A highly enantioselective chemoenzymatic synthesis of syn-3-amino-2-hydroxy esters: Key intermediates for taxol side chain and phenylnorstatine

Article abstract of DOI:10.1016/j.tetasy.2005.08.015

Starting from the bromination of α-ketoesters to obtain 3-bromo-2-oxoalkanoates and bioreduction with Saccharomyces cerevisiae entrapped in calcium alginate pellets with double gel layers, syn-(2R,3S)-β-bromo- α-hydroxy esters were obtained regioselectively in high yields and high ee. These chiral bromohydrins were cyclized to epoxides that were transformed into oxazolidines and finally opened by acidic hydrolysis to give syn-(2S,3S)-β-amino-α-hydroxy esters in high overall yields and high ee. The enantiomeric excesses of all the intermediates were maintained during the reaction sequence.

Full text of DOI:10.1016/j.tetasy.2005.08.015

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3099–3106
A highly enantioselective chemoenzymatic synthesis of
syn-3-amino-2-hydroxy esters: key intermediates for
taxol side chain and phenylnorstatine
J. Augusto R. Rodrigues,* Humberto M. S. Milagre,
´
Cıntia D. F. Milagre and Paulo J. S. Moran
State University of Campinas, Institute of Chemistry, CP 6154, 13084-971 Campinas-SP, Brazil
Received 20 July 2005; accepted 12 August 2005
Available online 8 September 2005
Abstract—Starting from the bromination of a-ketoesters to obtain 3-bromo-2-oxoalkanoates and bioreduction with Saccharomyces
cerevisiae entrapped in calcium alginate pellets with double gel layers, syn-(2R,3S)-b-bromo-a-hydroxy esters were obtained regio-
selectively in high yields and high ee. These chiral bromohydrins were cyclized to epoxides that were transformed into oxazolidines
and finally opened by acidic hydrolysis to give syn-(2S,3S)-b-amino-a-hydroxy esters in high overall yields and high ee. The enan-
tiomeric excesses of all the intermediates were maintained during the reaction sequence.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
KRI 1314,8 and some inhibitors of FIV and HIV prote-
ases.9 Herein, we report the preparation of 3-bromo-2-
ketoalkanoates and their bioreduction with Saccharo-
myces cerevisiae to obtain the corresponding (2S,3S)-3-
bromo-2-hydroxyalkanoates with high ee and yields,
followed by a highly efficient transformation to syn-
(2R,3S)-3-acylamino-2-hydroxyalkanoates. Earlier, two
groups have reported yeast catalyzed reductions of
a-ketoesters to produce chiral a-hydroxy esters to use
in a sequence route to obtain the Taxol side chain.10
However, the overall yields were both inferior to these
from the procedure described herein and they are not
of general applicability to allow the preparation of other
analogues, such as phenylnorstatine.
In recent years, the enantioselective syntheses of b-ami-
no-a-hydroxy acids, amides and esters have attracted
much attention not only because of the synthetic interest
but mainly due to their presence in various medicinally
important molecules.1 The importance of Taxol,2
a
complex diterpene, in cancer therapy is well established.3
Initially, its only source was from the bark of the pacific
yew tree, Taxus brevifolia, which cannot be considered a
renewable resource because of its slow growth and,
therefore, the supply of Taxol was quite limited. On
the other hand, the key terpenoid fragment 10-deacetyl-
baccatin III (10-DAB) is readily obtained from a rapidly
renewable resource, the yew bush: Taxus baccata.4 Since
the initial work by Potier,5 a number of methods have
been developed to convert 10-DAB to Taxol, all of
which rely on the coupling of a protected phenylisoseri-
nate to a 7-protected baccatin derivative.6 As the side
chain is not readily available from natural sources, its
sole supply is from chemical synthesis. While several ap-
proaches have been published, only a few examples are
enzyme-resolution-based syntheses.7 b-Amino-a-hydro-
xy acid derivatives are also found in a renin inhibitor
for hypertension, as a transition state mimics, including
2. Results and discussion
Bromination of ethyl 2-oxophenylbutanoate 1b was
carried out with a solution of bromine in chloroform at
room temperature for 3 h to give ethyl 3-bromo-2-oxo-
butanoate 2b as a yellow oil in 97% yield, after purifica-
tion by silica gel column chromatography. The
bromination procedure was extended to a-ketoesters
1a, 1c, and 1d to obtain the bromo derivatives in high
yields (Scheme 1). Bioreduction of 3-bromo-2-oxoalk-
anoates 2a–d was carried out by S. cerevisiae entrapped
in calcium alginate pellets with double gel layers under
*
Corresponding author. Tel.: +55 19 3788 3141; fax: +55 19 3788
3023; e-mail: jaugusto@iqm.unicamp.br
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.015

3100
J. Augusto R. Rodrigues et al. / Tetrahedron: Asymmetry 16 (2005) 3099–3106
OH
O
O
R
R
R
a
b
CO2Et
CO2Et
CO2Et
Br
Br
2a 98%
2b 95%
2c 98%
2d 98%
1a : R = C6H5
3a 40%, ee > 99%
3b 70%, ee = 96%
3c 74%, ee > 99%
3d 70%, ee > 99%
1b : R = CH2C6H5
1c : R = CH2CH(CH3)2
1d : R = n-C4H9
c
H
CO2Et
OH
O
e
d
R
R
N
H
CO2Et
O
R
CO2Et
HN
R1
R1
O
6a R1 = C6H5, 98%, ee > 99%
6b R1 = CH3, 95%, ee = 96%
6c R1 = CH3, 98%, ee > 99%
5a R1 = C6H5, 98%
5b R1 = CH3, 95%
5c R1 = CH3, 98%
4a 86%, ee > 99%
4b 90%, ee = 96%
4c 93%, ee > 99%
Scheme 1. Reagents and conditions: (a) Br2, CHCl3, room temp, 1 h; (b) S. cerevisiae entrapped in Ca-alginate pellets with double gel layers, pH 4,
30 ꢁC, 24 h; (c) K2CO3, EtOH, 12h; (d) BF 3ÆEt2O, R1CN (R1 = C6H5 or CH3), room temp, 3 h; (e) (i) HCl–MeOH, 1.5 h; (ii) NaHCO3, 16 h.
