Non-thiazolidinedione antihyperglycaemic agents. Part 5: Asymmetric aldol synthesis of (S)-(-)-2-oxy-3-arylpropanoic acids

Article abstract of DOI:10.1016/S0957-4166(99)00112-3

Boron-mediated asymmetric aldol reactions of substituted benzaldehyde 5 with 2-oxyethanoyloxazolidinones 4a-e, containing electron withdrawing, chelating, and bulky alkoxy and aryloxy groups, gave variable yields of syn- aldol adducts 6a-e in high diastereoisomeric excess. Dehydroxylation of these adducts afforded 7a-e in a sequence which complements the traditional Evans asymmetric alkylation strategy. Cleavage of the auxiliary from 7a-e afforded antihyperglycaemic (S)-(-)-2-oxy-3-arylpropanoic acids 3a-e in excellent enantiomeric excess.

Full text of DOI:10.1016/S0957-4166(99)00112-3

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1353–1367
Non-thiazolidinedione antihyperglycaemic agents.
Part 5: Asymmetric aldol synthesis of (S)-(−)-2-oxy-
3-arylpropanoic acids †
David Haigh,a,∗ Helen C. Birrell,b Barrie C. C. Cantello,a Drake S. Eggleston,a
R. Curtis Haltiwanger,c Richard M. Hindley,a Anantha Ramaswamy b 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
cDepartment of Physical and Structural Chemistry, SmithKline Beecham Pharmaceuticals, P.O. Box 1539, King of Prussia,
Pennsylvania 19406-0939, USA
Received 5 March 1999; accepted 25 March 1999
Abstract
Boron-mediated asymmetric aldol reactions of substituted benzaldehyde 5 with 2-oxyethanoyloxazolidinones
4a–e, containing electron withdrawing, chelating, and bulky alkoxy and aryloxy groups, gave variable yields of syn-
aldol adducts 6a–e in high diastereoisomeric excess. Dehydroxylation of these adducts afforded 7a–e in a sequence
which complements the traditional Evans asymmetric alkylation strategy. Cleavage of the auxiliary from 7a–e
afforded antihyperglycaemic (S)-(−)-2-oxy-3-arylpropanoic acids 3a–e in excellent enantiomeric excess. © 1999
Elsevier Science Ltd. All rights reserved.
1. Introduction
We have recently described2 the discovery and potent antihyperglycaemic activity of a novel series of
racemic 2-oxy-3-arylpropanoic acids 1. These carboxylic acids were designed as non-heterocyclic ana-
logues of thiazolidine-2,4-dione antihyperglycaemic agents currently being developed for the treatment
of non-insulin-dependent diabetes mellitus (NIDDM).3,4
∗
†
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)00112-3

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D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1353–1367
In contrast to the thiazolidine-2,4-diones which undergo rapid racemisation in solution,5 the individual
enantiomers of acids 1a–e retain their stereogenic integrity under a variety of conditions. It was important,
therefore, to establish an efficient methodology for the synthesis of these enantiomers. In our preceding
paper1 we described the resolution of acids 1a–e into their respective (R)- and (S)-enantiomers 2 and 3.
In subsequent biological evaluations, the (S)-enantiomers 3 clearly demonstrated greater potency than
their (R)-antipodes, both at a molecular target (in vitro PPARγ binding)6 and in an in vivo mouse model
of antihyperglycaemic activity.7,8 In order to establish further the full in vivo biological profile of 3, a
versatile route to multigram quantities of the drug candidates was required. In this paper we report the
development of a robust, asymmetric aldol sequence suitable for the facile preparation of the required
(S)-enantiomeric acids 3 in excellent enantiopurity.
2. Results and discussion
Development of the asymmetric aldol reaction9 utilising chiral 3-acyloxazolidin-2-ones, pioneered
by Evans9a,10 and Heathcock,9b,c,11 has made these reagents a first choice in the asymmetric synthesis
of 2-alkyl-substituted carbonyl compounds and derivatives. Within the last decade, extensions of this
methodology to encompass the preparation of chiral 2-alkoxycarbonyl compounds have also been
reported.12 However, despite the now widespread use of these reagents, the full scope of the reaction
of 3-(2-oxyethanoyl)oxazolidin-2-ones 4 with bulkier aromatic aldehydes has not been explored.12d,12m
Particularly important was the need to establish whether reagents carrying either electronegative (e.g. 4b)
or bulky (e.g. 4e) alkoxy and aryloxy groups, or those containing an additional chelating functionality
(e.g. 4c) would compromise the diastereoselectivity of the reaction.13
The oxazolidin-2-ones 4a–e were prepared by reaction of the anion of (S)-4-benzyloxazolidin-2-one
(n-butyllithium, THF, −78°C) with appropriate acid chlorides and isolated in variable yield‡ following
chromatography on silica gel (Table 1). Reaction of 4a–e with the substituted benzaldehyde 54 in
dichloromethane under ‘standard’ aldol conditions (1.1 equiv. di-n-butylboron triflate, 1.2 equiv. tri-
ethylamine, −70°C -→ 0°C), followed by oxidative workup afforded moderate yields of the desired aldol
‡
With the exception of compound 4b, the yields quoted for compounds 4 are those for unoptimised reactions. The yield of 4b
was optimised from 31% to 91% by utilising freshly distilled trifluoroethoxyethanoyl chloride. It is likely that similar increases
in yield could be obtained for the other analogues.

