloromethane (gradient, 5:95 to 10:90) as eluent to afford
5c (R2=Me), a colourless gum, 0.476 g, 37%; (found (M+H)+ (CI) 428.1946. C23H28N2O6 requires M
428.1948); νmax (film)/cm−1 1748 (CO); δH (270 MHz, CDCl3) 2.95 (2H, m, ArCH2CH), 3.29 (3H, s,
OMe), 3.35 (3H, s, NMe), 3.47 (3H, m, OCHHCH2OMe), 3.69 (4H, m, CO2Me and OCHHCH2OMe),

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3.93 (2H, t, J 5.2, NCH2), 4.06 (1H, t, J 5.8, ArCH2CH), 4.24 (2H, t, J 5.2, OCH2), 6.80 (2H, d, J 8.8,
aryl 3-H and 5-H) and 6.95–7.40 (6H, m, aryl H); m/z (CI) 429 [(M+H)+, 100%], 175 (15) and 148 (10).
4.6.2. Methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-benzyloxypropanoate 5d
(R2=Me)
Similarly prepared. A gum, 84%; (found M+ (EI) 460.2000. C27H28N2O5 requires M 460.1999); δH
(270 MHz, CDCl3) 2.98 (2H, m, ArCH2CH), 3.35 (3H, s, NMe), 3.69 (3H, s, OMe), 3.94 (2H, t, J
5.2, NCH2), 4.10 (1H, dd, J 7.7 and 5.5, ArCH2CH), 4.24 (2H, t, J 5.2, OCH2), 4.35 (1H, d, J 11.9,
OCHHPh), 4.64 (1H, d, J 11.9, OCHHPh), 6.79 (2H, d, J 8.8, aryl 3-H and 5-H) and 6.95–7.40 (11H,
m, aryl-H).
4.6.3. Methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(3-trifluoromethylphen-
oxy)propanoate 5e
Similarly prepared. (R2=Me), a gum, 78%; (found M+ (EI) 514.1717. C27H25F3N2O5 requires M
514.1716); δH (270 MHz, CDCl3) 3.18 (2H, d, J 6.4, ArCH2CH), 3.33 (3H, s, NMe), 3.71 (3H, s,
OMe), 3.93 (2H, t, J 5.2, NCH2), 4.23 (2H, t, J 5.2, OCH2), 4.77 (1H, t, J 6.4, ArCH2CH), 6.83 (2H, d,
J 8.8, aryl 3-H and 5-H) and 6.90–7.35 (10H, m, aryl-H).
4.7. Alkaline hydrolysis of esters 5
4.7.1. (ꢀ)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxypropanoic acid 1a
Aqueous sodium hydroxide hydrolysis of 5a afforded acid 1a as a white solid (50%), m.p. 109–110°C;
(found C, 65.6; H, 6.3; N, 7.4%; M+ (EI) 384.1686. C21H24N2O5 requires C, 65.6; H, 6.3; N, 7.3%; M
384.1685); νmax (KBr)/cm−1 3000–2500 (COOH), 1710 (CO); δH (270 MHz, CDCl3) 1.18 (3H, t, J 6.9,
OCH2CH3), 2.95 (1H, dd, J 14.0 and 7.2, ArCHHCH), 3.05 (1H, dd, J 14.0 and 5.0, ArCHHCH), 3.32
(3H, s, NMe), 3.45 (1H, m, OCHHCH3), 3.60 (1H, m, OCHHCH3), 3.91 (2H, t, J 5.0, NCH2), 4.04 (1H,
dd, J 7.2 and 5.0, ArCH2CH), 4.18 (2H, t, J 5.0, OCH2), 5.00 (1H, br, exchanges with D2O, CO2H),
6.79 (2H, d, J 8.8, aryl 3-H and 5-H) and 6.95–7.40 (6H, m, aryl-H); m/z (EI) 384 (M+, 9%), 311 (40),
175 (100), 161 (72) and 148 (100).
4.7.2. (ꢀ)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)-
propanoic acid 1b
Similarly prepared. A solid, 93%; m.p. 116–117°C; (found C, 57.4; H, 4.9; N, 6.4%; M+ (EI) 438.1403.