Table 1. Bioreduction of ethyl 3-bromo-2-oxoalkanoates mediated by Saccharomyces cerevisiae entrapped in calcium alginate pellets with double gel
layers
20
D
Compound
Yield (%)
Ratio
ee%
½aŠ
syn/anti
syn
anti
syn
anti
2aa
2bb
2cb
2db
40
8285/15
87
100/0
96
90/10
75/25
>99
99
>99
>99
—
+42.0
ꢀ16.8
+3.8
ꢀ18.1
ꢀ18.8
+6.4
+3.6
>99
>99
93
Reagents and conditions: (a) S. cerevisiae (30 g), buffer citrate, pH 4 (400 mL, 0.5 mol Lꢀ1), substrate (2.2 mmol), glucose (30 g), agitated for 24 h;
after each 6 h more glucose (6 g) was added; (b) S. cerevisiae (5 g), buffer citrate, pH 4 (400 mL, 0.5 mol Lꢀ1), substrate (2.2 mmol), glucose (8 g);
after every 6 h more glucose (1.6 g) was added.
OH
OH
optimized conditions to give the syn-bromo alcohols as
major compounds in excellent ee (Table 1).
CO2Et
CO2Et
Cl
Cl
Screenings of several fungi and bacteria were carried out
in order to find an ideal biocatalyst for the bioreduction.
From them, we chose S. cerevisiae due to the ease of
use and the high regio- and diastereoselectivity of the
desired syn-product. The relative configuration of syn-
2b was established by comparison with the known ethyl
(2S,3S)-3-chloro-2-hydroxy-4-phenylbutanoate11 while
the absolute configuration was determined by hydrogen-
olysis with H2 in the presence of Pd/C 5% of the syn-3b
to give the known ethyl (ꢀ)-(2R)-2-hydroxy-4-phenyl-
butanoate 8 in 95% yield {[a]20 = ꢀ32.5 (c 2.0, CHCl3)}
(Scheme 2).12 Bioreduction of ethyl 3-chloro-2-oxobut-
anoate by S. cerevisiae entrapped in alginate pellets with
double gel layers gave ethyl (2S,3S)-3-chloro-hydroxy-
butanoate 7 (85% ee) and its epimer, the (2S,3R)-deriv-
7a
7
OH
OH
H2- Pd/C
AcONa-EtOH
CO2Et
CO2Et
Br
syn-3b
8
Scheme 2.
NMR values matched those reported in the literature11)
and by extension for 3a, 3c, and 3d.
1
ative 7a (>99% ee; ratio 7/7a = 30:70) in 85% yield. H
Attempts to substitute the bromide of bromohydrin 3b
by azide to obtain the corresponding azido alcohol to
be reduced in the sequence to the amino alcohol were
unproductive. The isolated product was always the
2,3-epoxyester 4b, independent of the azide, solvent,
and temperature (10–50 ꢁC) used. Also unsuccessful
NMR coupling constants for 2-H and 3-H for syn-7 (d
4.44, J2,3 = 1.8 Hz) and anti-7a (d 4.24, J2,3 = 2.6 Hz)
have the same H as for syn-3b (d 4.50, J2,3 = 1.8 Hz)
and anti-3b (d 4.46, J2,3 = 2.6 Hz), confirming the pro-
posed absolute configuration for 3b (1H NMR and 13C

J. Augusto R. Rodrigues et al. / Tetrahedron: Asymmetry 16 (2005) 3099–3106
3101
OH
was the substitution of the bromo with an azide in
O
alcohol 3b protected with ethyl chloroformate. To over-
come these difficulties in preparing the azidoalcohol, we
decided to study a route via the epoxide. After many
attempts with different bases, such as KOH, KOH/tetra-
butylammonium chloride, NaOEt in EtOH and NaH,
the most successful procedure was with ethanol in
K2CO3 at room temperature for 12h, which gave the
2,3-epoxide 4 in high yield (Scheme 1). The configura-
tion of cis-4b was established by comparison of the cou-
pling constant J2,3 = 4.8 Hz for H-2at d 3.58 ppm with
similar data reported by Hoffman et al. for the racemic
compound.13
BF3.Et2O/TMSN3
CH2Cl2, rt
CO2Et
CO2Et
Bn
N3
4b
9
δ+
BF3
H
OH
R1CN
BF3OEt2
δ
O
–
O
H
H
H
R
R
CO2Et
R
CO2Et
R1
CO2Et
N
4a-c
CR1
N
C
a: R1 = C6H5
b: R1 = CH3
H
CO2Et
R
H
O
Two methodologies were evaluated to obtain b-amino-
a-hydroxy ester. Initially, we opened the epoxyester 4b
by employing a procedure developed by Behrens and
Sharpless14 using NaN3/NH4Cl, with a modification of
the solvent mixture changing from dimethoxyethane to
reflux for 5 h in ethanol–water, which has a lower bp
in order to preserve the azide integrity. Azido alcohol
9 was obtained in 80% yield with a minor isomer, ethyl
2-azido-3-hydroxy-4-phenylbutanoate (identified by
GC–MS), which we were unable to purify. Considering
that Lewis acids have been used to open epoxyamides14
and epoxyalcohols,15 we employed TMSN3 in the pres-
ence of boron trifluoride–diethyl etherate in dichloro-
methane at room temperature for 3 h to give 9 in 90%
yield. The cis-configuration of 9 was established by com-
parison of the coupling constant J2,3 = 1.8 Hz for H-2at
d 4.10 ppm, which is consistent with the data reported
by Hoffman et al. for the racemic compound.13 Pearson
and Hines reduced the azido with H2 in the presence of
Pd/C to obtain the corresponding amino alcohol in 86%
yield after 48 h. This product is an advanced intermedi-
ate for the synthesis of (ꢀ)-bestatin.16 For the synthesis
of aliphatic b-amino-a-hydroxy carboxylic esters such as
6c, the pathway via azido alcohols, obtained by reaction
of oxiranecarboxylic esters with azide ions, cannot be
used because of a lack of regioselectivity of this epoxide
opening.17 In the search for an alternative approach, we
employed the procedure developed by Zwanenburg,
which converted the oxiranecarboxylic esters into oxaz-
oline-5-carboxylic esters by a Ritter-type reaction with
acetonitrile or benzonitrile.18 Treatment of 4b with ace-
tonitrile in the presence of 2equiv of boron trifluoride
etherate at room temperature for 3 h produced oxazo-
line 5b in 95% yield. The same reaction with 4c gave
oxazoline 5c in 98% yield. Changing acetonitrile for
benzonitrile, and employing the same conditions, we
isolated oxazoline 5a in 98% yield from epoxide 4a.