D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1353–1367
1355
Table 1
Asymmetric aldol synthesis of (S)-3. Yields and isomer purity data
product, together with the unreacted starting materials (Scheme 1). Inspection of the 1H NMR spectrum
of the crude reaction mixture in each case suggested the presence of the expected syn-[3(2S,3R),4S]-
diastereoisomer 6 (∼90–95% d.e.), accompanied by small quantities of two other diastereoisomers.
Purification of the reaction mixture by chromatography on silica gel removed one of the minor isomers
and allowed the isolation of an inseparable mixture of 6 (generally >94% d.e.) and the anti-[3(2S,3S),4S]-
diastereoisomer 9 (Table 1). Assignment of the relative stereochemistry of 6 and 9 was based on literature
precedent (6, Jsyn 4.80–6.00 Hz; 9, Janti 6.60–8.30 Hz; Table 1) in combination with the subsequent
chemistry and X-ray crystal structure determination (see below). In the case of oxazolidinone 4b, this
reaction has been conducted at a 0.1 mol scale with no reduction in yield or diastereoselectivity.
Inspection of Table 1 shows that, in comparison with 2-ethoxyethanoyloxazolidin-2-one 4a, the
electronegative trifluoroethoxy analogue 4b does not affect the stereochemical outcome of the reaction.13
However, the aryloxy analogue 4e shows a small reduction in diastereoselectivity, with more of the anti-
diastereoisomer 9 being produced. Assuming that the reaction proceeds via the normal ‘Evans-syn’ closed
chair transition state, then reaction of the si-face of enolate 4e with the si-face of aldehyde 5 brings
the two bulky aryl groups into close proximity (Fig. 1). The resulting interaction may be sufficient to
partially overcome the 1,3-diaxial interaction between the aldehyde and the oxazolidinone that normally
precludes attack at the re-face of the aldehyde,9b,c thus accounting for the slight loss of stereocontrol at the
resulting hydroxy centre in 6e. Alternatively, Pridgen has recently suggested that formation of the anti-
diastereoisomer in boron-mediated aldol reactions arises from a twist-boat transition state (Fig. 2) and
that there is only a small energy difference between this and the chair transition state.14 It is possible that a
contribution from this transition state might also be involved in the production of the anti-diastereoisomer

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D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1353–1367
Scheme 1. For definition of substituents R1, see Table 1. Reagents: (i) 1.1 equiv. n-Bu2BOTf, 1.2 equiv. NEt3, CH2Cl2,
−70°C -→ 0°C. (ii) Et3SiH, CF3CO2H. (iii) 1.1 equiv. NaOMe, MeOH. (iv) 2.0 M HCl
Figure 1. Chair transition state for attack at si-faces of both enolate 4 and aldehyde 5, leading to syn-6
Figure 2. Twist-boat transition state for attack of si-face of enolate 4 and re-face of aldehyde 5, leading to anti-9
9. The reduced chemical yield of aldol product 6e may also be a reflection of these steric interactions.
Interestingly, the (2-methoxyethoxy) analogue 4c showed an increase in diastereoselectivity, although the
reasons for this effect are not clear. It is notable, however, that both 6c and 6e display larger Jsyn-coupling
constants than the other aldol products, suggesting that the conformation of the molecular backbone is
different in these two cases.
The yields of aldol products 6a–e obtained in this manner were modest by comparison with those
reported in the literature and so, in an attempt to optimise the product yield, a small study of the influence
of temperature and reaction time was undertaken using 2-(2,2,2-trifluoroethoxy)ethanoyloxazolidinone
4b as a substrate. In small-scale (1.5 mmol) experiments, reactions of 4b and 5 under our standard
conditions (1.1 equiv. n-Bu2BOTf, 1.2 equiv. NEt3, CH2Cl2, see Experimental for full details) afforded
yields (∼65%) and diastereoisomer ratios (∼95% d.e.) comparable to the larger scale reactions, as
1
determined from the 400 MHz H NMR spectrum of the crude reaction mixture following oxidative
workup. Attempts to improve the yield of 6b by increasing the time for enolate formation, conducting
the enolate formation at 0°C, or extending the reaction time for an additional period before quenching

D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1353–1367
1357
Table 2
Aldol products. 1H NMR data for diastereoisomers 6b, 9b, 10 and 11
had no effect on either the yield or d.e. of 6b, whereas shortening the reaction time reduced the yield
without affecting the diastereoisomer ratio.
These experiments suggest that the modest aldol product yield is attributable to incomplete enolate
formation, and may be a consequence of using commercial di-n-butylboron triflate15 rather than freshly
prepared material. In an attempt to circumvent this problem, an experiment was conducted using a
nominal 1.6 equiv. of the boron triflate and 1.6 equiv. of base. Under these conditions the yield was
increased to 78% of 6b, but diastereoselectivity was compromised (80% d.e.), consistent with an earlier
report by Heathcock.11 Finally, the effect of addition of 1.1 equiv. boron trifluoride etherate, a reagent
1
reported to induce aldol reaction via an open transition state,11 was also examined. The 400 MHz H
NMR spectrum of the crude product mixture from this experiment suggested the presence of all four
possible diastereoisomers, in which the normal ‘Evans’ syn-[3(2S,3R),4S]-6b and the anti-[3(2S,3S),4S]-
9b isomers were now accompanied by the ‘non-Evans’ syn-[3(2R,3S),4S]- and anti-[3(2R,3R),4S]-
diastereoisomers 10 and 11 in a ratio of 1.0, 0.3, 3.6 and 1.2, respectively (Table 2). Assignment of
stereochemistry to diastereoisomers 10 and 11 was based on literature precedent and was confirmed
by subsequent chemistry (not discussed). Thus, in contrast to Heathcock’s results,11 boron trifluoride
etherate was unsuccessful in promoting a clean anti-addition of trifluoroethoxyoxazolidinone 6b. Instead,
the results suggested that the reaction proceeds via a combination of different transition states in this
particular case.
With the aldol products 6a–e available, completion of the synthesis of chiral acids 3 was examined. Re-
moval of the unwanted hydroxy group from 6 was readily accomplished by treatment with triethylsilane
in trifluoroacetic acid.16 Dehydroxylation product 7 was isolated as a single diastereoisomer (64–95%
1
yield, >99.5% d.e., Table 1) in each case, as determined by H NMR spectroscopy. The observed
improvement in d.e. in going from 6 to 7 is a consequence of removal of the hydroxy group from the
mixture of 6 and its accompanying, inseparable minor isomer 9 and thus confirms the stereochemical