C21H21F3N2O5 requires C, 57.5; H, 4.8; N, 6.4%; M 438.1403); δH (270 MHz, CDCl3) 3.11 (2H,
m, ArCH2CH), 3.29 (3H, s, NMe), 3.76 (1H, m, OCHHCF3), 3.85 (2H, m, NCH2), 4.02 (2H, m,
OCH2CH2N), 4.10 (1H, m, OCHHCF3), 4.24 (1H, m, ArCH2CH), 6.75 (2H, d, J 8.8, phenyl 3-H and
5-H), 6.95–7.40 (6H, m, ArH) and 8.75 (1H, br, exchanges with D2O, COOH).
4.7.3. (ꢀ)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyethoxy)-
propanoic acid 1c
Similarly prepared. A solid, 92%; m.p. 87–89°C; (found C, 63.8; H, 6.5; N, 7.05%; M+ (EI) 414.1791.
C21H26N2O6 requires C, 63.8; H, 6.3; N, 6.8%; M 414.1791); δH (270 MHz, CDCl3) 2.91 (1H, dd, J
14.3 and 8.5, ArCHHCH), 3.14 (1H, dd, J 14.3 and 3.8, ArCHHCH), 3.33 (3H, s, NMe), 3.38 (3H, s,
OMe), 3.40–3.70 (5H, m, reduces to 4H on exchange with D2O, COOH and OCH2CH2OMe), 3.93 (2H,
t, J 5.2, NCH2), 4.05 (1H, dd, J 8.5 and 3.8, ArCH2CH), 4.21 (2H, t, J 5.2, OCH2), 6.80 (2H, d, J 8.6,
aryl 3-H and 5-H) and 6.96–7.40 (6H, m, aryl-H).

D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1335–1351
1345
4.7.4. (ꢀ)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-benzyloxypropanoic acid 1d
Similarly prepared. A foam, 91%; (found M+ (EI) 446.1843. C26H26N2O5 requires M 446.1842); δH
(270 MHz, CDCl3) 3.05 (2H, m, ArCH2CH), 3.31 (3H, s, NMe), 3.90 (2H, t, J 5.4, NCH2), 4.15 (3H, m,
ArCH2CH and OCH2CH2N), 4.45 (1H, d, J 11.5, PhCHHO), 4.70 (1H, d, J 11.5, PhCHHO), 6.70–7.40
(13H, m, aryl-H) and 7.50 (1H, br, exchanges with D2O, COOH).
4.7.5. (ꢀ)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(3-trifluoromethylphenoxy)-
propanoic acid 1e
Similarly prepared. A solid, 89%; m.p. 168–169°C; (found C, 62.4; H, 4.6; N, 5.7%; M+ (EI) 428.1946.
C26H23F3N2O5 requires C, 62.4; H, 4.6; N, 5.6%; M 428.1948); δH (270 MHz, CDCl3) 3.25 (5H, m,
ArCH2 and NMe), 3.83 (2H, t, J 4.9, NCH2), 4.00 (1H, br, exchanges with D2O, COOH), 4.04 (2H, t, J
4.9, OCH2), 4.86 (1H, t, J 6.0, ArCH2CH), 6.77 (2H, d, J 8.5, aryl 3-H and 5-H) and 6.95–7.40 (10H,
m, aryl-H).
4.8. General procedure for reaction of racemic 1a–c with (S)-2-phenylglycinol. Preparation of dia-
stereoisomeric α-ethoxyamides 6a and 7a
Oxalyl chloride (3.4 mL, 39 mmol) was added dropwise to a solution of ethoxyacid 1a (2.96 g,
7.7 mmol) in dry benzene (100 mL). The resulting mixture was heated at reflux for 2 h, cooled and
evaporated in vacuo to afford the acid chloride. This was dissolved in dry dichloromethane (150 mL) and
the solution added, over 5 min, to an ice-cooled solution of (S)-2-phenylglycinol (1.056 g, 7.7 mmol) and
triethylamine (2.2 mL, 15.4 mmol) in dichloromethane (150 mL) under argon. The mixture was allowed
to warm to ambient temperature and stirred for an additional 16 h before being evaporated. The residue
was chromatographed using isohexane:ethyl acetate (gradient, 25:75 to 0:100) as eluent to afford firstly
the [2R,N(1S)]-diastereoisomeric amide 6a, followed by the [2S,N(1S)]-diastereoisomer 7a.