The structures of oxazolines 5 were established on the
N
R1
5a-c
Scheme 3.
Successful ring opening of the oxazolines was obtained
using oxalic acid in boiling ethanol22 and HCl in reflux-
ing methanol.19 To avoid loss of stereochemical integ-
rity, we used less harsh conditions avoiding high
temperatures. Treatment of oxazolines with HCl in
methanol at 25 ꢁC for 1.5 h gave the amino alcohols 6
in good yields (>95%) and excellent ee (>96%). The ring
opening is an easy process since chloroform solutions of
the oxazolines spontaneously evolved into the N-acetyl-
aminohydroxy derivatives in one week at 25 ꢁC. The
structures of 6 were established on the basis of their
1H NMR spectra. The coupling constants of C2-H
and C3-H of ca. 2Hz are reliable evidence for the cis-
relationships of these hydrogens. It should be noted that
the enantiomeric excesses of 6a–c were maintained dur-
ing the reaction sequence from bromohydrins, since they
are identical to 3a–c.
The easy accessibility of both masked syn-b-amino-a-
hydroxy esters 5a–c and the N-acetyl protected syn-b-
amino-a-hydroxy ester 6a–c, formed by the present
enantioselective a-amination methodology, shows the
applicability of this sequence. These syn-b-amino-a-hy-
droxy ester fragments are present in many different
important compounds of pharmaceutical interest, such
as the renin inhibitor KRI 1314, inhibitors of FIV and
HIV proteases, and the side chain of Taxol analogues.23
Other reports24 have used oxazoline intermediate 5a to
prepare the Taxol side chain, but most did not prepare
it directly by the epoxide intermediate 4a, which makes
these routes longer. Others have employed the epoxide
4a, but did not transform it directly to 6a via oxazoline
5a,25 which also increases the number of steps, when
compared with the sequence described herein.
1
basis of their H NMR spectra. The coupling constants
of C4-H and C5-H of 6.6 Hz are reliable evidence for the
trans relationships of these hydrogens as demonstrated
by Botta19 and Tasic.20 No trace of cis-oxazoline could
be detected. The spectra revealed that the nitrile had
reacted regioselectively at C3 of the epoxide. The mech-
anistic pathway to the ring expanded products has been
proposed by Zwanenburg18 and also by Wohl.21 Initial
opening of the epoxide by the nitrile at C3 in an SN2
fashion produced a nitrilium ion that undergoes an
intramolecular ring closure reaction (Scheme 3).
3. Conclusion
In conclusion, we have developed a highly enantioselec-
tive route to 3-amino-2-keto esters by a biocatalytic

3102
J. Augusto R. Rodrigues et al. / Tetrahedron: Asymmetry 16 (2005) 3099–3106
asymmetric reduction of 3-bromo-2-keto esters. The
reaction gives an easy entry to optically active masked
syn-(2R,3S)-3-amino-2-hydroxy esters in high overall
yield and excellent ee.
4.1.4. Ethyl 3-bromo-2-oxoheptanoate 2d. Pale yellow
1
oil, 95% yield; H NMR values matched those reported
in the literature.27
4.2. General procedure for the reduction mediated by
S. cerevisiae entrapped in calcium alginate pellets of
double gel layers
4. Experimental
All reagents and solvents were obtained from commer-
cial sources. Ethyl acetate, hexane, and chloroform were
distilled under argon before use. The solvents, dichloro-
methane and methanol, were distilled under argon from
suspensions over calcium hydride and calcium oxide,
respectively. Acetonitrile was distilled from calcium
hydride and benzonitrile was dried over molecular
sieves. Thin layer chromatographic (TLC) analyses were
performed with precoated aluminum sheets (silica gel 60
Merck), while flash column chromatography was carried
out on silica (200–400 mesh, Merck). IR spectra were
recorded on a FT-IR BOMEM MB-100 from Hartmann
To a suspension of S. cerevisiae (5 g) in distilled water
(50 mL) was added a 3% solution of sodium alginate
and the mixture extruded using syringe nozzles with
inner diameters of 1.0 mm to a solution of CaCl2
(0.2mol L ꢀ1) to give beads with 3 mm diameter. After
20 min, the beads were filtered and surface dried, using
filter papers. Afterwards, the calcium alginate beads
were transferred into 400 mL of stirred 1.5% sodium
alginate. After 20 min, the beads were sieved, washed
with water, and hardened for 2h in a solution of CaCl 2
(0.2mol L ꢀ1). The beads with double gel layers
were washed with water to remove excess CaCl2. In
a 500 mL bioreactor, the beads were suspended in
citrate–phosphate buffer (300 mL, pH 4.0) containing
glucose (8 g) and stirred at 300 rpm at 30 ꢁC. After
activation of the yeast for 2h, the pH of the medium
was adjusted with a 10% solution of NH4OH and the
substrates 2a–d (2.2 mmol in 5.0 mL of ethanol), then
slowly added over 10 h, with stirring. Every 6 h, glucose
(1.6 g) was added. The reaction was monitored by GC–
MS and, at the end of the reaction (24 h), the beads were
filtered, washed with ethyl acetate, and the reaction mix-
ture extracted with ethyl acetate, dried over anhydrous
MgSO4, then filtered, and evaporated. The crude mate-
rial was purified by flash chromatography and eluted
with 20% of ethyl acetate in hexane.
1
and Braun. H NMR spectra were determined at 300
(Varian Gemini 300) or 500 MHz (INOVA-500), and
13C NMR spectra were determined at 75.5 MHz (Varian
Gemini 300) or 125.7 MHz (INOVA 500). Chemical
shifts are reported in parts per million relative to tetra-
methylsilane (TMS) in CDCl3. Gas chromatographic
analyses and mass spectra were obtained on a QP
5000-SHIMADZU or an AGILENT GC 6890/HEW-
LETT PACKARD 5973, equipped with a J&W Scien-
tific HP-5 (5% phenylmethylpolysiloxane, 30.0 m ·
250 lm · 0.25 lm) column. Gas chromatographic
analyses of reaction mixture samples were made after
evaporation and dilution with ethyl acetate. High-reso-
lution mass spectra were determined on a VG AUTO
SPEC from Micromass. Optical rotations were mea-
sured with a Perkin Elmer Polarimeter 341. Melting
points were measured on a Microquimica MQ APF-
301 apparatus.