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D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1353–1367
assignment of 9 as epimeric to 6 at the hydroxy centre. The absolute configuration of 7b was confirmed
by X-ray crystal structure determination (Fig. 3), thereby corroborating the stereochemical assignment
of 6 as consistent with literature predictions. In addition, compounds 7d and 7e prepared in this manner
were found to be identical with the slower eluting diastereoisomers obtained when the racemic acids
were resolved using the oxazolidinone auxiliary, thus confirming the stereochemical assignments detailed
in our preceding paper.1 The sequence of aldol and dehydroxylation reactions (4 -→ 7) described
above represents an alternative approach to the conventional Evans asymmetric alkylation chemistry
of acyloxazolidin-2-ones.17,18
Figure 3. X-Ray crystal structure of compound 7b
In order to avoid racemisation of the alkoxy stereocentre in 7, cleavage of the auxiliary was initially
accomplished by brief exposure to 1.1 equiv. of sodium methoxide19 to afford esters 8a–e (66–86% chro-
matographed, isolated yield; >99.4% e.e. throughout). Finally, acid hydrolysis of 8a–e gave the desired
(S)-(−)-acids 3a–e in good yield and excellent enantiopurity (Table 1), spectroscopically identical to those
produced by the resolution procedure detailed in the preceding paper.1 In a subsequent modification to
the cleavage step, it was found that 7b could be cleaved by treatment with aqueous sodium hydroxide to
afford 3b directly in higher yield (95%), without any loss of enantiopurity (99.6% e.e.) in the resulting
acid.20 This modification was not examined with the other analogues 7a and 7c–e.
3. Conclusions
In this paper we have shown that 2-oxyethanoyloxazolidinones 4a–e, bearing a range of electron
withdrawing, chelating, and bulky alkoxy and aryloxy groups undergo boron-mediated asymmetric
aldol reactions with substituted benzaldehyde 5 to afford syn-aldol adducts 6a–e in variable yield, but
with excellent stereocontrol (generally >94% d.e.) up to the 0.1 mol scale. Removal of the alcohol
functionality from 6 afforded 7 as a single diastereoisomer, thereby confirming the identity of the
minor diastereoisomer 9 derived from the aldol reaction. Sodium methoxide induced cleavage of the
auxiliary, and acid hydrolysis of the resulting ester afforded the desired acids (S)-(−)-3a–e in excellent
enantiomeric excess (generally >99% e.e.) and modest overall yield (17–53% from 4) in sufficient
quantities for biological evaluation. The absolute configuration of 7b, and hence of acids 3, was proved

D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1353–1367
1359
by X-ray crystallography and confirmed the stereochemical assignments inferred in our preceding paper.1
Chiral acids 3 are potent antihyperglycaemic agents, indicating that the (S)-2-oxy-3-arylpropanoate
moiety provides an effective bioisosteric replacement for 5-benzylthiazolidine-2,4-dione in this class
of compound.
4. Experimental
4.1. General experimental details
Mass spectroscopy was conducted using electron impact (EI), chemical ionisation (CI), with ammonia
or methane 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 a CDCl3 solution. Chemical
25
shifts are given in δ (ppm) relative to TMS and coupling constants J are given in hertz. Values of [α]D
are given in deg cm2 g−1. Dry solvents refer to the use of Aldrich Sure-Seal™ dried solvents. Di-n-
butylboron triflate was purchased from Aldrich as a 1.0 M solution in dichloromethane and each fresh
bottle was titrated before use by means of a small-scale reaction between 4b and 5, to ensure consistency.
All organic solutions obtained from aqueous extractions were dried over MgSO4. Chromatography refers
to flash chromatography on silica gel.
4.2. HPLC conditions
The enantiomeric excess of all chiral ester and acid samples was measured against the appropriate race-
mic standard.1 Chiral esters 8a–c and 8e were assayed on a Chiralpak AD column, using hexane:ethanol
(90:10 v/v) as the eluent for 8b, 8c and 8e. For ester 8a, hexane:PriOH (97:3 v/v) was used. Chiral
ester 8d was assayed on a Chiralcel OD column using hexane:PriOH (95:5 v/v). Chiral acids 3a,d were
resolved on a Chiralpak AD column using hexane:PriOH (92:8 v/v) containing CF3CO2H (0.05% v/v)
as an eluent; for acid 3b hexane:EtOH (97:3 v/v) containing CF3CO2H (0.05% v/v) was used, and for
acid 3c, hexane:EtOH (90:10 v/v) containing CF3CO2H (0.05% v/v) was used. Acid 3e was assayed on
a Chiralcel OJ column using hexane:EtOH (85:15 v/v) containing CF3CO2H (0.05% v/v) as an eluent.
Detection wavelength was either 220, 245 or 250 nm. The solvent flow rate was 1 mL min−1 except for
ester 8b, when a flow rate of 0.3 mL min−1 was used.
4.3. General procedure for preparation of 2-oxyacyloxazolidin-2-ones 4
4.3.1. (S)-4-Benzyl-3-[2-(2,2,2-trifluoroethoxy)ethanoyl]oxazolidin-2-one 4b
A solution of (S)-4-benzyloxazolidin-2-one (5.21 g, 29 mmol) in dry THF (60 mL) was cooled to
−70°C under argon. n-Butyllithium (1.6 M solution in hexane, 18.4 mL, 32 mmol) was added over 10 min
and the resulting mixture was stirred at −70°C for 20 min. A solution of (2,2,2-trifluoroethoxy)ethanoyl
chloride21 (5.19 g, 29 mmol) in dry THF (60 mL) was added over 10 min, the mixture was stirred at
−70°C for a further 30 min, then allowed to warm to room temperature overnight. The reaction was
quenched by addition of brine (20 mL) and concentrated in vacuo. The residue was diluted with brine
(300 mL) and extracted with ethyl acetate (3×300 mL). The combined organic extracts were dried and
evaporated, and then the residue chromatographed with dichloromethane as an eluent to give the imide
4b as a clear oil (8.38 g, 91%); (found MH+ (CI) 318.0934. C14H14NO4F3 requires M 318.0953); [α]D
25