4.8.1. [2R,N(1S)]-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxy-N-(2-
hydroxy-1-phenylethyl)propanamide 6a
A colourless gum (1.222 g, 32%); (found (M+H)+ (CI) 504.2491. C29H33N3O5 requires M 504.2499);
25
[α]D +21 (c 1.15 in CHCl3); d.e. 98.4% by HPLC; νmax (film)/cm−1 3420 (NH) and 1645 (CO); δH
(270 MHz, CDCl3) 1.12 (3H, t, J 7.0, OCH2Me), 2.65 (1H, br, exchanges with D2O, OH), 2.94 (1H, dd,
J 14.1 and 6.3, ArCHHCH), 3.10 (1H, dd, J 14.1 and 3.8, ArCHHCH), 3.33 (3H, s, NMe), 3.50 (2H, m,
OCH2Me), 3.65 (2H, m, CH2OH), 3.93 (2H, t, J 5.3, NCH2), 3.95 (1H, dd, J 6.3 and 3.8, ArCH2CH),
4.25 (2H, t, J 5.3, OCH2CH2N), 4.95 (1H, m, PhCHN) and 6.80–7.40 (14H, m, reduces to 13H on
exchange with D2O, aryl-H and NH); m/z (CI) 504 [(M+H)+, 100%], 486 (5), 440 (10) and 412 (3).
4.8.2. [2S,N(1S)]-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxy-N-(2-
hydroxy-1-phenylethyl)propanamide 7a
A colourless gum (1.278 g, 33%); (found (M+H)+ (CI) 504.2486. C29H33N3O5 requires M 504.2499);
25
[α]D −19 (c 1.25 in CHCl3); d.e. 100% by HPLC; νmax (film)/cm−1 3420 (NH) and 1645 (CO); δH
(270 MHz, CDCl3) 1.16 (3H, t, J 7.0, OCH2Me), 2.60 (1H, br, exchanges with D2O, OH), 2.86 (1H, dd,
J 14.2 and 6.8, ArCHHCH), 3.05 (1H, dd, J 14.2 and 3.7, ArCHHCH), 3.35 (3H, s, NMe), 3.55 (2H, m,
OCH2Me), 3.83 (2H, m, CH2OH), 3.95 (3H, m, NCH2 and ArCH2CH), 4.21 (2H, t, J 5.2, OCH2CH2N),
4.97 (1H, m, PhCHN) and 6.80–7.40 (14H, m, reduces to 13H on exchange with D2O, aryl-H and NH);
m/z (CI) 504 [(M+H)+, 100%] and 486 (5).

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D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1335–1351
4.8.3. [2R,N(1S)]-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoro-
ethoxy)-N-(2-hydroxy-1-phenylethyl)propanamide 6b
Similarly prepared. A foam, 32%; (found M+ (EI) 557.2136. C29H30F3N3O5 requires M 557.2138);
[α]D25 +39 (c 0.35 in MeOH); d.e. 100% by HPLC; δH (270 MHz, CDCl3) 2.40 (1H, br, exchanges with
D2O, OH), 3.00 (1H, dd, J 13.5 and 6.9, ArCHHCH), 3.18 (1H, dd, J 13.5 and 3.6, ArCHHCH), 3.33
(3H, s, NMe), 3.60–3.85 (4H, m, OCH2CF3 and CH2OH), 3.94 (2H, t, J 5.2, NCH2CH2O), 4.11 (1H,
dd, J 6.9 and 3.6, ArCH2CH), 4.26 (2H, t, J 5.2, NCH2CH2O), 5.00 (1H, m, PhCH), 6.83 (2H, d, J 8.8,
aryl 3-H and 5-H) and 6.90–7.40 (12H, m, aryl-H and NH).
4.8.4. [2S,N(1S)]-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoro-
ethoxy)-N-(2-hydroxy-1-phenylethyl)propanamide 7b
Similarly prepared. A foam, 34%; (found M+ (EI) 557.2136. C29H30F3N3O5 requires M 557.2138);
25
[α]D +14 (c 0.50 in MeOH); d.e. 99% by HPLC; δH (400 MHz, CDCl3) 2.30 (1H, br, exchanges with
D2O, OH), 2.90 (1H, dd, J 14.4 and 7.3, ArCHHCH), 3.13 (1H, dd, J 14.4 and 3.6, ArCHHCH), 3.36 (3H,
s, NMe), 3.70–3.87 (2H, m, OCH2CF3), 3.84 (2H, d, J 5.0, CH2OH), 3.95 (2H, t, J 5.2, NCH2CH2O),
4.12 (1H, dd, J 7.3 and 3.6, ArCH2CH), 4.22 (2H, t, J 5.2, NCH2CH2O), 5.01 (1H, m, PhCH), 6.75 (2H,
d, J 8.7, aryl 3-H and 5-H) and 6.95–7.40 (12H, m, aryl-H and NH).
