The asymmetric synthesis of β-aryl-α-hydroxy esters from β-aryl-α,β-dihydroxy esters

Article abstract of DOI:10.1016/S0040-4020(01)01176-0

α,β-Dihydroxy-β-aryl esters obtained via Sharpless asymmetric dihydroxylation (AD) of substituted cinnamate esters are reduced by sequential reaction with trimethyl orthoacetate and acetyl bromide followed by catalytic hydrogenolysis in methanol to give enantiomerically enriched β-aryl-α-hydroxy esters.

Full text of DOI:10.1016/S0040-4020(01)01176-0

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 613±619
The asymmetric synthesis of b-aryl-a-hydroxy esters from
b-aryl-a,b-dihydroxy esters
Nicholas J. Lawrencep and Stephen Brown
Department of Chemistry, University of Manchester Institute of Science and Technology, P.O. Box88, Manchester M60 1QD, UK
Received 31 August 2001; revised 24 October 2001; accepted 22 November 2001
AbstractÐa,b-Dihydroxy-b-aryl esters obtained via Sharpless asymmetric dihydroxylation (AD) of substituted cinnamate esters are
reduced by sequential reaction with trimethyl orthoacetate and acetyl bromide followed by catalytic hydrogenolysis in methanol to give
enantiomerically enriched b-aryl-a-hydroxy esters. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
reductase,12 or rhodium catalysts.13 Enantiomerically
enriched a-hydroxy acids can also be prepared by dynamic
kinetic resolution using a lipase.14 The asymmetric method
we adopted is an oxidative one, although overall the trans-
formation is effectively the regio- and enantioselective
hydration of an alkene. Our synthesis is based on the
Sharpless catalytic asymmetric dihydroxylation (AD)
reaction of substituted cinnamates. Cinnamates have proved
to be exceptionally good substrates for the AD reaction. The
resulting a,b-dihydroxy esters are obtained with high
enantiomeric excesses. To access the b-hydroxy acid we
therefore required a selective method for the reductive
replacement of the b-hydroxyl group. We knew through
our interest in the C-13 paclitaxel side-chain syntheses15
that the diol 2a derived from methyl cinnamate (1a) could
be transformed into the b-bromo-a-acetoxy ester 3a.6,17
This ester now possesses a group at the b position that
can be easily reduced. A related process involving the
reduction of a-hydroxy-b-iodo esters, (generated by the
regiospeci®c ring-opening of a,b-epoxy esters with
MgI2´Et2O), using tributyltin hydride is ef®cient.18 We
were reluctant to use tributyltin hydride to reduce 3a, as
tin-containing residues19 would make the assessment of
anticancer activity (via the MTT cell growth inhibition
assay) unreliable. A more attractive procedure was hydro-
genolysis and we report our results in full herein.20
a-Hydroxy esters are frequently encountered as parts of
natural products and also serve as useful intermediates in
organic synthesis.1 As part of a study of the anticancer
properties of a,b-unsaturated carbonyl compounds2 and
related analogues we had needed to synthesize materials
related to the a-hydroxy ester methyl 4-hydroxyphenyl-
lactate (MeHPLA) which possesses anticancer properties3
by binding to the nuclear type II estrogen receptor.4
A useful strategy for the preparation of such a-hydroxy
esters5 involves the oxidation of ester enolates with reagents
such as MoOPH6 and other oxidants.7 To probe the estrogen
receptor binding properties of MeHPLA analogues we
required a stereoselective method for the synthesis of the
required b-aryl-a-hydroxy esters.
The stereoselective oxidation of enolates (yielding
a-hydroxy acids) can be achieved in a diastereoselective
fashion by the reaction of chiral esters8 with MoOPH. The
corresponding enantioselective process can be achieved by
the oxidation of pro-chiral enolates by camphoryl-sulfonyl-
oxaziridine.9 Other methods for the asymmetric synthesis of
a-hydroxy esters include the alkylation of chiral glycolate
enolates;10 the catalytic hydrogenation of enol esters;11
reduction of a-keto esters using a bakers' yeast keto ester
2. Results and discussion
The diol 2a was prepared, with an enantiomeric excess of
89%, by the catalytic AD of methyl cinnamate (1a) using a
protocol of Sharpless, modi®ed by the use of OsO4.16 We
found that in this case the reaction was signi®cantly faster
than the reaction using K2OsO2(OH)4 as the source of the
osmium. The a-acetoxy-b-bromo ester 3a was obtained,
again using a procedure developed by Sharpless,21 by
treating the diol with trimethyl orthoacetate and acetyl
Keywords: a-hydroxy esters; asymmetric dihydroxylation; hydrogenolysis;
reduction; anticancer agents.
p Corresponding author. Present address: Department of Chemistry, Cardiff
University, P.O. Box 912, Cardiff CF10 3TB, UK. Tel.: 144-29-2087-
4000x7109; fax: 144-29-2087-4030; e-mail: lawrencenj1@cardiff.ac.uk
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)01176-0

614
N. J. Lawrence, S. Brown / Tetrahedron 58 (2002) 613±619
O
HO
O
Br
O
OAc O
and
i
ii, iii
Ar
OR
Ar
OR
Ar
OR
Ar
OR
OH
2a-e
OAc
3a-e
Br
4a-e
1a-e
iv
a Ar = Ph, R = Me
b Ar = p-MeC6H4, R = Me
c Ar = p-ClC6H4, R = Me
d Ar = 3,4,5-(MeO)3C6H2, R = Me
e Ar = 3,4-(OCH2O)C6H3, R = Et
O
Ar
OR
OH
5a-e
Scheme 1. Reagents and conditions: (i) OsO4/DHQ2PHAL, NMNO, tert-BuOH; (ii) MeC(OMe)3, TsOH (cat.); (iii) AcBr; (iv) H2, Pd/C, MeOH (EtOH for 5e).
bromide. Fortunately the bromoester 3a is easily separated
from its regioisomer 4a simply by recrystallisation. The
catalytic hydrogenation of the bromoacetate 3a with hydro-
gen and 10% Pd/C, resulted in the hydrogenolysis of the
carbon±bromine bond and unexpectedly the methanolysis
of the acetate group. The enantiomeric excess of the
hydroxy ester 5a was 89% (as determined by HPLC),
indicating there was no loss in stereochemical integrity of
the a-stereogenic centre; the optical rotation indicated that
the centre was con®gured R.8 The simultaneous cleavage of
the a-acetate group is a result of the generation of hydrogen
bromide, which is a by-product of this hydrogenolysis
reaction. It should be noted that the palladium catalysed
hydrogenation of 3a in the presence of NaOAc/AcOH in
ethyl acetate gives the acetate of 5a22 (Scheme 1).