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D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1353–1367
+48 (c 2.55, CHCl3); 100% e.e. by HPLC; νmax (film)/cm−1 1770 (CO) and 1705 (CO); δH (400 MHz,
CDCl3) 2.82 (1H, dd, J 13.4 and 9.5, PhCHH), 3.34 (1H, dd, J 13.4 and 3.4, PhCHH), 4.02 (2H, q,
3JHF 8.6, OCH2CF3), 4.30 (2H, m, oxazolidinone 5-H2), 4.69 (1H, m, oxazolidinone 4-H), 4.84 (2H, s,
OCH2CO) and 7.15–7.40 (5H, m, aryl-H); m/z (CI) 335 [(M+NH4)+, 100%], 318 [(M+H)+, 5] and 232
(10).
4.3.2. (S)-4-Benzyl-3-(2-ethoxyethanoyl)oxazolidin-2-one 4a
Similarly prepared. A gum, 32%; (found M+ (EI) 263.1158. C14H17NO4 requires M 263.1158);
25
[α]D +53 (c 1.62, CHCl3); δH (270 MHz, CDCl3) 1.30 (3H, t, J 7.2, Me), 2.82 (1H, dd, J 13.4
and 9.6, PhCHH), 3.33 (1H, dd, J 13.4 and 3.3, PhCHH), 3.65 (2H, q, J 7.2, OCH2Me), 4.25 (2H, m,
oxazolidinone 5-H2), 4.70 (2H, ABq, J 2.5, OCH2CO), 4.71 (1H, m, oxazolidinone 4-H) and 7.15–7.40
(5H, m, aryl-H).
4.3.3. (S)-4-Benzyl-3-[2-(2-methoxyethoxy)ethanoyl]oxazolidin-2-one 4c
Similarly prepared. A gum, 35%; (found M+ (EI) 293.1263. C15H19NO5 requires M 293.1264); [α]D
25
+50 (c 1.83, CHCl3); δH (270 MHz, CDCl3) 2.81 (1H, dd, J 13.5 and 9.6, PhCHH), 3.33 (1H, dd,
J 13.5 and 3.3, PhCHH), 3.41 (3H, s, OMe), 3.63 (2H, t, J 5.3, OCH2CH2OMe), 3.78 (2H, t, J 5.3,
OCH2CH2OMe), 4.25 (2H, m, oxazolidinone 5-H2), 4.70 (1H, m, oxazolidinone 4-H), 4.74 (1H, d, J
17.9, OCHHCO), 4.76 (1H, d, J 17.9, OCHHCO) and 7.10–7.50 (5H, m, aryl-H).
4.3.4. (S)-4-Benzyl-3-(2-benzyloxyethanoyl)oxazolidin-2-one 4d
Similarly prepared. A solid, 52%; m.p. 67–69°C; (found C, 69.9; H, 5.9; N, 4.4%; M+ (EI) 325.1314.
C19H19NO4 requires C, 70.1; H, 5.9; N, 4.3%; M 325.1314); [α]D25 +56 (c 1.71, CHCl3); δH (270 MHz,
CDCl3) 2.80 (1H, dd, J 13.5 and 9.4, PhCHH), 3.32 (1H, dd, J 13.5 and 3.3, PhCHH), 4.20 (2H, m,
oxazolidinone 5-H2), 4.70 (5H, m, oxazolidinone 4-H and CH2OCH2) and 7.10–7.50 (10H, m, aryl-H).
4.3.5. (S)-4-Benzyl-3-[2-(3-trifluoromethyl)phenoxyethanoyl]oxazolidin-2-one 4e
Similarly prepared. A gum, 73%; (found M+ (EI) 379.1031. C19H16F3NO4 requires M 379.1032);
25
[α]D +62 (c 2.3, CHCl3); δH (270 MHz, CDCl3) 2.85 (1H, dd, J 13.5 and 9.4, PhCHH), 3.35 (1H, dd,
J 13.5 and 3.3, PhCHH), 4.30 (2H, m, oxazolidinone 5-H2), 4.70 (1H, m, oxazolidinone 4-H) 5.28 (2H,
s, OCH2CO) and 7.10–7.50 (9H, m, aryl-H).
4.4. General procedure for asymmetric aldol reaction of 4
4.4.1. [3(2S,3R),4S]-3-[3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-3-hydroxy-2-(2,
2,2-trifluoroethoxy)propanoyl]-4-benzyloxazolidin-2-one 6b
(4S)-4-Benzyl-3-[2-(2,2,2-trifluoroethoxy)ethanoyl]oxazolidin-2-one 4b (31.7 g, 0.1 mol) was dis-
solved in dry dichloromethane (300 mL) under argon and cooled to −78°C (internal temperature
of solution). Triethylamine (16.72 mL, 0.12 mol) was added, followed by the slow addition, over
approximately 10 min, of di-n-butylboron triflate (1.0 M solution in dichloromethane, 110 mL, 0.11
mol) such that the reaction temperature was kept below −70°C. The mixture was stirred at −78°C
for 50 min, then the cooling bath was replaced with an ice bath and the mixture stirred at 0°C
for an additional 50 min before being recooled to −78°C. A solution of 4-[2-[N-(2-benzoxazolyl)-N-
methylamino]ethoxy]benzaldehyde 5 (29.6 g, 0.10 mol) in dry dichloromethane (220 mL), precooled to
−50°C, was added over ca. 12 min, such that the reaction temperature was maintained below −70°C.
The resulting mixture was stirred at −78°C for 30 min, then warmed from −78°C to 0°C over 60 min