4.8.5. [2R,N(1S)]-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyethoxy)-
N-(2-hydroxy-1-phenylethyl)propanamide 6c
Similarly prepared. A gum, 44%; (found M+ (EI) 533.2526. C30H35N3O6 requires M 533.2526);
25
[α]D +34 (c 1.7 in CHCl3); d.e. 90.8% by HPLC; δH (400 MHz, CDCl3) 2.86 (1H, br, exchanges
with D2O, OH), 2.92 (1H, dd, J 14.2 and 7.8, ArCHHCH), 3.11 (3H, s, OMe), 3.17 (1H, dd, J 14.2
and 3.3, ArCHHCH), 3.34 (3H, s, NMe), 3.35 (1H, m, OCHHCH2OMe), 3.47 (2H, m, OCH2CH2OMe),
3.55 (1H, m, OCHHCH2OMe), 3.70 (2H, m, CH2OH), 3.94 (2H, t, J 5.3, NCH2), 3.95 (1H, dd, J 7.8
and 3.3, ArCH2CH), 4.26 (2H, t, J 5.3, NCH2CH2O), 4.96 (1H, m, PhCH), 6.83 (2H, d, J 8.7, aryl 3-H
and 5-H), 6.95–7.35 (11H, m, aryl-H) and 7.57 (1H, br, exchanges with D2O, NH).
4.8.6. [2S,N(1S)]-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyethoxy)-
N-(2-hydroxy-1-phenylethyl)propanamide 7c
Similarly prepared. A gum, 27%; (found M+ (EI) 533.2526. C30H35N3O6 requires M 533.2526);
25
[α]D −33 (c 1.1 in CHCl3); d.e. 92.6% by HPLC; δH (400 MHz, CDCl3) 2.81 (1H, dd, J 14.3 and
8.3, ArCHHCH), 3.07 (1H, dd, J 14.3 and 3.2, ArCHHCH), 3.30 (1H, br, exchanges with D2O, OH),
3.35 (3H, s, OMe), 3.36 (3H, s, NMe), 3.48–3.65 (4H, m, OCH2CH2OMe), 3.71 (1H, dd, J 11.8 and 7.5,
NCHPhCHHOH), 3.82 (1H, dd, J 11.8 and 4.0, NCHPhCHHOH), 3.93 (2H, t, J 5.3, NCH2), 3.94 (1H,
dd, J 8.3 and 3.2, ArCH2CH), 4.22 (2H, t, J 5.3, NCH2CH2O), 5.05 (1H, m, PhCH), 6.85 (2H, d, J 8.7,
aryl 3-H and 5-H), 6.95–7.35 (11H, m, aryl-H) and 7.54 (1H, br, exchanges with D2O, NH).
4.9. General procedure for reaction of racemic 1d and 1e with (S)-4-benzyloxazolidin-2-one. Prepara-
tion of diastereoisomeric 3-(trifluoromethyl)phenoxyacyloxazolidin-2-ones 11e and 12e
Oxalyl chloride (2.62 mL) was added dropwise to a solution of the acid 1e (3.0 g, 6.0 mmol) in dry
benzene (120 mL). The mixture was heated at reflux for 2.5 h, cooled and evaporated in vacuo. Repeated
re-evaporation from dry THF afforded the crude acid chloride, a gum.
A solution of n-butyllithium (1.6 M in hexane, 7.5 mL, 12.0 mmol) was added dropwise, over 10
min, to a −70°C solution of (S)-4-benzyloxazolidin-2-one (2.12 g, 6.0 mmol) in dry THF (50 mL) under

D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1335–1351
1347
argon. The mixture was stirred at −70°C for an additional 10 min prior to the addition, over 10 min, of a
solution of the acid chloride (above) in dry THF (100 mL). Stirring was continued at −70°C for 1 h and the
mixture was then allowed to warm to room temperature overnight (20 h), then concentrated. The residue
was diluted with water (500 mL), extracted with ethyl acetate (3×500 mL) and the combined ethyl acetate
solutions washed with water (500 mL) and brine (500 mL), dried and evaporated. Chromatography using
ethyl acetate:isohexane (30:70) as eluent afforded firstly the [3(2R),4S]-diastereoisomer 11e, followed by
the [3(2S),4S]-diastereoisomer 12e.