4.2.1. Ethyl (2S,3S)-3-bromo-2-hydroxyphenylpropano-
20
ate 3a. White solid, mp 84–87 ꢁC. ½aŠ ¼ þ42.0 (c
D
1.3, CHCl3); IR (film) mmax: 3503, 2946, 2919, 2890,
1717, 1450, 1361, 1284, 1250, 1025 cmꢀ1; MS m/z (%):
272 (1), 254 (10), 228 (1), 201 (3), 193 (30), 169 (52),
4.1. Bromination of 2-ketoesters
1
119 (48), 103 (10), 91 (100), 77 (8), 65 (11), 51 (8); H
A solution of 2-oxoketoesters 1a–c (24.2 mmol) in
chloroform (7 mL) was added slowly to a solution of
bromine in carbon tetrachloride (1.06 mol Lꢀ1) until
the color of the solution became red-orange. The excess
of bromine was destroyed with a saturated sodium thio-
sulfate solution and the reaction mixture was extracted
with ethyl acetate, dried over anhydrous MgSO4, then
filtered, and evaporated. The crude material was purified
by flash chromatography and eluted with 20% ethyl ace-
tate in hexane.
NMR (300 MHz, CDCl3): d 1.33 (3H, t, J 7.3 Hz),
4.33 (2H, m), 4.46 (1H, dd, J 2.2 and 7.3 Hz, H-3),
5.37 (1H, d, J 2.3 Hz, H-2), 7.32 (5H, m, aromatic);
13C NMR (75 MHz, CDCl3): d 14.8 (CH3), 56.3 (CH,
C-3), 63.2(CH 2), 74.8 (CH, C-2), 128.9 (CH, aromatic),
130.0 (2CH, aromatic), 130.1 (CH, aromatic), 133.5 (C,
C-4), 160.3 (C@O); HRMS: calcd for C11H13BrO3:
272.00481; found: 271.99918.
4.2.2. Ethyl (2S,3S)-3-bromo-2-hydroxyphenylbutanoate
20
3b. Colorless oil, ½aŠ ¼ ꢀ16.8 (c 2.1, CHCl3); IR
D
4.1.1. Ethyl 3-bromo-2-oxophenylbutanoate 2a. Pale
(film) mmax: 3503, 3066, 3027, 2983, 2929, 1732, 1596,
1499, 1455, 1367, 1256, 1110, 1017, 740, 701 cmꢀ1; MS
m/z (%): 206 (2), 189 (15), 177 (1), 161 (5), 143 (15),
133 (51), 115 (66), 91 (100), 77 (15), 55 (20), 51 (15);
1H NMR (300 MHz, CDCl3): d 1.29 (3H, t, J 7.1 Hz,
H-12), 3.32 (2H, m, H-4), 4.14 (1H, d, J 1.8 Hz, H-2),
4.26 (2H, m, H-11), 4.50 (1H, dt, J 1.8 and 8.1 Hz, H-
2), 7.26 (5H, m, aromatic); 13C NMR (75 MHz, CDCl3):
d 14.8 (CH3), 42.4 (CH2, C-4), 56.9 (CH, C-3), 62.9
(CH2, OCH2), 71.5 (CH, C-2), 127.6 (CH, aromatic),
129.1 (2CH, aromatic), 129.7 (2CH, aromatic), 138.0
1
yellow oil, 97% yield; H NMR values matched those
reported in the literature.26
4.1.2. Ethyl 3-bromo-2-oxophenylpropanoate 2b. Pale
1
yellow oil, 95% yield; H NMR values matched those
reported in the literature.27
4.1.3. Ethyl 3-bromo-5-methyl-2-oxohexanoate 2c. Pale
1
yellow oil, 95% yield; H NMR values matched those
reported in the literature.27

J. Augusto R. Rodrigues et al. / Tetrahedron: Asymmetry 16 (2005) 3099–3106
3103
(C, aromatic), 172.2 (C@O). HRMS: calcd for
matic); 13C NMR (75 MHz, CDCl3): d 14.6 (CH3, C-
11), 57.2 (CH, C-3), 58.3 (CH, C-2), 62.2 (CH2, aro-
matic), 126.3 (CH, aromatic), 129.1 (2CH, aromatic),
129.4 (CH, aromatic), 135.4 (C, aromatic), 168.6
(C@O).
C12H15BrO3: 286.02046; found: 286.02051.
4.2.3.
(2S,3S)-3-Bromo-2-hydroxy-5-methylhexanoate
20
3c. Colorless oil, ½aŠ ¼ þ3.8 (c 1.5, CHCl3); IR (film)
D
m
max: 3430, 2958, 2908, 2820, 1733, 1027 cmꢀ1; MS m/z
(%): 181 (21), 173 (5), 163 (17), 155 (36), 99 (55), 81
(100), 69 (18), 57 (60); H NMR (300 MHz, CDCl3): d
0.90 (3H, d, J 7.3 Hz, H-6), 0.97 (3H, d, J 7.3 Hz, H-
7), 1.33 (3H, m, H-9), 1.4–2.3 (3H, m, H-4 and H-5),
3.16 (1H, d, J 7.3 Hz, OH), 4.22 (2H, dd, J 1.8 and
7.3 Hz, H-2), 4.32 (2H, m, H-8), 4.42 (ddd, 1H, J 1.8,
5.2, and 10.1 Hz, H-3); 13C NMR (75 MHz, CDCl3): d
4.3.2. Ethyl (2R,3R)-4-phenyl-2,3-oxiranebutanoate
20
1
4b. Pale yellow oil, ½aŠ ¼ þ4.2( c 0.9, CHCl3); IR
D
(film) mmax: 3458, 3062, 3028, 2930, 1733, 1603, 1496,
1455, 1379, 1253, 1197, 1094, 1031, 701, 697 cmꢀ1; MS
m/z (%): 206 (2), 188 (1), 177 (5), 161 (3), 143 (15),
133 (100), 115 (33), 103 (33), 91 (40), 77 (35), 65 (20);
1H NMR (300 MHz, CDCl3): d 1.32(3H, t, J 7.3 Hz),
2.90 (1H, dd, J 6.6 and 14.6 Hz, H-4), 3.10 (1H, dd, J
6.5 and 14.3 Hz, H-4), 3.38 (1H, td, J 6.6 and 4.8 Hz,
H-3), 3.58 (1H, d, J 4.8 Hz, H-2), 4.30 (2H, q, J
7.3 Hz, aromatic), 7.23 (5H, aromatic); 13C NMR
(75 MHz, CDCl3): d 14.3 (CH3), 33.8 (CH2, C-4), 52.8
(CH, C-3), 57.7 (CH, C-2), 61.6 (CH2), 126.8 (CH, aro-
matic), 128.7 (2CH, aromatic), 128.9 (2CH, aromatic),
136.5 (C, aromatic), 168.2(C @O).