D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1353–1367
1361
along a linear gradient (warming rate ∼1.3°C min−1) and stirred at 0°C for a further 75 min. The reaction
mixture was poured into a quenching solution of methanol (500 mL), pH 7 phosphate buffer (250 mL) and
hydrogen peroxide (27.5% w/v, 110 mL) and stirred vigorously for 30 min. Water (4 L) was added and the
aqueous solution was extracted with dichloromethane (3×1 L). The combined dichloromethane solutions
1
were washed with water (2 L) and brine (2 L), dried and evaporated to afford a foam (60.18 g). H
NMR of this crude reaction mixture suggested a mixture of the desired aldol product (84% conversion, 3
diastereoisomers, comprising 95% major diastereoisomer) and starting materials. The crude mixture was
chromatographed using ethyl acetate:dichloromethane (gradient 15:85 to 50:50) as an eluent to afford
the aldol product 6b as a foam (40.89 g, 67%); (found M+ (EI) 613.2042. C31H30F3N3O7 requires M
613.2036); [α]D25 +45 (c 2.82, CHCl3); two diastereoisomers, 95.4% d.e. by 1H NMR; νmax (KBr)/cm−1
3432 (OH), 1780 (CO) and 1707 (CO); δH (400 MHz, CDCl3) 2.75 (1H, dd, J 13.5 and 9.5, PhCHH),
2.90 (1H, d, J 6.1, exchanges with D2O, OH), 3.25 (1H, dd, J 13.5 and 3.3, PhCHH), 3.34 (3H, s, NMe),
3.80–4.00 (5H, m, NCH2, OCH2CF3 and oxazolidinone 5-Ha), 4.07 (1H, dd, J 9.0 and 2.0, oxazolidinone
5-Hb), 4.24 (2H, t, J 5.2, NCH2CH2O), 4.45 (1H, m, oxazolidinone 4-H), 4.99 (1H, apparent t, J 4.8,
CHOH), 5.48 (1H, d, J 4.8, CHOCH2CF3), 6.85 (2H, d, J 8.8, aryl 3-H and 5-H) and 6.95–7.40 (11H,
m, aryl-H); m/z (EI) 613 (M+, 5%), 317 (23), 296 (51), 198 (22), 175 (24), 161 (82), 148 (100), 134 (27),
113 (66) and 91 (62).
4.4.2. [3(2S,3R),4S]-3-[3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxy-3-
hydroxypropanoyl]-4-benzyloxazolidin-2-one 6a
Similarly prepared. A foam, 45%; (found M+ (EI) 559.2317. C31H33N3O7 requires M 559.2319);
25
1
[α]D +53 (c 2.5, CHCl3); two diastereoisomers, 96% d.e. by H NMR; δH (270 MHz, CDCl3) 1.20
(3H, t, J 6.9, OCH2CH3), 2.75 (1H, dd, J 13.5 and 9.6, PhCHH), 3.15 (1H, br, exchanges with D2O,
OH), 3.29 (1H, dd, J 13.5 and 3.3, PhCHH), 3.32 (3H, s, NMe), 3.50 (1H, m, OCHHCH3), 3.65 (1H, m,
OCHHCH3), 3.75 (1H, m, oxazolidinone 5-Ha), 3.92 (2H, t, J 5.3, NCH2), 4.01 (1H, dd, J 9.1 and 1.9,
oxazolidinone 5-Hb), 4.21 (2H, t, J 5.3, OCH2CH2), 4.40 (1H, m, oxazolidinone 4-H), 4.85 (1H, ∼d, J
4.95, CHOH), 5.34 (1H, d, J 4.95, CHOEt) and 6.80–7.40 (13H, m, aryl-H).
4.4.3. [3(2S,3R),4S]-3-[3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-3-hydroxy-2-(2-
methoxyethoxy)propanoyl]-4-benzyloxazolidin-2-one 6c
Similarly prepared. A foam, 57%; (found (M+H)+ (FAB) 590.2472. C32H35N3O8 requires M
25
1
590.2502); [α]D +49 (c 1.14, CHCl3); two diastereoisomers, 99% d.e. by H NMR; δH (400 MHz,
CDCl3) 2.71 (1H, dd, J 13.3 and 9.7, PhCHH), 3.25 (1H, dd, J 13.3 and 3.2, PhCHH), 3.31 (3H, s, NMe),
3.35 (3H, s, OMe), 3.56 (2H, m, CH2OMe), 3.72 (2H, m, oxazolidinone 5-Ha and OCHHCH2OMe), 3.78
(1H, d, J 4.3, exchanges with D2O, OH), 3.85–4.00 (4H, m, NCH2, OCHHCH2OMe and oxazolidinone
5-Hb), 4.22 (2H, t, J 5.2, OCH2CH2N), 4.31 (1H, m, oxazolidinone 4-H), 4.89 (1H, dd, J 6.0 and 4.3,
CHOH), 5.42 (1H, d, J 6.0, CHOCH2CH2OMe) and 6.80–7.40 (13H, m, aryl-H).
4.4.4. [3(2S,3R),4S]-3-[3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-benzyloxy-
3-hydroxypropanoyl]-4-benzyloxazolidin-2-one 6d
Similarly prepared. A foam, 52%; (found M+ (EI) 621.2474. C36H35N3O7 requires M 621.2475);
25
1
[α]D +58 (c 1.25, CHCl3); two diastereoisomers, 94% d.e. by H NMR; δH (400 MHz, CDCl3) 2.56
(1H, dd, J 13.5 and 9.8, PhCHH), 3.05 (1H, br, exchanges with D2O, OH), 3.05 (1H, dd, J 13.5 and
3.2, PhCHH), 3.32 (3H, s, NMe), 3.76 (1H, t, J 8.1, oxazolidinone 5-Ha), 3.95 (3H, m, NCH2 and
oxazolidinone 5-Hb), 4.24 (2H, t, J 5.3, OCH2CH2), 4.33 (1H, m, oxazolidinone 4-H), 4.57 (2H, s,