4.9.1. [3(2R),4S]-3-[3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-[3-(trifluoro-
methyl)phenoxy]propanoyl]-4-benzyloxazolidin-2-one 11e
A white foam (1.08 g, 28%); (found (M+H)+ (CI) 660.2319. C36H32F3N3O6 requires M 660.2322);
[α]D +29 (c 1.00 in CHCl3); d.e. 100% by HPLC; νmax (KBr)/cm−1 1780, 1710 and 1645 (CO); δH
25
(400 MHz, CDCl3) 2.72 (1H, dd, J 13.5 and 9.6, PhCHHCH), 3.11 (1H, dd, J 14.0 and 8.9, ArCHHCH),
3.23 (1H, dd, J 13.5 and 3.3, PhCHHCH), 3.26 (1H, dd, J 14.0 and 3.2, ArCHHCH), 3.32 (3H, s, NMe),
3.92 (2H, t, J 5.3, NCH2), 4.23 (2H, t, J 5.3, OCH2CH2N), 4.25 (1H, dd, J 9.0 and 3.5, oxazolidinone
5a-H), 4.31 (1H, t, J 9.0, oxazolidinone 5b-H), 4.71 (1H, m, oxazolidinone 4-H), 5.97 (1H, dd, J 8.9 and
3.3, ArCH2CH), 6.83 (2H, d, J 8.7, aryl 3-H and 5-H), 6.92 (1H, dd, J 8.3 and 2.6, CF3-phenoxy 6-H)
and 6.99–7.36 (14H, m, aryl-H); m/z (CI) 660 [(M+H)+, 100%], 500 (9), 483 (4), 371 (5), 325 (7), 297
(7) and 195 (85).
4.9.2. [3(2S),4S]-3-[3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-[3-(trifluoro-
methyl)phenoxy]propanoyl]-4-benzyloxazolidin-2-one 12e
A white foam (0.73 g, 19%); (found (M+H)+ (CI) 660.2319. C36H32F3N3O6 requires M 660.2322);
25
[α]D +62 (c 1.01 in CHCl3); d.e. 97.2% by HPLC; νmax (KBr)/cm−1 1780, 1710 and 1640 (CO); δH
(400 MHz, CDCl3) 2.73 (1H, dd, J 13.5 and 9.5, PhCHHCH), 3.18 (2H, d, J 6.6, ArCH2CH), 3.18 (1H,
dd, J 13.5 and 3.3, PhCHHCH), 3.32 (3H, s, NMe), 3.92 (2H, t, J 5.3, NCH2), 4.02 (1H, dd, J 9.1 and 7.7,
oxazolidinone 5a-H), 4.15 (1H, dd, J 9.1 and 2.4, oxazolidinone 5b-H), 4.23 (2H, t, J 5.3, OCH2CH2N),
4.52 (1H, m, oxazolidinone 4-H), 6.13 (1H, t, J 6.6, ArCH2CH), 6.82 (2H, d, J 8.7, aryl 3-H and 5-H)
and 6.95–7.40 (15H, m, aryl-H); m/z (CI) 660 [(M+H)+, 100%], 500 (15), 297 (4) and 195 (92).
4.9.3. [3(2R),4S]-3-[3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-benzyloxy-
propanoyl]-4-benzyloxazolidin-2-one 11d
Similarly prepared. A foam, 24%; (found M+ (EI) 605.2525. C36H35N3O6 requires M 605.2526);
[α]D25 +32 (c 1.09 in CHCl3); d.e. 97.8% by HPLC; δH (270 MHz, CDCl3) 2.66 (1H, dd, J 13.2 and 9.3,
PhCHHCH), 2.80–3.20 (3H, m, ArCH2 and PhCHHCH), 3.34 (3H, s, NMe), 3.94 (2H, t, J 5.5, NCH2),
4.10–4.30 (4H, m, OCH2CH2N and oxazolinone 5-H2), 4.38 (1H, d, J 11.6, PhCHHO), 4.51 (1H, d, J
11.6, PhCHHO), 4.55 (1H, m, oxazolidinone 4-H), 5.21 (1H, dd, J 9.3 and 3.8, ArCH2CH), 6.81 (2H, d,
J 8.8, aryl 3-H and 5-H) and 6.95–7.40 (16H, m, aryl-H).