14.2(CH , C-9), 21.4 (CH3, C-7), 22.6 (CH2, C6), 26.1
3
(CH2, C-5), 44.1 (CH2, C-4), 55.9 (CH, C-3), 62.4
(CH2, C-8), 73.1 (CH, C-2), 171.8 (C@O). HRMS: calcd
for C9H17BrO3: 252.03611; found: 252.03605.
4.2.4.
Ethyl
(2S,3S)-3-bromo-2-hydroxyoctanoate
20
3d. Colorless oil, ½aŠ ¼ ꢀ18.1 (c 1.6, CHCl3); IR
D
(film) mmax: 3440, 2958, 2908, 2890, 2820, 1737,
1055 cmꢀ1; MS m/z (%): 207 (2), 181 (30), 163 (18),
155 (52), 127 (15), 99 (35), 81 (100), 75 (12), 57 (61);
1H NMR (300 MHz, CDCl3): d 0.93 (3H, t, J 7.3 Hz,
H-7), 1.31 (7H, m, H-5, H-6, and H-9), 1.30–2.00 (4H,
m, H-4 and H-6), 4.20–4.40 (2H, m, H-2 and H-3),
4.27 (2H, q, J 7.2Hz, H-8); 13C NMR (75 MHz,
CDCl3): d 13.9 (CH3, C-9); 14.1 (CH3, C-7), 22.1
(CH2, C6), 29.9 (CH2, C-5). 35.4 (CH2, C-4); 57.5
(CH, C-3), 62.4 (CH2, C-8), 72.8 (C-2), 171.9 (C@O).
HRMS: calcd for C9H17BrO3: 252.03611; found:
252.03604.
4.3.3. Ethyl (2R,3R)-5-methyl-2,3-oxirane-hexanoate
20
4c. Colorless oil, ½aŠ ¼ ꢀ3.0 (c 1.0, CHCl3); IR (film)
D
m
max: 2953, 2949, 2920, 1752, 1183, 1016 cmꢀ1; MS m/z
(%): 157 (15), 144 (12), 139 (1), 129 (20), 115 (50), 99
(45), 85 (100), 81 (42), 69 (90), 55 (60); 1H NMR
(300 MHz, CDCl3): d 0.94 (3H, d, J 7.3 Hz, H-6), 0.99
(3H, d, J 7.3 Hz, H-7), 1.31 (3H, m, H-9), 1.33–1.87
(3H, m, H-4 and H-5), 3.19 (1H, m, H-3), 3.51 (2H, d,
J 4.7 Hz, H-2), 4.27 (2H, q, J 7.2Hz, H-8); 13C NMR
(75 MHz, CDCl3): d 14.6 (CH3, C-9), 22.6 (CH3, C-7),
23.1 (CH2, C6), 26.7 (CH2, C-5), 36.2(CH , C-4), 53.1
2
4.2.5. Ethyl 3-chloro-2-hydroxy-4-phenylbutanoates 7a
and 7b. The reduction of 3-chloro-2-oxo-4-phenylbut-
anoate was carried out by the procedure described
above for 2a–d. The crude products were separated by
flash chromatography and eluted with hexane/ethyl
(CH, C-3), 53.1 (CH, C-2), 61.8 (CH2, C-8), 168.8
(C@O). HRMS: calcd for C9H16O3: 172.10995; found:
172.10975.
4.4. General procedure to obtain 4,5-dihydrooxazoles
5a–c
1
acetate (5:1). IR and H NMR values matched those
reported in the literature for 7a and 7b.11
To a solution of oxiranes 4a–c (0.3 mmol) in anhydrous
acetonitrile or benzonitrile (1 mL) under argon was
added BF3ÆEt2O (0.2mL) and the reaction kept at room
temperature for 4 h. The solvent was evaporated and the
residue dissolved with ether (5 mL) and neutralized with
a 10% solution of sodium bicarbonate. The organic
phase was dried over anhydrous MgSO4, filtered, and
the solvent evaporated. The crude product was purified
by flash chromatography and eluted with 15% ethyl ace-
tate in hexane.
4.3. General procedure to obtain the oxiranes 4a–c
To a 50 mL double-necked round bottomed flask with a
CaCl2 drying tube were added bromohydrin
3
(0.3 mmol), dry ethanol (10 mL), and potassium carbon-
ate (0.58 g, 0.42mmol). After 2.5 h, K 2CO3 (30 mg) was
added and the reaction kept at room temperature for
7 h. Water (100 mL) was then added and the reaction
extracted with ethyl acetate. The organic phase was
dried over anhydrous MgSO4, filtered, and the solvent
evaporated. The crude product was purified by flash
chromatography and eluted with 20% ethyl acetate in
hexane.
4.4.1. Ethyl (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-
20
carboxylate 5a. Brown oil, ½aŠ ¼ þ20.0 (c 1.0,
D
CHCl3); IR (film) mmax: 3017, 3005, 2958, 2923, 2222,
1752, 1654, 1455, 1361, 1016, 970 cmꢀ1; MS m/z (%):
222 (100), 194 (11), 193 (66), 166 (4), 165 (15), 145 (2),
132 (2), 119 (20), 105 (72), 89 (93), 91 (89), 77 (70), 65
(50), 51 (60); 1H NMR (300 MHz, CDCl3): d 1.35
(3H, t, J 7.3 Hz), 4.33 (2H, m), 4.88 (1H, d, J 6.6 Hz,
H-4), 5.43 (1H, d, J 6.6 Hz, H-5), 7.24 (10H, m, aro-
matic); 13C NMR (75 MHz, CDCl3): d 14.6 (CH3),
62.3 (CH2), 73.9 (CH, C-4), 75.1 (CH, C-5), 126.9–
133.1 (CH, aromatic), 141.0 (C, aromatic), 170.6 (C,
4.3.1. Ethyl (2R,3R)-3-phenyl-2,3-oxiranepropanoate
20
4a. Colorless oil, ½aŠ ¼ þ15.0 (c 1.8, CHCl3); IR (film)
D
mmax
: 3015, 2978, 2951, 2919, 2880, 1733, 1455,
1361, 1046 cmꢀ1; MS m/z (%): 192(12), 176 (8), 146
(14), 135 (85), 118 (39), 107 (46), 91 (100), 79 (42), 65
(19), 55 (11); 1H NMR (300 MHz, CDCl3): d 1.02
(3H, t, J 7.3 Hz), 3.83 (1H, d, J 4.8 Hz, H-3), 4.11
(2H, m), 4.27 (1H, d, J 4.8 Hz, H-2), 7.24 (5H, m, aro-

3104
J. Augusto R. Rodrigues et al. / Tetrahedron: Asymmetry 16 (2005) 3099–3106
heterocyclic), 178.1 (C@O). HRMS: calcd for
C18H17NO3: 295.12084; found: 295.12071.