for the methylenedioxy substituted series. The pattern of
regioselectivity in general matches the electron releasing
nature of the para substituent. Such an electron-donating
group would weaken the C-3±Obond of the intermediate
acetoxonium ion 6 (Scheme 3). The p-methoxy group of 5d
is presumably not as electron releasing as the methyl group
of 5b because of the buttressing effects of the two ¯anking
methoxyl groups. The conformational restriction imposed
by the 5-membered ring presumably reduces the electron
Table 1. Yields and enantiomeric excesses in the transformations 1!5
1!2
Yield (%)
2!3 and 4
Yield (%)
3!5
Yield (%)
ee (%)
3/4
ee (%)
89c
a
b
c
d
e
75
74
66
34
81
89a
92c
68c
91f
89c
52b
±
3:1
12:1
6:1
2:1
1:1
67
84d
70d
61d
35d
±
±
e
To assess the generality of the procedure, a series of substi-
tuted cinnamic esters 1b±e was prepared and subjected to
Sharpless dihydroxylation. The Cinnamates 1b±d were
prepared by acid-catalysed Fischer±Speier esteri®cation of
the corresponding available cinnamic acids. The ethyl ester
1e was prepared in 81% yield by the DBU/LiCl mediated
Horner±Wadsworth±Emmons reaction of piperonal and
triethyl phosphonoacetate (Scheme 2).23
e
±
±
±
93g
84c
a
Enantiomeric excesses determined by GC: b-cyclodextrin dimethyl;
1648C, mean ¯ow 25 mL s21
Enantiomeric excesses determined by yield of pure 4a.
.
b
c
Enantiomeric excesses determined by HPLC: Chiracel OB; 90:10 hexane/
IPA; 1 mL min21
.
d
e
f
Enantiomeric excesses determined by yield of 5 from 2.
Enantiomeric excesses not determined.
Enantiomeric excesses determined by HPLC: Chiracel OD; 80:20
Sharpless dihydroxylation of the cinnamates was performed
as before to yield the corresponding diols 2b±e in good to
high enantiomeric excess, as determined by HPLC
(Scheme 1 and Table 1). Racemic samples of the 2b±e
were prepared to ensure that the minor peak observed in
the HPLC traces was actually the enantiomer of each diol.
These racemic samples were prepared by the same AD
reaction but substituting the DHQ2PHAL ligand with
pyridine. Sequential treatment of the diols with triethyl
orthoacetate/TsOH and acetyl bromide led to mixtures of
regioisomeric bromoacetates 3b±e and 4b±e. The ratio of
3/4 in each case was determined by integration of the peaks
hexane/IPA; 1 mL min21
.
g
Enantiomeric excesses determined by HPLC: Chiracel OD; 90:10
hexane/IPA; 1 mL min21
.
1
corresponding to H-2 and H-3 in the H NMR spectrum of
the crude reaction mixture. This ratio varied from good
(12:1) for the p-methyl substituted series (b) to poor (1:1)
O
O
O
O
i
O
O
H
OEt
81%
1e
Scheme 2. Reagents and conditions: (i) EtO2CCH2P(O)(OEt)2, DBU, LiCl,
MeCN, rt 48 h.
Scheme 3.

N. J. Lawrence, S. Brown / Tetrahedron 58 (2002) 613±619
615
donating effects of the substituents of 5e. However in this
case the comparison with the other members of the series is
only rough since 5e is an ethyl ester. The mixtures of 3b±e
and 4b±e proved dif®cult to separate either by chromato-
graphy or by crystallization. However it was not essential to
separate these regioisomers, as it was possible to cleanly
isolate the a-hydroxy ester 5b±e after hydrogenolysis of
the mixture. The hydrogenation reactions were performed
as before except in the case of the mixture of 3e and 4e.
Because this series incorporated an ethyl ester, ethanol was
chosen as the reaction solvent to avoid complications of
transesteri®cation. The overall yields of the a-hydroxy
esters 3b±d are good. Only the yield of 5e is low, re¯ecting
the lack of regioselectivity in the reaction of 2e. The
enantiomeric excess of the esters 5d and 5e corresponded
closely, within experimental error, to that of the diols 2d and
2e, respectively. This provides further evidence that the
transformation 1!3 and 4 does not affect the stereo-
chemical integrity of the stereogenic centre adjacent to the
ester group. Unfortunately we were not able to effect the
analytical HPLC separation of the enantiomers of 5b or 5c.
We have to assume that these are similar to those of 2b and
2c, respectively.
Bruker AC 300 spectrometer was used to record 300 MHz
1H and 75 MHz 13C NMR spectra. Coupling constant (J)
values are given in Hz. Chemical ionisation, (CI), and
electron impact, (EI), mass spectra were recorded using a
Kratos MS25 mass spectrometer; fast atom bombardment
(FAB) mass spectra were recorded using a Kratos MS50
mass spectrometer using a meta-nitrobenzyl-alcohol matrix.
Accurate mass determinations were performed using a
Kratos Concept IS mass spectrometer. Elemental analysis
was performed using a Carlo±Erba 1106 elemental
analyser. Infra red spectra were recorded using a Phillips
Analytical PU9625 pulsed-FT spectrometer. Melting points
were determined using a BuÈchi 510 melting point apparatus
and are not corrected. KugelruÈhr distillation was performed
using a BuÈchi GKR-51 apparatus. Column chromatography
was conducted using silica gel 60 (230±400 mesh, Merck
and Co.) and silica TLC was conducted on pre-coated
aluminium sheets (60 F254) with a 0.2 mm thickness
(Aldrich Chemical Co.). Ether refers to diethyl ether and
was distilled prior to use. Hexane used for column chroma-
tography was also distilled prior to use. Anhydrous ether,
anhydrous dichloromethane, anhydrous methanol and
anhydrous N,N-dimethylformamide (DMF) were obtained
from the Aldrich Chemical Co. and used as supplied.
Anhydrous toluene was distilled from sodium metal and
The esters 5b±e showed no in vitro cytotoxicity (all
IC50s.50 mM) against K562 (human Caucasian chronic
myelogenous leukaemia), BT20 (human breast cancer)
and MCF7 (human breast cancer) cell lines. The MCF7
cell line is estrogen positive whilst the BT20 cell line is
estrogen negative. Differential activity against these cell
lines is indicative of antiestrogenic activity. However, the
lack of any activity is disappointing and probably points to
the importance of the para-hydroxyl group in determining
the activity of MeHPLA. The results may also support the
assumption that endogenous MeHPLA is the l-form (S
enantiomer).24 Racemic samples of 5a, 5b and 5d were
also inactive against the K562 cell line. Further work to
study the relationship between the activity and stereo-
chemistry of MeHPLA is underway.
Ê
stored under nitrogen in the presence of 4 A molecular
sieves. Anhydrous dimethyl sulfoxide was distilled under
reduced pressure and stored under nitrogen in the presence
Ê
of 4 A molecular sieves. THF was distilled from sodium
metal in the presence of benzophenone immediately prior
to use. Commercially available (Lancaster) methyl
cinnamate (1a) was used without puri®cation.