4.9.4. [3(2S),4S]-3-[3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-benzyloxy-
propanoyl]-4-benzyloxazolidin-2-one 12d
Similarly prepared. A gum, 17%; (found M+ (EI) 605.2525. C36H35N3O6 requires M 605.2526);
25
[α]D +39 (c 1.02 in CHCl3); d.e. 89.8% by HPLC; δH (400 MHz, CDCl3) 2.66 (1H, dd, J 13.5 and
9.5, PhCHHCH), 2.92 (1H, dd, J 13.6 and 8.3, ArCHHCH), 3.00 (1H, dd, J 13.6 and 4.8, ArCHHCH),
3.17 (1H, dd, J 13.5 and 3.3, PhCHHCH), 3.33 (3H, s, NMe), 3.93 (2H, t, J 5.3, NCH2), 4.04 (1H, m,
oxazolidinone 5a-H), 4.10 (1H, m, oxazolidinone 5b-H), 4.24 (2H, t, J 5.3, OCH2CH2N), 4.43 (1H, d, J

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D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1335–1351
11.7, PhCHHO), 4.51 (1H, m, oxazolidinone 4-H), 4.53 (1H, d, J 11.7, PhCHHO), 5.33 (1H, dd, J 8.3
and 4.8, ArCH2CH), 6.80 (2H, d, J 8.6, aryl 3-H and 5-H) and 6.95–7.40 (16H, m, aryl-H).
4.10. General procedure for hydrolysis of diastereoisomeric amides 6 and 7
4.10.1. (R)-(+)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl-2-ethoxypropanoic acid 8a
A solution of amide 6a (1.137 g, 2.3 mmol), sulphuric acid (1.0 M, 23 mL), water (46 mL) and dioxan
(46 mL) was heated at 90°C for 48 h, cooled, diluted with water (300 mL) and the pH adjusted to 2.5 by
addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate
(3×250 mL) and the combined organic solutions washed with water (500 mL) and brine (500 mL), dried
and evaporated. The residue was chromatographed with methanol:dichloromethane (gradient, 1.5:98.5 to
3.5:96.5) as eluent to afford acid 8a, (0.324 g, 37%), a foam, spectroscopically identical with racemate
25
1a; (found M+ (EI) 384.1687. C21H24N2O5 requires M 384.1685); [α]D +15 (c 0.90 in MeOH); e.e.
93.2% by HPLC.
4.10.2. (S)-(−)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl-2-ethoxypropanoic acid 9a
Similarly prepared. A foam, 38%; (found M+ (EI) 384.1684. C21H24N2O5 requires M 384.1685);
25
[α]D −16 (c 1.08 in MeOH); e.e. 93.6% by HPLC; otherwise identical with racemate 1a.
4.10.3. (R)-(+)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl-2-(2,2,2-trifluoroethoxy)-
propanoic acid 8b
Similarly prepared. A solid, 51%; m.p. 115°C; (found C, 57.8; H, 4.7; N, 6.7%; M+ (EI) 438.1403.
25
C21H21F3N2O5 requires C, 57.5; H, 4.8; N, 6.4%; M 438.1403); [α]D +24 (c 0.31 in CHCl3); e.e.
96.6% by HPLC; otherwise identical with racemate 1b.
4.10.4. (S)-(−)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)-
propanoic acid 9b
Similarly prepared. A solid, 48%; m.p. 116–117°C; (found C, 57.9; H, 4.7; N, 6.8%; M+ (EI) 438.1403.
C21H21F3N2O5 requires C, 57.5; H, 4.8; N, 6.4%; M 438.1403); [α]D25 −25 (c 0.24 in CHCl3); e.e. 95.2%
by HPLC; otherwise identical with racemate 1b.
4.10.5. (R)-(+)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyeth-
oxy)propanoic acid 8c
Similarly prepared. A foam, 60%; (found M+ (EI) 414.1791. C22H26N2O6 requires M 414.1791);
25
[α]D +28 (c 0.63 in CHCl3); e.e. 94% by HPLC; otherwise identical with racemate 1c.