139.2(C, aromatic), 167.1 (C, C @O), 173.3 (C, C@O).
HRMS: calcd for: C18H19NO4: 313.13141; found:
313.13139.
4.4.2. Ethyl (4S,5R)-4-benzyl-2-methyl-4,5-dihydrooxaz-
20
D
ole-5-carboxylate 5b. Brown oil, ½aŠ ¼ ꢀ14.5 (c 1.3,
4.5.2. Ethyl (2R,3S)-3-acetylamino-2-hydroxy-4-phenyl-
110–114 ꢁC,
CHCl3); IR (film) mmax: 2923, 1774, 1759, 1738, 1496,
1455, 1367, 1247, 1220, 701, 698 cmꢀ1; MS m/z (%):
247 (3), 206 (5), 188 (1), 174 (10), 156 (42), 144 (5),
133 (10), 112 (20), 103 (10), 84 (100), 77 (20), 65 (20),
butanoate
6b. White
solid,
mp
20
½aŠ ¼ ꢀ38.0 (c 1.3, CHCl3); IR (film) mmax: 3346,
D
2923, 1774, 1759, 1738, 1496, 1455, 1367, 1247, 1220,
701, 698 cmꢀ1; MS m/z (%): 247 (3), 206 (5), 188 (1),
174 (10), 156 (42), 144 (5), 133 (10), 112 (20), 103 (10),
84 (100), 77 (20), 65 (20), 43 (33); 1H NMR
(300 MHz, CDCl3): d 1.25 (3H, t, J 7.1 Hz), 2.02 (3H,
s), 2.93 (1H, m, H-4), 3.40 (1H, d, J 3.7 Hz, OH), 4.07
(br s, 1H, H-2), 4.37 (2H, m), 4.60 (1H, m, H-3), 5.84
(1H, d, J 9.2Hz, NH), 7.30 (5H, m, aromatic); 13C
NMR (75 MHz, CDCl3): d 14.2(CH 3), 14.4 (CH3),
42.0 (CH2, C-4), 62.3 (CH2), 72.9 (CH, C-3), 80.7
(CHOH, C-2), 129.7 (CH, C-8), 128.3 (2CH, aromatic),
130.1 (2CH, aromatic), 137.8 (C, aromatic), 169.9
(C@O, C-13), 174.2(C @O, C-1). HRMS: calcd for
C14H19NO4: 265.13141; found: 265.13242.
1
43 (33); H NMR (300 MHz, CDCl3): d 1.18 (3H, t, J
7.3 Hz), 2.02 (3H, s, H-1), 2.84 (1H, dd, J 14.0 and
7.0 Hz), 3.05 (1H, dd, J 14.0 and 7.0 Hz), 4.11 (2H, q,
J 7.0 Hz), 4.40 (1H, m, H-5), 4.51 (1H, d, J 6.6 Hz, H-
5), 7.23 (5H, m, aromatic); 13C NMR (75 MHz, CDCl3):
d 14.2(CH ), 14.4 (CH3, C-1), 42.0 (CH2), 62.3 (CH2),
3
72.9 (CH, C-4), 80.7 (CH, C-5), 129.7 (CH, C-11),
128.3 (2CH, aromatic), 130.1 (2CH, aromatic), 137.8
(C, heterocyclic), 171.4 (C@O). HRMS: calcd for
C14H17NO3: 247.12084; found: 247.12088.
4.4.3. Ethyl (4S,5R)-4-isopropyl-2-methyl-4,5-dihydroox-
20
D
azole-5-carboxylate 5c. Brown oil, ½aŠ ¼ ꢀ3.2( c
1.6, CHCl3); IR (film) mmax: 2963, 2920, 2880, 1808,
1732, 1016 cmꢀ1; MS m/z (%): 213 (1), 198 (7), 184
(1), 170 (5), 156 (100), 140 (40), 129 (13), 115 (16), 98
(8), 84 (85), 68 (46), 55 (15); 1H NMR (300 MHz,
CDCl3): d 0.98 (6H, m, H-8 and H9), 1.30 (3H, t, J
7.0 Hz, H-12), 1.32–1.99 (3H, m, H-6 and H-7), 2.05
(3H, s, H-1), 4.1 (1H, m, H-4), 4.2(2H, m, H-11), 4.42
(2H, d, J 6.6 Hz, H-5); 13C NMR (75 MHz, CDCl3): d
4.5.3. Ethyl (2R,3S)-3-acetylamino-2-hydroxy-5-methyl-
20
hexanoate 6c. Colorless oil, ½aŠ ¼ þ13.0 (c 1.6,
D
CHCl3); IR (film) mmax: 3335, 2991, 2924, 2820, 1810,
1728, 1203 cmꢀ1; EM m/z (%): 86 (100), 216 (1), 207
(1), 198 (1), 174 (3), 158 (10), 128 (60), 116 (9), 86
(100), 60 (10); 1H NMR (300 MHz, CDCl3): d 0.97
(6H, d, J 6.7 Hz, H-6 and H7), 1.32(3H, t, J 7.1 Hz,
H-9), 1.33–2.21 (3H, m, H-4 and H-5), 1.97 (3H, s, H-
11), 4.18 (1H, d, J 2.5 Hz, H-2), 4.22 (2H, q, J 7.1 Hz,
H-8), 4.44 (2H, m, H-3), 5.63 (1H, d, J 6.8 Hz, H-12);
13C NMR (75 MHz, CDCl3): d 14.1 (CH3, C-9),
22.3 (CH3, C-6 and C-7), 22.8 (CH3, C-11), 24.8 (CH2,
C-5), 41.1 (CH2, C-4), 49.6 (CH, C-3), 62.4 (CH2, C-8),
72.2 (CH, C-2), 169.6 (C, C@O), 173.4 (C, C@O).
HRMS: calcd for C11H21NO4: 231.14706; found:
231.14700.