1362
D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1353–1367
PhCH2O), 4.90 (1H, t, J 4.9, CHOH), 5.43 (1H, d, J 4.9, CHOCH2Ph), 6.83 (2H, d, J 8.8, aryl 3-H and
5-H) and 7.00–7.40 (16H, m, aryl-H).
4.4.5. [3(2S,3R),4S]-3-[3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-3-hydroxy-2-(3-
trifluoromethyl)phenoxypropanoyl]-4-benzyloxazolidin-2-one 6e
Similarly prepared. A foam, 31%; (found (M+H)+ (CI) 676.2269. C36H32F3N3O7 requires M
25
1
676.2271); [α]D +74 (c 1.14, CHCl3); two diastereoisomers, 90.4% d.e. by H NMR; δH (400 MHz,
CDCl3) 2.68 (1H, dd, J 13.5 and 9.3, PhCHH), 3.05 (1H, dd, J 13.5 and 3.2, PhCHH), 3.11 (1H, d,
J 5.1, exchanges with D2O, OH), 3.31 (3H, s, NMe), 3.70 (1H, m, oxazolidinone 5-Ha), 3.92 (2H, m,
NCH2), 3.99 (1H, dd, J 9.0 and 1.9, oxazolidinone 5-Hb), 4.23 (2H, t, J 5.2, OCH2CH2), 4.31 (1H, m,
oxazolidinone 4-H), 5.14 (1H, dd, J 5.4 and 5.1, CHOH), 6.23 (1H, d, J 5.4, CHOAr) and 6.80–7.40
(17H, m, aryl-H).
4.5. Aldol reaction in the presence of boron trifluoride etherate
This experiment was conducted on a 1.5 mmol scale in an identical manner to the aldol reaction
described above, but with the addition of boron trifluoride etherate (1.65 mmol) immediately prior to
1
the addition of the aldehyde. H NMR (400 MHz, CDCl3) of the crude reaction product following the
standard oxidative workup suggested a mixture of starting materials and aldol products (69% conversion,
four diastereoisomers, 6b, 9b, 10 and 11; ratios 1.0, 0.3, 3.6 and 1.2, respectively). These were partially
separated by chromatography, using ethyl acetate:dichloromethane (gradient, 10:90 to 15:85) as an
1
eluent, and the 400 MHz H NMR spectra of 10 and 11 were recorded. See Table 2 for comparison
of the CHOH signals of all four diastereoisomers.
4.6. General procedure for dehydroxylation of 6
4.6.1. [3(2S),4S]-3-[3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoro-
ethoxy)propanoyl]-4-benzyloxazolidin-2-one 7b
Triethylsilane (120 mL, 0.75 mol) was added to a vigorously stirred, ice-cooled solution of
[3 (2S, 3R), 4S]-3-[3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-3-hydroxy-2-(2,2,2-tri-
fluoroethoxy)propanoyl]-4-benzyloxazolidin-2-one 6b (46.23 g, 0.075 mol) in trifluoroacetic acid (650
mL). The mixture was stirred at 0°C for 1 h, then at room temperature for a further 60 h. The bulk
of the solvent and residual triethylsilane was removed by rotary evaporation, firstly at 40 mmHg, and
finally at ∼5 mmHg. The residue was dissolved in dichloromethane (800 mL) and water (800 mL),
then stirred vigorously during the cautious addition of solid sodium bicarbonate (∼29 g) (frothing!)
until the pH of the aqueous layer was pH 7. The layers were separated and the aqueous solution was
extracted with dichloromethane (800 mL). The combined dichloromethane solutions were washed with
water (600 mL), dried and evaporated. The residue was triturated with hot hexane and the resulting solid
filtered off and dried under vacuum to afford the title compound 7b (42.54 g, 95%). Recrystallisation
from diethyl ether–hexane afforded an analytical sample, m.p. 107–109°C, a single diastereoisomer by
1
400 MHz H NMR spectroscopy; (found C, 62.1; H, 4.9; N, 7.2%; M+ (EI) 597.2089. C31H30N3O6F3
25
requires C, 62.3; H, 5.1; N, 7.0%; M 597.2087); [α]D +38 (c 1.51, CHCl3); >99.5% d.e. by 1H NMR;
νmax (KBr)/cm−1 1775 (CO) and 1695 (CO); δH (400 MHz, CDCl3) 2.82 [1H, dd, J 13.5 and 9.5,
oxazolidinone 4-(CHHPh)], 2.96 (1H, dd, J 13.9 and 8.3, ArCHHCH), 3.04 (1H, dd, J 13.9 and 4.4,
ArCHHCH), 3.32 [1H, dd, J 13.5 and 3.4, oxazolidinone 4-(CHHPh)], 3.34 (3H, s, NMe), 3.70 (1H, m,
OCHHCF3), 3.88 (1H, m, OCHHCF3), 3.94 (2H, t, J 5.2, NCH2), 4.12 (1H, m, oxazolidinone 5-Ha),

D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1353–1367
1363
4.18 (1H, m, oxazolidinone 5-Hb), 4.25 (2H, t, J 5.2, NCH2CH2O), 4.57 (1H, m, oxazolidinone 4-H),
5.34 (1H, dd, J 8.3 and 4.4, CHOCH2CF3), 6.82 (2H, d, J 8.8, aryl 3-H and 5-H) and 7.00–7.35 (11H,
m, aryl-H); m/z (CI, ammonia) 598 [(M+H)+, 100%].
4.6.2. [3(2S),4S]-3-[3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxypropanoyl]-
4-benzyloxazolidin-2-one 7a
Similarly prepared. A foam, 83%; (found M+ (EI) 543.2399. C31H33N3O6 requires M 543.2370);
25
1
[α]D +45 (c 1.03, CHCl3); >99.5% d.e. by H NMR; δH (270 MHz, CDCl3) 1.16 (3H, t, J 6.9,
OCH2CH3), 2.79 (1H, dd, J 13.5 and 9.6, PhCHH), 2.92 (2H, m, ArCH2CH), 3.32 (1H, m, PhCHH),
3.33 (3H, s, NMe), 3.38 (1H, m, OCHHCH3), 3.55 (1H, m, OCHHCH3), 3.92 (2H, t, J 5.5, NCH2), 4.08
(2H, m, oxazolidinone 5-H2), 4.23 (2H, t, J 5.3, OCH2CH2), 4.55 (1H, m, oxazolidinone 4-H), 5.21 (1H,
d, J 4.95, CHOEt) and 6.79–7.40 (13H, m, aryl-H).
4.6.3. [3(2S),4S]-3-[3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxy-
ethoxy)propanoyl]-4-benzyloxazolidin-2-one 7c
Similarly prepared. A gum, 87%; (found M+ (EI) 573.2473. C32H35N3O7 requires M 573.2475);
[α]D +43 (c 1.78, CHCl3); >99.5% d.e. by 1H NMR; δH (400 MHz, CDCl3) 2.76 (1H, dd, J 13.2 and
25
9.6, PhCHH), 2.94 (2H, m, ArCH2CH), 3.30 (3H, s, NMe), 3.33 (4H, m, OMe and PhCHH), 3.40–3.70
(4H, m, OCH2CH2OMe), 3.93 (2H, t, J 5.3, NCH2), 4.00 (1H, dd, J 7.1 and 5.3, oxazolidinone 5-
Ha), 4.12 (1H, dd, J 7.1 and 2.5, oxazolidinone 5-Hb), 4.22 (2H, t, J 5.3, OCH2CH2N), 4.52 (1H, m,
oxazolidinone 4-H), 5.31 (1H, dd, J 9.4 and 5.5, CHOCH2CH2OMe) and 6.79–7.40 (13H, m, aryl-H).
4.6.4. [3(2S),4S]-3-[3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-benzyloxy-
propanoyl]-4-benzyloxazolidin-2-one 7d
Similarly prepared. A foam, 66%; (found M+ (EI) 605.2525. C36H35N3O6 requires M 605.2526);
[α]D +40 (c 1.01, CHCl3); >99.5% d.e. by 1H NMR; δH (400 MHz, CDCl3) 2.66 (1H, dd, J 13.5 and
25
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 5-Ha), 4.10 (1H, m, oxazolidinone 5-Hb), 4.24 (2H, t, J 5.3, OCH2CH2N), 4.43 (1H, d, J
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).
4.6.5. [3(2S),4S]-3-[3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(3-trifluoro-
methyl)phenoxypropanoyl]-4-benzyloxazolidin-2-one 7e
Similarly prepared. A foam, 64%; sample slowly crystallised on standing, m.p. 98–100°C; (found C,
65.1; H, 4.8; N, 6.4%; (M+H)+ (CI) 660.2319. C36H32F3N3O6 requires C, 65.5; H, 4.9; N, 6.4%; M
660.2322); [α]D25 +67 (c 1.23, CHCl3); >99.5% d.e. by 1H NMR; 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 5-Ha), 4.15 (1H, dd,
J 9.1 and 2.4, oxazolidinone 5-Hb), 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).