4.2. General method for the synthesis of cinnamates 1
Cinnamates 1b, c and d were prepared by esteri®cation
(MeOH, H2SO4 (cat.)); 1b: (4.44 g, 58%); mp 56±588C
{lit.25 mp 57±588C}; (Found: C, 75.3; H, 7.1. C11H12O2
requires C, 75.0; H, 6.8%); 1c: (4.85 g, 63%); mp 72±
748C (lit.26 mp 73±758C); (Found: C, 61.0; H, 4.7; Cl,
18.4. C10H9O2Cl requires C, 61.1; H, 4.6; Cl, 18.1%); 1d:
(5.91 g, 78%); mp 94±958C (lit.27 mp 94±978C); (Found: C,
61.6; H, 6.4. Requires C, 61.9; H, 6.4%).
3. Conclusions
In summary, we have successfully demonstrated that it is
possible to synthesize a-hydroxy esters from syn-1,2-diols,
starting from readily available materials that are
inexpensive. The reduction avoids the use of tributyltin
hydride. The method is also a good example of a seren-
dipitous one-pot, two-step synthesis. The sequence is a
curious tandem process, since the hydrogen bromide that
is released in the hydrogenolysis reaction catalyses the
subsequent methanolysis of the acetyl group. The inactivity
of the esters 5a±e illustrates that the presence of the
p-hydroxy group of MeHPLA contributes to its anticancer
properties.
4.2.1. Ethyl 3-[(30,40-methylenedioxy)phenyl]propenoate
(1e). This was prepared using the general method of
Masamune and co-workers.23 Triethyl phosphonoacetate
(12.3 g, 55 mmol) and then DBU (7.48 mL, 55 mmol)
were added to a mixture of piperonal (7.49 g, 50 mmol)
and lithium chloride (2.22 g, 52 mmol) in dry acetonitrile
(160 mL). The mixture was stirred at rt for 48 h then poured
into water (500 mL) and extracted with chloroform
(3£150 mL). The combined organic extracts were dried
(magnesium sulfate) and evaporated to leave a yellow
waxy solid. The crude material was recrystallised from
toluene to afford 1e as colourless crystals (8.85 g, 81%);
mp 66±678C; (Found: C, 65.2; H, 5.5. C12H12O4 requires
C, 65.5; H, 5.5%); nmax (KBr disc) 3000 (w), 2900 (w), 1700
(s), 1650 (m), 1610 (m), 1510 (s), 1490 (s), 1370 (m), 1360
(m), 1300 (w), 1250 (bs), 1180 (m), 1100 (w), 1030 (m), 860
(w), 800 (m) cm21; dH (300 MHz, CDCl3) 1.32 (3H, t,
Jˆ7.2 Hz, CH3), 4.24 (2H, q, Jˆ7.2 Hz, CH2CH3), 6.00
(2H, s, OCH2O), 6.25 (1H, d, Jˆ16.0 Hz, H2), 6.80 (1H,
4. Experimental
4.1. General
1
200 MHz H NMR spectra were recorded using a Bruker
AC 200 spectrometer using CHCl3 as an internal standard. A

616
N. J. Lawrence, S. Brown / Tetrahedron 58 (2002) 613±619
d, Jˆ1.7 Hz, H20), 6.98±7.03 (2H, m, H50 and H60), 7.58
(1H, d, Jˆ16.0 Hz, H3); dC (75 MHz, CDCl3) 14.4 (CH3),
60.5 (CH2CH3), 101.6 (C70), 106.5 (C50), 108.6 (C10), 116.3
(C2), 124.5 (C60), 128.9 (C10), 144.4 (C3), 148.4 (C40),
149.6 (C30), 167.3 (C1); m/z (FAB) 221 (85%, [M1H]1),
220 (100, M1), 175 (80%, [M2OEt]1).
CH3CvO), 3.71 (3H, s, CH3), 5.34 (1H, d, Jˆ7.0 Hz,
PhCH), 5.64 (1H, d, Jˆ7.0 Hz, CH), 7.32±7.47 (5H, m,
aromatic); dC (75 MHz, CDCl3) 20.4 (CH3CvO), 49.1
(PhCH), 52.6 (CH3), 75.1 (COAc), 128.5 (CH), 128.6
(CH), 129.0 (CH), 136.6 (C), 167.2 (CvO), 169.4
(CvO); m/z (FAB) 303 {30%, [M(81Br)1H]1}, 301
{30%, [M(79Br)1H]1}, 243 {100, [M(81Br)2AcOH]1},
241 {90, [M(79Br)2AcOH]1}.
4.2.2. Methyl (2R,3S)-2,3-dihydroxy-3-phenylpropionate
(2a). This was prepared according to the method of
Sharpless and co-workers.16 NMO(31 mL, 60% in water)
and OsO4 (4 mL, of a solution made from 1 g in t-BuOH
(100 mL)) were added to (E)-methyl cinnamate (20.55 g,
127 mmol) and DHQ2PHAL (500 mg, 0.64 mmol) in
t-BuOH (62 mL). The mixture was stirred vigorously at rt
for 8 h, then quenched with saturated aqueous sodium sul®te
solution (100 mL) and then stirred at rt for a further 1 h.
Water (100 mL) was added and the mixture was extracted
with EtOAc (2£150 mL). The combined organic extracts
were washed with HClaq. (4£50 mL, 1 M) then dried
(MgSO4) and evaporated to leave a cream coloured solid
(20.30 g). The crude material was puri®ed by crystallisation
from toluene to afford the diol 2a as colourless crystals
(18.65 g, 75, 89% ee). The enantiomeric excess was
measured by GC; b-cyclodextrin dimethyl (B-DM),
1648C, mean ¯ow rate ca. 25 mL s21. Retention times:
major enantiomer 21.94 min, minor enantiomer
25.17 min); mp 84±858C (lit.16, mp 84±868C);
[a]Dˆ15.9 (c 1.0 in EtOH) {lit.16, [a]Dˆ13.4 (c 1.2 in
EtOH); lit.28 [a]Dˆ18.2 (c 1.2 in EtOH)}; (Found: C,
61.2; H, 6.3. C10H12O4 requires C, 61.2; H, 6.1%); Rf 0.22
(silica; 3:1; hexane/EtOAc, v/v); nmax (KBr disc) 3500 (vs),
3400 (vs), 2960 (w), 1715 (s), 1460 (m), 1400 (m), 1325
(m), 1220 (s), 1110 (s), 720 (m) cm21; dH (300 MHz,
CDCl3) 2.70 (1H, d, Jˆ7.0 Hz, OH), 3.08 (1H, d,
Jˆ7.0 Hz, OH), 3.83 (3H, s, CH3), 4.38 (1H, dd, Jˆ3.0,
7.0 Hz, PhCH), 5.03 (1H, dd, Jˆ3.0, 7.0 Hz, CH), 7.30±
7.43 (5H, m, aromatic); dC (75 MHz, CDCl3) 52.7 (CH3),
74.4 (CH), 74.8 (CH), 126.2 (CH), 127.9 (CH), 128.4 (CH),
139.9 (C), 173.1 (CvO); m/z (FAB) 197 (20%, [M1H]1),
179 (100, [M2OH]1), 119 (40, [M2Ph]1).