4.10.6. (S)-(−)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyeth-
oxy)propanoic acid 9c
Similarly prepared. A foam, 43%; e.e. 88% by HPLC. Repeated crystallisation of the (S)-(−)-1-
phenylethylamine salt subsequently afforded acid 9c, a foam; (found C, 63.6; H, 6.4; N, 6.8%; M+ (EI)
25
414.1791. C22H26N2O6 requires C, 63.8; H, 6.3; N, 6.8%; M 414.1791); [α]D −28 (c 0.63 in CHCl3);
e.e. 94% by HPLC; otherwise identical with racemate 1c.

D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1335–1351
1349
4.11. General procedure for recovery of chiral α-oxyacids 8d,e and 9d,e from diastereoisomeric
acyloxazolidin-2-ones 11 and 12
4.11.1. (R)-(+)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-[3-(trifluoromethyl)-
phenoxy]propanoic acid 8e
A freshly prepared solution of sodium methoxide in methanol [sodium hydride (60% dispersion in
oil, 0.064 g, 1.6 mmol) dissolved in methanol (2.5 mL)] was added to a 0°C solution of imide 11e
(0.940 g, 1.4 mmol) in methanol (30 mL). The mixture was stirred at 0°C for 13 min, then quenched
by the addition of dilute hydrochloric acid (2.0 M, 0.7 mL, 1.4 mmol) and concentrated in vacuo. The
residue was suspended in water (100 mL) and extracted with ethyl acetate (3×200 mL). The combined
ethyl acetate solutions were washed with brine, dried and evaporated. Chromatography using ethyl
acetate:dichloromethane (3:97) as eluent afforded the ester 13e (0.586 g, 81%), a gum, spectroscopically
identical with racemate 5e; (found M+ (EI) 514.1717. C27H25F3N2O5 requires M 514.1716); [α]D25 +12
(c 1.33 in CHCl3); e.e. 97% by HPLC.
A solution of ester 13e (0.543 g, 1.1 mmol), dilute hydrochloric acid (2.0 M, 55 mL) and dioxan (55
mL) was heated at 90°C for 6.5 h then concentrated in vacuo. The residue was suspended in brine (150
mL) and sufficient aqueous sodium hydroxide solution (2.5 M) was added until the solution was at pH
1.5. The mixture was extracted with ethyl acetate (3×300 mL) and the combined ethyl acetate solutions
dried and evaporated to afford the crude acid 8e, a solid (0.511 g, 93%), spectroscopically identical with
racemate 1e. A sample of this material was recrystallised form dichloromethane–hexane to afford an
analytical sample, m.p. 151–152°C; (found C, 62.0; H, 4.5; N, 5.4%; M+ (EI) 500.1568. C26H23F3N2O5
requires C, 62.4; H, 4.6; N, 5.6%; M 500.1559); [α]D25 +8 (c 0.7 in MeOH); e.e. 98% by HPLC.
4.11.2. (S)-(−)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-[3-(trifluoromethyl)-
phenoxy]propanoic acid 9e
Similarly prepared. Methyl ester 14e: a gum, 86%; [α]D25 −12 (c 1.2 in CHCl3); e.e. 96.4% by HPLC.
Acid 9e: a solid, 85%; m.p. 149–151°C; (found C, 62.3; H, 4.6; N, 5.5%. C26H23F3N2O5 requires C,
62.4; H, 4.6; N, 5.6); [α]D25 −7 (c 1.09 in MeOH); e.e. 98% by HPLC; otherwise identical with racemate
1e.
4.11.3. (R)-(+)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-benzyloxypropanoic
acid 8d
Similarly prepared. Methyl ester 13d: a gum, 80%; (found M+ (EI) 460.2000. C27H28N2O5 requires
25
25
M 460.1999); [α]D +31 (c 0.4 in CHCl3); e.e. 96% by HPLC. Acid 8d: a foam, 68%; [α]D +24 (c
1.00 in CHCl3); e.e. 96% by HPLC; otherwise identical with racemate 1d.
4.11.4. (S)-(−)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-benzyloxypropanoic
acid 9d
25
Methyl ester 14d: a gum, 75%; [α]D −34 (c 0.55 in CHCl3); e.e. 88% by HPLC. Acid 9d: a foam,
71%; [α]D25 −27 (c 1.46 in CHCl3); e.e. 88% by HPLC; otherwise identical with racemate 1d.
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3
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