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D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1353–1367
4.7. General procedure for recovery of chiral α-oxyacids (S)-(ꢀ)-3 from 7
4.7.1. (S)-(−)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)-
propanoic acid 3b
A solution of sodium methoxide [prepared from sodium hydride (60% dispersion in mineral oil,
138 mg, 3.41 mmol) and dissolved in dry methanol (3.5 mL)] was added to an ice-cooled and stir-
red suspension of [3(2S),4S]-3-[3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-
trifluoroethoxy)propanoyl]-4-benzyloxazolidin-2-one 7b (1.879 g, 3.10 mmol) in dry methanol (100
mL). The mixture was stirred at 0°C for 20 min then the reaction was quenched by the addition of dilute
aqueous hydrochloric acid (2.0 M, 1.75 mL) and concentrated in vacuo. The residue was suspended
in water (100 mL), extracted with ethyl acetate (3×200 mL) and the combined ethyl acetate solutions
washed with brine (500 mL), dried and evaporated. The resulting gum was chromatographed using ethyl
acetate:dichloromethane (4:96) as an eluent to afford ester 8b as a gum (1.368 g, 97%); (found (EI) M+
25
452.1561. C22H23N2O5F3 requires M 452.1559); [α]D −17 (c 1.24, CHCl3); >99.9% e.e. by HPLC.
A mixture of the ester 8b (1.256 g, 2.8 mmol), aqueous hydrochloric acid (2.0 M, 50 mL) and dioxan
(50 mL) was heated at reflux for 7 h, cooled and concentrated in vacuo. The residue was suspended
in brine (200 mL) and extracted with ethyl acetate (3×300 mL). The combined ethyl acetate solutions
were dried (MgSO4) and evaporated to afford a waxy solid which was triturated with hexane to give
the acid 3b (1.011 g, 83%). Recrystallisation from dichloromethane:diethyl ether (25:75) afforded an
analytical sample, m.p. 119–120°C; (found C, 57.25; H, 4.8; N, 6.3%; M+ (EI) 438.1408. C21H21F3N2O5
requires C, 57.5; H, 4.8; N, 6.4%; M 438.1403); [α]D25 −32 (c 1.02, CHCl3); 99.4% e.e. by HPLC; νmax
(Nujol)/cm−1 3000–2300 (COOH) and 1718 (CO); δH (400 MHz, CDCl3) 3.05 (1H, dd, J 14.4 and 7.3,
ArCHHCH), 3.13 (1H, dd, J 14.4 and 4.6, ArCHHCH), 3.31 (3H, s, NMe), 3.72 (1H, m, OCHHCF3),
3.89 (2H, m, NCH2), 4.04–4.14 (3H, m, OCHHCF3 and NCH2CH2O), 4.21 (1H, dd, J 7.3 and 4.6,
CHOCH2CF3), 6.78 (2H, d, J 8.6, aryl 3-H and 5-H), 7.00–7.40 (6H, m, aryl-H) and 11.20 (1H, br,
exchanges with D2O, COOH); m/z (EI) 438 (M+, 28%), 419 (2), 311 (21), 175 (41), 161 (41) and 148
(100).
4.7.2. (S)-(−)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxypropanoic acid 3a
Similarly prepared. Methyl ester 8a: a gum, 86%; (found M+ (EI) 398.1848. C22H26N2O5 requires
M 398.1842); [α]D −11 (c 1.11, CHCl3); 99.6% e.e. by HPLC. Acid 3a: a foam, 86%; (found M+
25
25
(EI) 384.1684. C21H24N2O5 requires M 384.1685); [α]D −19 (c 1.15, MeOH); e.e. 99.4% by HPLC;
δH (270 MHz, CDCl3) 1.17 (3H, t, J 7.0, Me), 2.95 (1H, dd, J 14.2 and 7.4, ArCHHCH), 3.06 (1H,
dd, J 14.2 and 4.5, ArCHHCH), 3.34 (3H, s, NMe), 3.45 (1H, m, OCHHMe), 3.50 (1H, br, exchanges
with D2O, COOH), 3.58 (1H, m, OCHHMe), 3.92 (2H, t, J 5.3, NCH2), 4.03 (1H, dd, J 7.4 and 4.5,
ArCH2CH), 4.22 (2H, t, J 5.3, OCH2) and 6.79–7.40 (8H, m, aryl-H).
4.7.3. (S)-(−)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyeth-
oxy)propanoic acid 3c
Similarly prepared. Methyl ester 8c: a gum, 66%; (found M+ (EI) 428.1947. C23H28N2O6 requires M
25
428.1948); [α]D −12 (c 1.26, CHCl3); >99.8% e.e. by HPLC. Acid 3c: a gum, 67%; (found M+ (EI)
25
414.1779. C22H26N2O6 requires M 414.1791); [α]D −27 (c 0.73, CHCl3); e.e. 99.8% by HPLC; δH
(400 MHz, CDCl3) 2.90 (1H, dd, J 14.3 and 8.8, ArCHHCH), 3.15 (1H, dd, J 14.3 and 2.4, ArCHHCH),
3.33 (3H, s, NMe), 3.37 (3H, s, OMe), 3.40–3.70 (5H, m, reduces to 4H on exchange with D2O, COOH
and OCH2CH2OMe), 3.93 (2H, t, J 5.3, NCH2), 4.05 (1H, dd, J 8.8 and 2.4, ArCH2CH), 4.21 (2H, t, J
5.3, OCH2), 6.81 (2H, d, J 8.6, aryl 3-H and 5-H) and 6.95–7.40 (6H, m, aryl-H).