4.2.4. Methyl (2R)-2-hydroxy-3-phenylpropanoate (5a).
A mixture of methyl ester 3a (148 mg, 0.49 mmol) and
palladium (10%) on carbon (10 mg) was stirred in dry
MeOH (5 mL) under H2 (1 atm.) at rt for 2 days. The
mixture was then ®ltered through Celitew and concentrated
to leave an orange oil (94 mg). The crude material was
puri®ed by chromatography (silica; CHCl3) to afford 5a as
a colourless solid (73 mg, 67%); mp 36±388C; [a]Dˆ19.7
(c 1.0 in CHCl3), 23.0 (c 1.0 in MeOH) and 18.7 (c 1.3 in
acetone) {lit.8 [a]Dˆ22.4 (c 2.7 in MeOH) and 18.5 (c 3.9
in acetone)}; (Found: C, 66.5; H, 6.5. C10H12O3 requires C,
66.6; H, 6.7%); Rf 0.35 (silica; CHCl3); nmax (KBr disc)
3500±3200 (bw), 1750 (vs), 1500 (w), 1450 (bw), 1275
(bw), 1110 (bs), 750 (s), 705 (s) cm21; dH (300 MHz,
CDCl3) 2.66 (1H, d, Jˆ6.7 Hz, OH), 2.96 (1H, dd, Jˆ6.7,
13.9 Hz, CHaHb), 3.14 (1H, dd, Jˆ4.4, 13.9 Hz, CHaHb),
3.77 (3H, s, OMe), 4.46 (1H, dt, Jˆ4.4, 6.7 Hz, CH),
7.18±7.34 (5H, m, aromatic); dC (75 MHz, CDCl3) 40.5
(CH2), 52.4 (CH), 71.2 (CH3), 127.2 (CH), 128.4 (CH),
129.4 (CH), 136.2 (C), 174.5 (CvO); m/z (FAB) 181
(40%, [M1H]1), 162 (40, [M2H2O]1).
4.2.5.
Methyl
(2R,3S)-2,3-dihydroxy-3-(40-methyl-
phenyl)propanoate (2b). Dihydroxylation of the propeno-
ate 1b (1.99 g, 11.31 mmol) was performed as described
earlier (reaction time 24 h). The crude material was
recrystallised from toluene to afford 2b as colourless
plate-like crystals (1.76 g, 74, 92% ee). The ee was deter-
mined by HPLC: Chiracel OB; 90:10 hexane/IPA;
1 mL min21; mp 92±948C; [a]Dˆ19.28 (c 1.0 in CHCl3);
(Found: C, 62.9; H, 6.8. C11H14O4 requires C, 62.8; H,
6.7%); nmax (KBr disc) 3500 (vs), 3390 (bs), 3020 (w),
2960 (w), 1740 (vs), 1520 (w), 1450 (m), 1320 (m), 1230
(m), 1110 (vs), 1055 (m), 990 (w), 890 (w) cm21; dH
(300 MHz, CDCl3) 2.34 (3H, s, Me), 2.64 (1H, bd,
Jˆ6.5 Hz, OH), 3.06 (1H, bd, Jˆ5.6 Hz, OH), 3.82 (3H,
s, OMe), 4.36 (1H, bs, H2), 4.99 (1H, bs, H3), 7.18 (2H,
bd, Jˆ8.0 Hz, aromatic), 7.29 (2H, bd, Jˆ8.0 Hz,
aromatic); dC (75 MHz, CDCl3) 21.0 (CH3), 52.5 (OMe),
74.3 (CH), 74.7 (CH), 125.6 (CH), 128.9 (CH), 136.9 (C),
137.5 (C), 173.1 (CvO); m/z (FAB) 233 (70%, [M1Na]1),
209 (20, [M2H]1), 193 (100, [M2OH]1), 133 (80), 121
(30), 105 (60).
4.2.3. Methyl (2S,3R)-2-acetoxy-3-bromo-3-phenylpro-
pionate (3a). This was prepared according to the method
of Sharpless and co-workers.16 Trimethyl orthoacetate
(38 mL) was added to the diol 2a (20.30 g, 104 mmol)
and TsOH (292 mg, 1.7 mmol) in dry CH2Cl2 (80 mL).
The mixture was stirred at rt for 2 days. The volatile compo-
nents were evaporated in vacuo to leave a yellow oil that
was dissolved in CH2Cl2 (80 mL). Acetyl bromide (7.8 mL,
105 mmol) was added to the mixture at 08C, and stirred for a
further 2 h at 08C then stored at 48C for 16 h. The solvent
was then evaporated to leave a pale brown solid that was
stirred in a mixture of hexane and ether (70 mL, 6:4, v/v) for
40 min and then ®ltered. The residue was washed with more
of the same solvent to afford the bromo ester 3a as pale
orange crystals. The ®ltrate was concentrated and recrystal-
lised a second time to give further 3a (16.32 g, 52%
combined yield); mp 85±868C {lit.16 mp 86±878C};
[a]Dˆ2105 (c 1.0 in EtOH) {lit.16 [a]Dˆ2113 (c 1.3 in
EtOH)}; (Found: C, 47.9; H, 4.3; Br, 26.6. C12H13BrO4
requires C, 47.8; H, 4.3; Br, 26.5%); nmax (KBr disc) 2980
(w), 1750 (vs), 1450 (m), 1380 (m), 1220 (s), 1190 (s), 900
(w), 700 (m) cm21; dH (300 MHz, CDCl3) 2.11 (3H, s,
4.2.6. Methyl (2R,3S)-2,3-dihydroxy-3-(40-chlorophenyl)-
propanoate (2c). This was prepared in the same way as
diol 2b, from the propenoate 1c (2.74 g, 13.94 mmol).
Recrystallisation of the crude material from toluene gave
2c as ®ne colourless crystals (2.11 g, 66, 68% ee). The
enantiomeric excess was determined by HPLC: Chiracel
OB; 90:10 hexane/IPA; 1 mL min21; mp 113±1158C;
[a]Dˆ7.42 (c 1.3 in CHCl3); (Found: C, 51.7; H, 5.3; Cl,
15.5. C10H11O4Cl requires C, 52.1; H, 4.8; Cl, 15.4%); nmax
(KBr disc) 3540 (m), 3470 (bm), 2960 (w), 2900 (w), 1910

N. J. Lawrence, S. Brown / Tetrahedron 58 (2002) 613±619
617
(w), 1740 (vs), 1500 (s), 1445 (w), 1225 (bs), 1110 (s), 1060,
(m), 1020 (m), 940 (w), 830 (w), 790 (w) cm21; dH
(300 MHz, CDCl3) 2.74 (1H, bs, OH), 3.11 (1H, bs, OH),
3.83 (3H, s, CH3), 4.34 (1H, bs, H2), 4.99 (1H, bs, H3), 7.35
(4H, bs, aromatic); dC (75 MHz, CDCl3) 53.1 (CH3), 73.9
(CH), 74.8 (CH), 127.8 (CH), 128.7 (CH), 134.0 (C), 138.0
(C), 173.1 (CvO); m/z (FAB) 255 {20%, [M(37Cl)1Na]1},
253 {60, [M(35Cl)1Na]1}, 215 {30, [M(37Cl)2OH]}, {100,
[M(35Cl)2OH]}.