14.2(CH ), 14.5 (CH3, C-8 and C-9), 22.8 (CH3, C-1),
3
25.2 (CH2, C-7), 46.2(CH 2, C-6), 62.0 (CH2), 70.3
(CH, C-4), 81.6 (CH, C-5), 164.1 (heterocyclic), 171.0
(C@O). HRMS: calcd for C11H19NO3: 213.13649;
found: 213.13632.
4.5. General procedure to obtain the (2R,3S)-3-amino-2-
hydroxyalkanoates 6a–c
To a stirred solution of HCl (0.5 mol Lꢀ1, 10 mL) were
added 4,5-dihydrooxazole-5-carboxylate (0.84 mmol)
5a–c and the solution was kept for 1.5 h at room temper-
ature. Then, a saturated solution of NaHCO3 was added
to pH 9 and the solution stirred overnight. The reaction
product was extracted with dichloromethane (3 ·
20 mL) and the organic phase dried over anhydrous
MgSO4, filtered, and the solvent evaporated. The crude
product was purified by recrystallization in hexane
(3 mL) with 5% ethyl acetate to give white crystals.
4.5.4. (ꢀ)-(2R)-2-Hydroxy-4-phenylbutanoate 8. To a
solution of 3b (182mg, 0.7 mmol) in anhydrous ethanol
(3 mL) were added under argon sodium acetate (57 mg,
0.7 mmol) and 5% palladium on carbon (16 mg). After
stirring for 2h at room temperature, the reaction mix-
ture was filtered over Celite, extracted with ethyl acetate
(3 · 50 mL), and washed with NaCl saturated solution.
The organic phase was dried over anhydrous MgSO4,
filtered, and the solvent removed under reduced pres-
sure. The crude product was purified by silica gel chro-
matography and eluted with hexane and ethyl acetate
4.5.1. Ethyl (2R,3S)-3-benzoylamino-2-hydroxy-3-phen-
(15%) to give
8
(138 mg, 95%). Yellow oil,
20
20
ylpropanoate 6a. White solid, mp 162–164 ꢁC, ½aŠ
¼
½aŠ ¼ ꢀ32.5 (c 2.0, CHCl3); 1H NMR (300 MHz,
D
D
ꢀ21.7 (c 1.0, CHCl3); IR (film) mmax: 3474, 3446, 3005,
2919, 2923, 2807, 1713, 1635, 1450, 1354 cmꢀ1; MS m/
z (%): 222 (100), 194 (11), 193 (66), 166 (4), 165 (15),
145 (2), 132 (2), 119 (20), 105 (72), 89 (93), 91 (89), 89
(93), 77 (70), 65 (50), 51 (60); 1H NMR (300 MHz,
CDCl3): d 1.26 (3H, t, J 7.3 Hz), 3.26 (1H, s), 4.25
(2H, m), 4.62 (1H, d, J 1.9 Hz, H-2), 5.74 (1H, dd, J
2.0 and 9.0 Hz, H-3), 6.98 (1H, d, J 9.0 Hz), 7.24
(10H, m, H-5 aromatic); 13C NMR (75 MHz, CDCl3):
CDCl3): d 1.28 (3H, t, J 7.0 Hz, H-12), 1.90–2.18 (2H,
m, H-4), 2.77 (2H, m, H-3), 4.20 (2H, q, J 7.0 Hz, H-
11), 7.26 (5H, m, aromatic).12
4.5.5. Ethyl (2R,3S)-3-azido-2-hydroxyphenylbutanoate
9. To a solution of the oxirane 4b (200 mg, 0.7 mmol)
in anhydrous dichloromethane (2mL) were added bor-
on trifluoride–diethyl etherate (0.25 mL) and azidotri-
methylsilane (0.08 g, 0.7 mmol) under argon. The
mixture was stirred at room temperature for 3 h. The
reaction mixture was diluted with dichloromethane,
d 14.7 (CH3), 55.2(CH, C-3), 63.3 (CH ), 73.8 (CH,
2
C-2), 127.3–132.1 (CH, aromatic), 134.6 (C, aromatic),

J. Augusto R. Rodrigues et al. / Tetrahedron: Asymmetry 16 (2005) 3099–3106
3105
sis of b-Amino Acids; Wiley-VCH: New York, 1997; (e)
Andruszkiewicz, R. Pol. J. Chem. 1998, 72, 1.
2. For a review, see: Miller, R. W. J. Nat. Prod. 1990, 43,
425.
washed with sodium bicarbonate solution, dried over
magnesium sulfate, and the solvent removed under re-
duced pressure. The residue was purified by column
chromatography with silica gel and eluted with ethyl
3. (a) Taxol, Science and Applications; Suffness, M., Ed.;
CRC: Boca Raton, FL, 1995; (b) The Chemistry and
Pharmacology of Taxol and its Derivatives; Farina, V., Ed.;
Elsevier: Amsterdam, New York, 1995; (c) Taxane Anti-
cancer Agents: Basic Science and Current Status; Gerg, G.
I., Ed.; ACS Symposium Series 583, 1995; (d) Paclitaxel in
Cancer Treatment; McGuire, W. P., Rowinsky, E. K.,
Eds.; Maecel Dekker: New York, 1995.
acetate to give 9 (156.9 mg, 90% yield, 96% ee) as a yel-
20
low oil. ½aŠ ¼ ꢀ12.0 (c 1.8, CHCl3); IR (film) mmax
:
D
3489, 3031, 2990, 2928, 2114, 1743, 1603, 1496, 1450,
1367, 1259, 1114, 1022, 748, 697 cmꢀ1; EM m/z (%):
91 (100), 221 (1), 206 (2), 189 (1), 177 (1), 161 (2), 148
(5), 133 (15), 118 (20), 104 (15), 91 (100), 76 (20), 65
(27), 51 (20); 1H NMR (300 MHz, CDCl3): d 1.29
(3H, t, J 7.1 Hz, H-12), 3.11 (2H, m, H-4), 3.75 (1H,
td, J 1.8 and 7.7 Hz, H-3), 4.10 (1H, dd, J 1.8 and
5.1 Hz, H-2), 4.28 (2H, m), 7.31 (5H, m, aromatic);
13C NMR (75 MHz, CDCl3): d 14.1 (CH3, C-12), 36.2
(CH2, C-4), 62.5 (CH2, C-11), 64.3 (CH, C-3), 71.4
(CHOH, C-2), 127.1 (CH, aromatic), 128.8 (2CH, aro-
matics), 129.4 (2CH, aromatics), 136.7 (aromatic),
172.7 (C@O).13
4. Wuts, P. G. M.; Gu, R. L.; Northuis, J. M. Tetrahedron:
Asymmetry 2000, 11, 2117.