D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1353–1367
1365
4.7.4. (S)-(−)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-benzyloxypropanoic acid
3d
Similarly prepared. Methyl ester 8d: a gum, 75%; (found M+ (EI) 460.2000. C27H28N2O5 requires
25
M 460.1999); [α]D −34 (c 0.55, CHCl3); >99.9% e.e. by HPLC. Acid 3d: a foam, 81%; (found
25
M+ (EI) 446.1844. C26H26N2O5 requires M 446.1842); [α]D −27 (c 1.46, CHCl3); e.e. 98.2% by
HPLC; δH (270 MHz, CDCl3) 2.99 (1H, dd, J 14.0 and 7.1, ArCHHCH), 3.10 (1H, dd, J 14.0 and 4.7,
ArCHHCH), 3.33 (3H, s, NMe), 3.95 (2H, m, NCH2), 4.20 (3H, m, OCH2CH2 and ArCH2CH), 4.25
(1H, br, exchanges with D2O, CO2H), 4.44 (1H, d, J 11.8, PhCHHO), 4.64 (1H, d, J 11.8, PhCHHO),
6.79 (2H, d, J 8.8, aryl 3-H and 5-H) and 7.00–7.40 (11H, m, aryl-H).
4.7.5. (S)-(−)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(3-trifluoromethylphen-
oxy)propanoic acid 3e
Similarly prepared. Methyl ester 8e: a gum, 86%; (found M+ (EI) 514.1717. C27H25F3N2O5 requires
M 514.1716); [α]D25 −12 (c 1.2, CHCl3); 99.6% e.e. by HPLC. Acid 3e: a solid, 85%; m.p. 166–167°C;
(found C, 62.3; H, 4.6; N, 5.5%; M+ (EI) 500.1568. C26H23F3N2O5 requires C, 62.4; H, 4.6; N, 5.6%; M
25
500.1559); [α]D −8 (c 1.10, MeOH); e.e. 99% by HPLC; 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. Sodium hydroxide hydrolysis of 7b
4.8.1. (S)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)-
propanoic acid 3b
An aqueous sodium hydroxide solution (2.5 M, 65 mL, 163 mmol) was added to a stirred so-
lution of [3(2S),4S]-3-[3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoro-
ethoxy)propanoyl]-4-benzyloxazolidin-2-one 7b (42.5 g, 71 mmol) in THF (500 mL) and water (125
mL). After 20 min, the reaction was diluted with water (1 L) and washed with dichloromethane (3×700
mL) (this dichloromethane solution contained (S)-4-benzyloxazolidin-2-one which was recycled). The
aqueous solution was acidified to pH 3.5 with dilute hydrochloric acid and re-extracted with dichloro-
methane (3×700 mL). The dichloromethane solution from the acid extraction was dried and evaporated
to give a solid (29.7 g, 95%). Recrystallisation from dichloromethane:diethyl ether (25:75) afforded the
acid 3b, m.p. 119.5–120.5°C; (found C, 57.7; H, 4.7; N, 6.25%. C21H21F3N2O5 requires C, 57.5; H, 4.8;
N, 6.4%); [α]D25 −31 (c 2.50, CHCl3); 99.6% e.e. by HPLC; otherwise identical with that produced from
ester 8b.
4.9. X-Ray crystallography of oxazolidinone 7b
Oxazolidinone 7b was recrystallised from a mixture of hexane and ethyl acetate to provide crystals
suitable for study. Lattice parameters were determined from the setting angles of 25 reflections well
distributed in reciprocal space measured on an Enraf Nonius CAD-4 diffractometer. Intensity data were
collected on the diffractometer using graphite monochromated copper radiation and an ω–2θ variable
speed scan technique. The structure was solved by direct methods using the SHELXS program and
refined using the SHELXL-93 program. The trifluoromethyl moiety is disordered over two equally
occupied orientations which were modelled as idealised CF3 sites. Atomic positions for non-hydrogen

1366
D. Haigh et al. / Tetrahedron: Asymmetry 10 (1999) 1353–1367
atoms were eventually refined with anisotropic displacement parameters. Hydrogen atoms were included
in idealised positions riding on the atom to which they are attached.
Crystal data: C31H30F3N3O6; M=597.58; T=223(2) K; λ=1.54178 Å; clear colourless needles; crys-
tal size 0.50×0.10×0.10 mm; monoclinic; space group P21; unit cell dimensions a=4.6300(10) Å,
b=11.852(2) Å, c=26.535(5) Å; β=90.27(2)°, V=1456.1(5) Å3; Z=2; Dcalc=1.363 Mg/m3; µ=0.913
mm−1; F(000)=624; θ range for data collection 1.66 to 62.96°; index ranges 0≤h≤5, −13≤k≤13,
−30≤l≤30; reflections collected 6067; independent reflections 4732 (Rint=0.034); refinement method
full-matrix least-squares on F2; data:restraints:parameters 4732:37:413; goodness-of-fit on F2 1.078;
final R-indices: 4353 data; I>2σ(I) R1=0.040, wR2=0.102, all data R1=0.046, wR2=0.106; absolute
structure parameter 0.14(17); extinction coefficient 0.0028(4); largest diff. peak and hole 0.23 and −0.19
eÅ−3.
References
1. For Part 4 see Haigh, D.; Birrell, H. C.; Cantello, B. C. C.; Hindley, R. M.; Ramaswamy, A.; Rami, H. K.; Stevens, N. C.
Tetrahedron: Asymmetry 1999, 10, 1335.
2. Buckle, D. R.; Cantello, B. C. C.; Cawthorne, M. A.; Dean, D. K.; Faller, A.; Haigh, D.; Hindley, R. M.; Jefcott, L. J.;
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