(300 MHz, CDCl3) (isomer 3b) 2.11 (3H, s, CH3), 2.33
(3H, s, CH3), 3.70 (3H, s, CH3), 5.33 (1H, d, Jˆ6.3 Hz,
H3), 5.63 (1H, d, Jˆ6.3 Hz, H2), 7.12 (2H, d, Jˆ8.0 Hz,
aromatic), 7.29 (2H, d, Jˆ8.0 Hz, aromatic); dH (300 MHz,
CDCl3) (isomer 4b) 2.00 (3H, s, CH3), 2.35 (3H, s, CH3),
3.78 (3H, s, CH3), 4.50 (1H, d, Jˆ9.9 Hz, H3), 6.05 (1H, d,
Jˆ9.9 Hz, H2), 7.10±7.75 (4H, aromatic); dC (75 MHz,
CDCl3) (isomer 3b) 20.3 (CH3), 21.1 (CH3), 49.2 (CH3),
52.6 (CH), 75.3 (CH), 128.0 (CH), 129.2 (CH), 133.7 (C),
139.0 (C), 167.2 (CvO), 169.4 (CvO); (Found: M1,
314.0144. C13H15BrO4 requires M1, 314.0154); m/z (FAB)
317 {85%, [M(81Br)1H]1}, 315 {100, [M(79Br)1H]1},
285 (40), 283 (45), 257 (35), 255 (35), 235 (50), 193
(100).
4.2.7.
Methyl
(2R,3S)-2,3-dihydroxy-3-(30,40,50-tri-
methoxyphenyl)propanoate (2d). This was prepared in
the same way as diol 2b, from the propenoate 1d (2.018 g,
8.01 mmol). Recrystallisation of the crude material from
toluene gave 2d as ®ne colourless needles (0.773 g, 34,
91% ee). The enantiomeric excess was determined by
HPLC: Chiracel OD; 80:20 hexane/IPA; 1 mL min21; mp
126±1288C; [a]Dˆ12.88 (c 1.1 in CHCl3); (Found: C, 54.6;
H, 6.5. C13H18O7 requires C, 54.6; H, 6.3%); nmax (KBr disc)
3550 (s), 3500 (s), 3000 (w), 2975 (w), 2950 (w), 2850 (w),
1745 (vs), 1600 (vs), 1515, (s), 1470 (s), 1430 (s), 1340 (s),
1140 (vs), 1110 (vs), 1075 (s), 1005 (s), 845 (m), 765 (m)
cm21; dH (300 MHz, CDCl3) 2.63 (1H, bs, OH), 3.03 (1H,
bs, OH), 3.83 (3H, s, OMe), 3.84 (3H, s, OMe), 3.86 (6H, s,
OMe), 4.37 (1H, d, Jˆ2.6 Hz, H2), 4.96 (1H, d, Jˆ2.6 Hz,
H3), 6.63 (2H, s, aromatic); dC (75 MHz, CDCl3) 52.6
(OMe), 56.1 (OMe), 60.8 (OMe), 74.5 (CH), 74.9 (CH),
103.3 (CH), 135.9 (C), 137.4 (C), 153.2 (C), 173.1
(CvO); m/z (FAB) 309 (20%, [M1Na]1), 286 (40, M1),
269 (85, [M2OH]1), 197(100).
4.2.10. Methyl (2S,3R)-2-acetoxy-3-bromo-3-(40-chloro-
phenyl)propanoate (3c) and methyl (2S,3S)-2-bromo-3-
acetoxy-3-(40-chlorophenyl)propanoate (4c). These were
prepared in the same way as bromo ester 3a from the diol 2c
(867 mg, 3.76 mmol). The crude product was puri®ed
quickly by column chromatography (silica; 5:1; hexane/
ethyl acetate, v/v) to afford 3c and 4c as a colourless solid
(813 mg, 64%) as a (6.5:1, 3c/4c) mixture of regioisomers
1
(determined by H NMR); mp 54±568C (dec.); Rf 0.39
(silica; 5:1 hexane/EtOAc, v/v); nmax (KBr disc) 3000 (m),
2940 (m), 1750 (bs), 1590 (m), 1490 (m), 1440 (m), 1360
(m), 1200 (bs), 1090 (m), 1000 (m), 820 (m) cm21; dH
(300 MHz, CDCl3) (isomer 3c) 2.12 (3H, s, CH3), 3.69
(3H, s, OMe), 5.32 (1H, d, Jˆ6.1 Hz, H3), 5.62 (1H, d,
Jˆ6.1 Hz, H2), 7.26 (4H, m, aromatic); dH (300 MHz,
CDCl3) (isomer 4c) 2.02 (3H, s, CH3), 3.81 (3H, s, OMe),
4.43 (1H, d, Jˆ9.8 Hz, H3), 6.08 (1H, d, Jˆ9.8 Hz, H2),
7.26±7.42 (4H, m, aromatic); dC (75 MHz, CDCl3) 20.4,
20.5, 45.6, 47.9, 52.6, 53.1, 74.6, 74.9, 128.2, 128.3,
128.4, 129.1, 129.8, 130.1, 134.9, 135.0, 167.8, 169.3,
170.7, 172.1; (Found: [M1NH4]1, 351.9945. C12H12BrClO4
requires [M1NH4]1, 351.9951); m/z (CI) 352 {70%,
[M(79Br35Cl)1NH4]1}, 354 {100, [M(81Br35Cl and
79Br37Cl)1NH4]1}, 356 {20, [M(81Br37Cl)1NH4]1}.
4.2.8. Ethyl (2R,3S)-2,3-dihydroxy-3-[(30,40-methylene-
dioxy)phenyl]propanoate (2e). This was prepared in the
same way as diol 2b, from the propenoate 1e (2.285 g,
10.3 mmol). The crude material was puri®ed by chromato-
graphy (silica; 3:1; hexane/EtOAc, v/v) to afford 2e as a
white solid (2.130 g, 81, 89% ee). The enantiomeric excess
was determined by HPLC: Chiracel OB; 90:10 hexane/IPA;
1 mL min21; mp 77±788C; [a]Dˆ11.7 (c 1.5 in CHCl3);
(Found: C, 56.5; H, 5.6. C12H14O6 requires C, 56.7; H,
5.6%); Rf 0.11 (silica; 3:1; hexane/EtOAc, v/v); nmax (KBr
disc) 3520 (m), 3380 (bs), 3000 (w), 2980 (w), 2900 (w),
1720 (s), 1490 (m), 1450 (s), 1320 (m), 1290 (m), 1220 (s),
1110 (s), 1050 (m), 930 (w), 750 (w) cm21; dH (300 MHz,
CDCl3) 1.28 (3H, t, Jˆ7.0 Hz, CH3), 2.73 (1H, d, Jˆ6.0 Hz,
OH), 3.15 (1H, d, Jˆ5.9 Hz, OH), 4.26 (2H, q, Jˆ7.0 Hz,
CH2CH3), 4.28 (1H, bs, H2), 4.89 (1H, bs, H3), 5.95 (2H, s,
H70), 6.76±6.86 (2H, m, H50,60), 6.93 (1H, d, Jˆ1.2 Hz,
H20); dC (75 MHz, CDCl3) 14.0 (CH3), 62.0 (CH2), 74.3
(CHOH), 74.9 (CHOH), 101.0 (C70), 107.0 (C20), 107.9
(C50), 119.7 (C60), 133.9 (C10), 147.2 (C40), 147.6 (C30),
172.6 (CvO); m/z (FAB) 254 (40%, M1), 253 (70,
[M2H]1), 237 (100, [M2OH]1).