´
´
5. Gueritte-Voegelein, F.; Seinilh, V.; David, B.; Guenard,
D.; Potier, P. Tetrahedron 1986, 42, 4451.
6. For a review on the semi-synthesis of Taxol, see: (a) Wuts,
P. G. M. Curr. Opin. Drug Discovery Dev. 1998, 1, 329; (b)
Holton, R. A. Eur. Pat. Appl. EP 400971A1, 30 May
1990.; Chem. Abstr. 114, P164568q.; (c) Oijima, I.; Sun, C.
M.; Zucco, M.; Park, Y. H.; Ducios, O.; Kuduck, S.
Tetrahedron Lett. 1993, 34, 4149; (d) Holton, R. A., U.S.
Patent Appl. US50157744, 14 November, 1989; Holton,
R. A. Eur. Pat. Appl. EP 428786A1, 13 November, 1990;
Chem. Abstr. 115, P114817v. (e) Swindell, C. S.; Drauss,
N. E.; Horwitz, S. B.; Ringel, I. J. Med. Chem. 1991, 34,
1176; (f) Didier, E.; Fouque, E.; Tallepied, I.; Commer-
con, A. Tetrahedron Lett. 1994, 35, 2349; (g) Dennis, J.-N.;
Greene, A. E.; Guenard, D.; Gueritte-Voegelein, F.;
Mangatal, F.; Potier, P. J. Am. Chem. Soc. 1988, 110,
5917; (h) Kingston, D. G. I.; Chaudhary, A. G.; Guna-
tilaka, A. A. L.; Middleton, M. L. Tetrahedron Lett. 1994,
35, 4483.
7. (a) Ho¨nig, H.; Seufer-Wasserthal, P.; Weber, H. Tetra-
hedron 1990, 46, 3841; (b) Hamamoto, H.; Mamedov, V.
A.; Kitamoto, M.; Hayashi, N.; Tsuboi, S. Tetrahedron:
Asymmetry 2000, 11, 4485.
8. Iizaka, K.; Kamijo, T.; Harada, H.; Akahane, K.; Kubota,
T.; Umeyama, H.; Ishida, T.; Kiso, Y. J. Med. Chem.
1990, 33, 2707.
4.5.6. Ethyl 2-oxo-5-methylhexanoate. To a double-
necked round bottomed flask with magnesium turnings
(0.64 g, 0.027 mol) and iodine crystals in anhydrous
THF under argon was added 1-bromo-2-methylpropane
(4.03 g, 0.26 mol) dissolved in THF (15 mL) slowly over
45 min. This solution of Grignard reagent was added
over 30 min to a stirred solution of diethyl oxalate
(3.85 g, 0.026 mol) in anhydrous THF (30 mL) at
ꢀ10 ꢁC under argon. The reaction mixture was hydro-
lyzed with 2M solution of HCl, extracted with ethyl ace-
tate, and washed with saturated NaCl solution. The
organic phase was dried over anhydrous MgSO4, fil-
tered, and the solvent removed under reduced pressure.
The crude product was purified by silica gel chromato-
graphy and eluted with hexane and ethyl acetate (6%)
to give ethyl 2-oxo-6-methylhexanoate in 85% yield.
Pale green oil; IR (film) mmax: 2953, 2934, 2880, 1727,
1723, 1469, 1245, 1070 cmꢀ1; MS m/z (%): 172 (2), 126
9. Mak, C. C.; Brik, A.; Lerner, D. A.; Elder, J. H.; Morris,
G. M.; Olson, A. J.; Wong, C.-H. Biorg. Med. Chem. 2003,
11, 2025.
1
(14), 99 (100), 81 (92); H NMR (CDCl3): d 0.95 (d,
6H, J 2.2 Hz, H-6 and H-7), 1.33 (t, 3H, J 7.3 Hz, H-
9), 1.37 (m, 3H, H-4 and H-5), 2.83 (m, 1H, H-3), 4.35
(q, 2H, J 7.3 Hz, H-8). 13C NMR (75 MHz, CDCl3): d
14.6 (CH3, C-9), 22.9 (2 CH3, C6 and C-7), 28.1 (CH,
C-5); 32.3 (CH2, C-4), 37.9 (CH2, C-8), 62.9 (CH2, C-
3), 161.7 (C@O); 195.2(C @O).28
10. (a) Kearns, J.; Kayser, M. M. Tetrahedron Lett. 1994, 35,
2848; (b) Kayser, M. M.; Mihovilovic, M. D.; Kearns, J.;
Feicht, A.; Stewart, J. D. J. Org. Chem. 1999, 64, 6603.
11. Tsuboi, S.; Furutani, H.; Ansari, M. H.; Sakai, T.; Utaka,
M.; Takeda, A. J. Org. Chem. 1993, 58, 486.
12. Dao, D. H.; Hornes, S.; Okamura, M.; Akasaka, T.;
Kawai, Y.; Hida, K.; Ohno, A. Bull. Chem. Soc. Jpn. 1998,
71, 425.
13. Hoffman, R. V.; Johnson, M. C.; Okonya, J. F. J. Org.
Chem. 1997, 62, 2458.
14. Behrens, C. H.; Sharpless, K. B. J. Org. Chem. 1985, 50,
5696.
4.5.7. Ethyl 2-oxoheptanoate. Procedure as above for
ethyl 2-oxo-6-methylhexanoate, giving IR and 1H
NMR values matching those reported in the literature.29
15. Catasu´s, M.; Moyano, A.; Pericas, M. A.; Riera, A.
Tetrahedron Lett. 1999, 40, 9309.
16. Pearson, W. H.; Hines, J. V. J. Org. Chem. 1989, 54, 4235.
17. (a) Legters, J.; Thijs, L.; Zwanenburg, B. Tetrahdron Lett.
Acknowledgments
The authors are indebted to FAPESP, CAPES, UNI-
CAMP-FUNCAMP, and CNPq for financial support.
´
1989, 30, 4881; (b) Solladie-Cavallo, A.; Lupattelli, P.;
Bonini, C. J. Org. Chem. 2005, 70, 1605.
18. Legters, J.; van Dienst, E.; Thijs, L.; Zwanenburg, B. Rec.
Trav. Chim. Pays-Bas 1992, 111, 69.
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