4.2.11. Methyl (2S,3R)-2-acetoxy-3-bromo-3-(30,40,50-
trimethoxyphenyl)propanoate (3d) and methyl (2S,3S)-
2-bromo-3-acetoxy-3-(30,40,50-trimethoxyphenyl)propano-
ate (4d). These were prepared in the same way as the bromo
ester 3a from the diol 2d (439 mg, 1.53 mmol). The crude
material was puri®ed quickly by column chromatography
(silica; CHCl3) to afford 3d and 4d as a colourless oil
(543 mg, 90%) as a (2:1, 3d/4d) mixture of regioisomers
1
(determined by H NMR); mp 62±64 8C; Rf 0.34 (silica;
CHCl3); nmax (KBr disc) 3000 (bw), 2950 (bw), 2840 (w),
1755 (vs), 1595 (s), 1510 (s), 1465 (bs), 1435 (m), 1375 (m),
1220 (bs), 1130 (s), 1010 (m), 915 (bw), 735 (m) cm21; dH
(300 MHz, CDCl3) (isomer 3d) 2.09 (3H, s, CH3), 3.74 (3H,
s, OMe), 3.75±3.77 (6H, s, OMe), 5.28 (1H, d, Jˆ6.7 Hz,
H3), 5.65 (1H, d, Jˆ6.7 Hz, H2), 6.58 (2H, s, aromatic); dH
(300 MHz, CDCl3) (isomer 4d) 2.21 (3H, s, CH3), 3.70 (3H,
s, OMe), 3.75±3.77 (6H, s, OMe), 5.31 (1H, d, Jˆ5.1 Hz,
H2), 5.43 (1H, d, Jˆ5.1 Hz, H3), 6.58 (2H, s, aromatic); dC
(75 MHz, CDCl3) 20.4, 20.5, 49.6, 51.3, 52.7, 52.9, 56.0,
56.1, 60.8, 75.0, 75.6, 77.6, 105.5, 105.8, 107.2, 107.5,
132.4, 139.6, 152.9, 153.1, 167.3, 169.3, 169.6; (Found:
[79Br] M1, 390.0313. C15H19BrO7 requires [79Br] M1
390.0315); m/z (FAB) 392 [40%, M(81Br)1], 390 [40,
4.2.9. Methyl (2S,3R)-2-acetoxy-3-bromo-3-(40-methyl-
phenyl)propanoate (3b) and methyl (2S,3S)-2-bromo-3-
acetoxy-3-(40-methylphenyl)propanoate (4b). These were
prepared in the same way as bromo ester 3a, from the diol
2b (810 mg, 3.85 mmol). The crude reaction product was
puri®ed quickly by column chromatography (silica; CHCl3)
to afford 3b and 4b as a colourless solid (721 mg, 59%), as a
1
(12:1, 3b/4b) mixture of regioisomers (determined by H
NMR); mp 458C (dec); Rf 0.60 (silica; CHCl3); dH

618
N. J. Lawrence, S. Brown / Tetrahedron 58 (2002) 613±619
M(79Br)1], 311 (100), 279 (50), 269 (100), 252 (70), 237
(70).
(wb), 2960 (w), 1750 (vs), 1500 (s), 1440 (s), 1410 (w),
1350 (w), 1290 (m), 1220 (s), 1180 (m), 1110 (s), 1100
(s), 1020 (s), 980 (w), 810 (s), 710 (m) cm21; dH
(300 MHz, CDCl3) 2.76 (1H, d, Jˆ6.7 Hz, OH), 2.91 (1H,
dd, Jˆ6.7, 14.0 Hz, CHaHb), 3.10 (1H, dd, Jˆ4.3, 14.0 Hz,
CHaHb), 3.77 (3H, s, OMe), 4.43 (1H, dt, Jˆ4.3, 6.7 Hz,
CH), 7.16 (2H, d, Jˆ8.4 Hz, aromatic), 7.29 (2H, d,
Jˆ8.4 Hz, aromatic); dC (75 MHz, CDCl3) 39.9 (CH2),
46.9 (OMe), 71.1 (CH), 128.5 (CH), 131.1 (CH), 132.9
(C), 135.0 (C), 174.6 (CvO); (Found: [M1H]1,
215.0480. C10H11ClO3 requires [M1H]1, 215.0475); m/z
(FAB) 239 {10%, [M(37Cl)1Na]1}, 237 {30,
[M(35Cl)1Na]1}, 217 {25, [M(Cl37)1H]1}, 215 {75,
[M(Cl35)1H]1}, 196 (45), 165 (25), 155 (100), 137 (35),
125 (50).
4.2.12. Ethyl (2S,3R)-2-acetoxy-3-bromo-3-[(3040-methyl-
enedioxy)phenyl]propanoate (3e) and ethyl (2S,3S)-2-
bromo-3-acetoxy-3-[(30,40-methylenedioxy)phenyl]pro-
panoate (4e). These were prepared in the same way as the
bromo ester 3a from the diol 2e (439 mg, 1.53 mmol). The
crude material was then puri®ed by ¯ash column chromato-
graphy (silica; 4:1; hexane/EtOAc, v/v) to afford 3e and 4e
as a pale yellow oil (1.434 g, 95%) as a (1:1, 3e/4e) mixture
of regioisomers. This material was not rigorously puri®ed
and was used immediately in the next step; Rf 0.23 (silica;
4:1; hexane/EtOAc, v/v); dH (300 MHz, CDCl3) 1.17 (3H, t,
Jˆ7.1 Hz, CH3), 1.21 (3H, t, Jˆ7.1 Hz, CH3), 2.17 (3H, s,
CH3), 2.22 (3H, s, CH3), 4.10±4.20 (4H, m, CH2CH3), 5.30
(1H, d, Jˆ5.5 Hz), 5.32 (1H, d, Jˆ5.9 Hz), 5.36 (1H, d,
Jˆ5.5 Hz), 5.57 (1H, d, Jˆ5.9 Hz), 5.97 (4H, s, H70),
6.70 (1H, d, Jˆ7.1 Hz), 6.72 (1H, d, Jˆ7.0 Hz), 6.85 (1H,
dd, Jˆ1.8, 7.0 Hz, H60), 6.86 (1H, dd, Jˆ1.9, 7.1 Hz, H60),
7.00 (1H, d, Jˆ1.9 Hz), 7.04 (1H, d, Jˆ1.8 Hz); dC
(75 MHz, CDCl3) 13.8 (CH3), 13.9 (CH3), 20.3 (CH2),
20.3 (CH2), 49.6 (C2 or C3), 51.3 (C2 or C3), 61.8 (OAc),
61.9 (OAc), 75.3 (C2 or C3), 75.8 (C2 or C3), 101.4 (C10),
101.5 (C10), 107.6 (C5), 107.8 (C5), 108.9 (C8), 109.1
(C8), 121.8 (C9), 122.3 (C9), 130.4 (C4), 130.7 (C4),
147.7 (C6 or C7), 147.8 (C6 or C7), 147.9, (C6 or C7),
148.2 (C6 or C7), 166.3 (OAc), 166.6 (OAc), 169.3 (C1),
169.6 (C1); (Found: M1, 358.0052. C14H15BrO6 requires
M1, 358.0052); m/z (FAB) 361 {10%, [M(81Br)1H]1},
360 [30, M(81Br)1], 359 {30, [M(79Br)1H]1}, 358 [80,
M(79Br)1], 279 (100, [M2Br]1), 237 (90).
4.2.15. Methyl (2R)-2-hydroxy-3-(30,40,50-trimethoxy-
phenyl)propanoate (5d). This was prepared in the same
way as 5b from 3d/4d to afford 5d as a white solid
(126 mg, 61, 93% ee). The enantiomeric excess was deter-
mined by HPLC: Chiracel OD; 90:10 hexane/IPA;
1 mL min21; mp 75±768C; [a]Dˆ18.2 (c1.0 in CHCl3);
(Found: C, 57.7; H, 6.7. C13H18O6 requires C, 57.7; H,
6.7%); Rf 0.13 (silica; CHCl3); nmax (KBr disc liquid ®lm)
3400 (s), 3000 (m), 2950 (m), 2820 (m), 1730 (s), 1600 (s),
1510 (s), 1450 (m), 1430 (m), 1370 (w), 1340 (w), 1290 (m),
1250 (m), 1220 (m), 1130 (vs), 1020 (m), 830 (s) cm21; dH
(300 MHz, CDCl3) 2.76 (1H, d, Jˆ6.1 Hz, OH), 2.89 (1H,
dd, Jˆ6.1, 14.0 Hz, CHaHb), 3.07 (1H, dd, Jˆ4.1, 14.0 Hz,
CHaHb), 3.79 (3H, s, OMe), 3.82 (3H, s, OMe), 3.86 (6H, s,
OMe), 4.45 (1H, dt, Jˆ6.1, 4.1 Hz, CHOH), 6.43 (2H, s,
aromatic); dC (75 MHz, CDCl3) 40.6 (CH2), 52.3 (CH),
55.9 (OMe), 60.7 (OMe), 71.2 (OMe), 106.3 (CH), 131.7
(C), 136.8 (C), 153.1 (C), 174.3 (CvO); (Found: M1,
270.1104. C13H18O6 requires M1, 270.1103); m/z (FAB)
270 (60%, M1), 252 (40, [M2H2O]1), 211 (40), 181 (100).
4.2.13. Methyl (2R)-2-hydroxy-3-(40-methylphenyl)pro-
panoate (5b). The bromo acetates 3b/4b (1.63 g,
5.18 mmol) and palladium on carbon (10 mg, 10%) were
stirred vigorously in dry MeOH (4 mL) under H2 (1 atm.)
at rt for 24 h. The mixture was ®ltered through Celitew,
poured into water (100 mL) and extracted with chloroform
(3£50 mL). The combined organic extracts were dried
(MgSO4) and evaporated to leave an orange coloured oil.
The crude material was puri®ed by column chromatography
(silica; CHCl3) to afford 5b as a colourless oil (0.780 g,
78%); [a]Dˆ17.9 (c 1.5 in CHCl3); Rf 0.36 (silica;
CHCl3); nmax (KBr disc) 3500 (wb), 2960 (m), 2920 (m),
1740 (vs), 1520 (s), 1440 (m), 1270 (bs), 1220 (bs), 1120 (s),
1100 (s), 1030 (w), 810 (m), 790 (w) cm21; dH (300 MHz,
CDCl3) 2.31 (3H, s, CH3), 2.66 (1H, d, Jˆ6.5 Hz, OH), 2.92
(1H, dd, Jˆ6.5, 14.0 Hz, HaHb), 3.08 (1H, dd, Jˆ4.4,
14.0 Hz, HaHb), 3.78 (3H, s, OMe), 4.44 (1H, dt, Jˆ4.4,
6.5 Hz, CH), 7.10 (4H, s, aromatic); dC (75 MHz, CDCl3)
21.1 (CH3), 40.2 (CH2), 52.4 (CH3), 71.4 (CH), 129.2 (CH),
129.4, (CH), 133.3 (C), 136.4 (C), 174. 7 (CvO); (Found:
[M1NH4]1, 212.1288. C11H15O3 requires [M1NH4]1,
212.1286); m/z (CI) 212 (100%, [M1NH4]1), 204 (80),
198 (60), 194 (10, M1).
4.2.16. Ethyl (2R)-2-hydroxy-3-[(30,40-methylenedioxy)-
phenyl]propanoate (5e). This was prepared in the same
way as 5b from 3e/4e to afford 5e as a colourless oil
(313 mg, 35, 84% ee). The enantiomeric excess was deter-
mined by HPLC: Chiracel OB; 90:10 hexane/IPA;
1 cm23 min21; [a]Dˆ123.7 (c 1.0 in CHCl3); Rf 0.22
(silica; 3:1; hexane/EtOAc, v/v); nmax (KBr disc) 3500
(bs), 3000 (m), 2900 (m), 1740 (vs), 1510 (s), 1490 (s),
1450 (s), 1370 (w), 1250 (bs), 1200 (bs), 1100 (bs), 1040
(s), 940 (s), 810 (m) cm21; dH (300 MHz, CDCl3) 1.29 (3H,
t, Jˆ7.2 Hz, CH3), 2.77 (1H, d, Jˆ5.2 Hz, OH), 2.88 (1H,
dd, Jˆ6.6, 14.0 Hz, CHaHb), 3.24 (1H, dd, Jˆ4.4, 14.0 Hz,
CHaHb), 4.22 (2H, q, Jˆ7.2 Hz, CH2CH3), 4.34±4.41 (1H,
m, H2), 5.92 (2H, s, H70), 6.64±6.74 (3H, m, H20,50,60); dC
(75 MHz, CDCl3) 14.2 (CH3), 40.2 (CH2CH3), 61.7 (C3),
71.3 (C2), 100.9 (C70), 108.1 (C20), 109.9 (C50), 122.5
(C60), 130.0 (C10), 146.5 (C40), 147.5 (C30), 174.1 (C1);
(Found: M1, 224.0685. C12H14O5 requires [M2CH2]1,
224.0684); m/z (CI) 242 (100%, [M2CH21NH4]1), 225
(20, [M2CH21H]1), 224 (5, [M2CH2]1).
4.2.14. Methyl (2R)-2-hydroxy-3-(40-chlorophenyl)pro-
panoate (5c). This was prepared in the same way as 5b
from 3c/4c to afford 5c as a colourless solid (68 mg,
70%); [a]Dˆ111.6 (c 1.0 in CHCl3); (Found: C, 55.8; H,
5.0; Cl, 16.4. C10H11O3Cl requires C, 56.0; H, 5.2; Cl,
16.5%); Rf 0.40 (silica; CHCl3); nmax (KBr disc) 3250
Acknowledgements
We thank Pharmachemie B. V. for a studentship (to SB)
and the EPSRC for Research Grants (GR/L52246: NMR

N. J. Lawrence, S. Brown / Tetrahedron 58 (2002) 613±619
619
9. Davis, F. A.; Haque, M. S.; Ulatowski, T. G.; Towson, J. C.
J. Org. Chem. 1986, 51, 2402±2404.
spectrometer; GR/L84391: chromatographic equipment).
We thank Dr Alan McGown and Sally Haran, Dee
Whitacker and Tim Ward of the Cell Culture Unit of the
Paterson Institute for Cancer Research for maintaining the
cell lines, and providing valuable assistance during the cell
growth inhibition experiments. We thank Paul Crump for
evaluating the cytotoxicity of the hydroxy esters 5b±e.
10. Jung, J. E.; Ho, H.; Kim, H.-D. Tetrahedron Lett. 2000, 41,
1793±1796.
11. Burk, M. J.; Kalberg, C. S.; Pizzano, A. J. Am. Chem. Soc.
1998, 120, 4345±4353.
12. Kawai, Y.; Hida, K.; Tsujimoto, M.; Kondo, S.; Kitano, K.;
Nakamura, K.; Ohno, A. Bull. Chem. Soc. Jpn 1999, 72, 99±
102.
13. Carpentier, J.-F.; Mortreux, A. Tetrahedron: Asymmetry 1997,
8, 1083±1099.
References
È
14. Huerta, F. F.; Laxmi, Y. R. S.; Backvall, J.-E. Org. Lett. 2000,
2, 1037±1040.
1. a-Hydroxy Acids in Enantioselective Syntheses; Coppola,
G. M., Schuster, H. F., Eds.; VCH: Weinheim, 1997; p 23.
2. Ducki, S.; Had®eld, J. A.; Liu, C.-Y.; Zhang, X.; McGowm,
A. T. Planta Med. 1996, 62, 185±186. Ducki, S.; Had®eld,
J. A.; Hepworth, L. A.; Lawrence, N. J.; Liu, C.-Y.; McGown,
A. T. Bioorg. Med. Chem. Lett. 1997, 7, 3091±3094. Dicki, S.;
Forrest, R.; Had®eld, J. A.; Kendall, A.; Lawrence, N. J.;
McGown, A. T.; Rennison, D. Bioorg. Med. Chem. Lett.
1998, 8, 1051±1056.
15. Brown, S.; Jordan, A. M.; Lawrence, N. J.; Pritchard, R. G.;
McGown, A. T. Tetrahedron Lett. 1998, 39, 3559±3562. Boa,
A. N.; Jenkins, P. R.; Lawrence, N. J. Contemp. Org. Synth.
1994, 1, 47±75.
16. Wang, Z.-M.; Kolb, H. C.; Sharpless, K. B. J. Org. Chem.
1994, 59, 5104±5105.
17. For the related b-bromo-a-benzoyloxy ester see Hu, Z.;
Erhardt, P. W. Org. Process Res. Dev. 1997, 1, 387±390.
18. Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett.
1987, 28, 4435±4436.
3. Markaverich, B. M.; Gregory, R. R.; Alejandro, M. A.;
Kittrell, K. S.; Medina, D.; Clark, J. H.; Varma, M.; Varma,
R. S. Cancer Res. 1990, 50, 1470±1478. (b) Markaverich, B.
M.; Clark, J. H.; Gregory, R.; Alejandro, M.; Middlemitch, B.
S.; Johnson, G. A.; Varma, R. S. International Patent WO89/
00849, 1989.
19. Boyer, I. J. Toxicology 1989, 55, 253±298. Baguley, P. A.;
Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3073±3082.
20. Whilst we were carrying out our study a way to achieve the
reduction of 2,3-dihydroxy esters was reported. The reduction
of racemic cyclic thionocarbonates can be accomplished with
magnesium in ethanol. See Rho, H.-S.; Ko, B.-S. Synth.
Commun. 1999, 29, 2875±2880.
4. Brown, S. PhD Thesis, University of Manchester Institute of
Science and Technology, 1998.
5. For recent synthesis of a-hydroxy acids and esters see: Gaul,
C.; Scharer, K.; Seebach, D. J. Org. Chem. 2001, 66, 3059±
3073. Hao, J.; Hatano, M. Org. Lett. 2000, 2, 4059±4062.
Zhang, M.; Wang, P. G. J. Org. Chem. 2000, 65, 4732±
4735. Chang, J. W.; Jang, D. P.; Uang, B. J.; Liao, F. L.;
Wang, S. L. Org. Lett. 1999, 1, 2061±2063. Lawrence, N. J.;
Lamarche, O.; Thurrab, N. Chem. Commun. 1999, 689±690.
Wang, Z.; La, B.; Fortunak, J. M.; Meng, X.-J.; Kabalka, G. W.
Tetrahedron Lett. 1998, 39, 5501±5504. Evans, D. A.;
Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tegay, S. W.
J. Am. Chem. Soc. 1978, 43, 188±196.
21. Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515±
10530.
22. Fleming, P. R.; Sharpless, K. B. J. Org. Chem. 1991, 56,
2869±2875.
23. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essen®eld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
1984, 25, 2183±2186.
24. Markaverich, B. M.; Gregory, R. R.; Alejandro, M.-J.; Clark,
J. H.; Johnson, G. A.; Middleditch, B. S. J. Biol. Chem. 1988,
263, 7203±7210.
6. Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978,
43, 188±196.
25. Ramage, G. R. J. Chem. Soc. 1938, 397±400.
26. Winkler, T.; Bencze, W. L. Helv. Chim. Acta 1980, 63, 402±
405.
7. Wasserman, H. H.; Lipshutz, B. H. Tetrahedron Lett. 1975,
1731±1734. Konen, D. A.; Silbert, L. S.; Pfeffer, P. E. J. Org.
Chem. 1975, 40, 3253±3258. Moriarty, R. M.; Hu, M.
Tetrahedron Lett. 1981, 22, 2747±2750.
27. Ikeya, Y.; Sugama, K.; Okada, M.; Mitsuhashi, H. Chem.
Pharm. Bull. 1991, 39, 2600±2605.
Â
28. Carda, M.; Murga, J.; Falomir, E.; Gonzalez, F.; Marco, J. A.
Tetrahedron 2000, 56, 677±683.
8. Gamboni, R.; Tamm, C. Helv. Chim. Acta 1986, 69, 615±620.