Asymmetric synthesis of chiral α-keto esters via Grignard addition to oxalates

Article abstract of DOI:10.1016/j.tetasy.2003.08.013

While enroute to an asymmetric synthesis of the chlorine containing metabolite (-)-cryptosporiopsin an efficient and reliable asymmetric synthesis of chiral α-keto esters was required. These compounds can be conveniently generated in 51-84% yields via Gri

Full text of DOI:10.1016/j.tetasy.2003.08.013

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3177–3181
Asymmetric synthesis of chiral a-keto esters via Grignard
addition to oxalates
David I. MaGee,* Tammy C. Mallais and Marijanna Eic
Department of Chemistry, PO Box 45222, University of New Brunswick, Fredericton, N.B., E3B 6E2, Canada
Received 16 June 2003; accepted 5 August 2003
Abstract—While enroute to an asymmetric synthesis of the chlorine containing metabolite (−)-cryptosporiopsin an efficient and
reliable asymmetric synthesis of chiral a-keto esters was required. These compounds can be conveniently generated in 51–84%
yields via Grignard addition to either symmetrical or mixed oxalates at −40°C in tetrahydrofuran. The reaction works equally well
with aliphatic or aromatic Grignard reagents.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
acyl cyanides,5 oxidative cleavage of cyano ketophos-
phoranes,6 the reaction of organometallic species with
oxalic ester derivatives,7 and acylation or alkylation of
mono-substituted 1,3-dithianes.8 Surprisingly most of
these procedures have only been used to construct
simple a-keto-esters, for instance methyl or ethyl esters.
In fact, we could only find a single report where an
a-keto-ester bearing a chiral ester functionality was
generated.9
While involved in a synthetic program targeted at the
chlorine fungal metabolite (−)-cryptosporiopsin1 1 we
required a short and efficient synthesis of a variety of
chiral a-keto-esters derivatives such as 2, Fig. 1. There
are numerous literature reports that describe the syn-
thesis of a-keto esters.2 These compounds have
attracted attention as synthetic targets due to the fact
that their functionality is present in many natural prod-
ucts and that they play an important role in biological
processes.3 Common methods of synthesis include oxi-
dation of a-hydroxy esters with either PCC or Dess–
Martin periodinane,4 hydrolysis and esterification of
Unsure which route would prove most useful for our
purposes we pursued several different avenues. The
oxidation of a variety of caproic acid ester enolates
with camphorsulfonyl oxaziridine or dimethyl dioxirane
proved capricious since the yields of product ranged
from 29–73% depending upon which ester was used.
Using the Corey procedure proved equally frustrating.
Starting with 2-butyl-1,3-dithiane and acylating the
anion with CO2 proceeded uneventfully, however,
attempts to generate the ester under a variety of condi-
tions met with little success, yields in the order of
25–38% being normal. Reversing the steps, namely
acylating first and then alkylating the anion proved
equally unsuccessful. Granted moderate success was
realized in some instances, however, to carry out the
research we planned it was necessary to have a short
and general synthesis since we were going to have to
screen a number of a-keto-esters possessing a chiral
alcohol auxiliary. Consequently it was decided to
explore the utility of the most direct route, namely
Grignard addition to an oxalate.
Figure 1. (−)-Cryptosporiopsin 1 and the requisite chiral enol-
ester required for its synthesis.
* Corresponding author. Tel.: 506-453-4870; fax: 506-453-4981;
e-mail: dmagee@unb.ca
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.013

3178
D. I. MaGee et al. / Tetrahedron: Asymmetry 14 (2003) 3177–3181
ing oxalate; in such cases treatment of the crude reac-
2. Results and discussion
tion mixture with TMSCl or TBSCl and DBU in
refluxing THF provided the silyl-enol ether esters which
could be conveniently separated from other by-prod-
ucts. Simple hydrolysis (TBAF, HF/Py or 1 M HCl)
then regenerated the requisite a-keto esters.
The initial foray into this line of research began with
menthol as the chiral auxiliary. To this end, menthol, 3,
was reacted with oxalyl chloride, 4, in the presence of
pyridine to give dimenthyl oxalate 5 in 43% yield,
Scheme 1. Following a literature protocol,10 one equiv-
alent of Grignard reagent was added slowly over one
hour to oxalate 5 while the temperature was kept at
0°C. This resulted in the isolation of the desired a-keto
ester 6 in 15% yield. The yield was improved to 56% by
increasing the amount of Grignard reagent to 1.5 equiv-
alents and using a faster addition time of 45 min.
Although yields as high of 56% could be obtained the
results were inconsistent and in many runs extremely
low yields were obtained. There was precedent for
encountering difficulties using this route.11
Given the success of this approach, it seemed appropri-
ate to investigate whether this reaction could be con-
ducted without releasing one equivalent of the chiral
alcohol along with the desired a-keto ester product.
Although this is not a concern when using commer-
cially available alcohols as auxiliaries it becomes prob-
lematic when more precious alcohols have to be
retrieved. Recently Flynn and Beight9 reported the
addition of phenylethyl magnesium bromide to a mixed
oxalate, therefore there was optimism that this would
prove equally viable in our study.
The need therefore became to improve the Grignard
reaction between chiral oxalates and alkyl Grignard
reagents. Recently, Rambaud7 and Singh12 indepen-
dently demonstrated that alkyl Grignard reagents could
be efficiently added to diethyl oxalate when the temper-
ature was maintained at −80°C and one equivalent of
Grignard reagent was used. They found that control of
the stoichiometry (1:1) of the reactants along with low
temperatures were the key to success in this reaction.
With this in mind, subjecting symmetrical dimenthyl
oxalate 5 with commercial n-butyl magnesium chloride
under these conditions for several hours led to no
reaction! Given the previous results at 0°C it became
evident that temperature was having a profound effect
on the outcome of this reaction. Consequently a study
was initiated to delineate what temperature would give
rise to the highest yields. The results of this study are
shown in Table 1 and it is easily seen that this Grignard
reaction is very sensitive to the reaction conditions.
However, with appropriate attention to detail an excel-
lent and reproducible yield could be achieved if the
reaction was run at −40°C, external bath temperature,
in the presence of 1.5 equivalents of Grignard reagent.
To initiate this, the requisite mixed oxalates were syn-
thesized following Flynn and Bleight’s protocol.9 Sub-
jection of each mixed oxalate to our standard
conditions generated the expected a-keto-esters in mod-
erate to good yields, Table 2. It is evident from com-
parison of the two routes that use of unsymmetrical
oxalates generally produces a-keto esters with slightly
inferior yields. This is primarily due to the fact that
Grignard addition is not completely regioselective and
that some methyl 2-oxo-hexanoate is produced.
Attempts to completely suppress this side reaction by
varying the conditions, including temperature, failed.
3. Conclusion
We have shown that Grignard addition to symmetrical
and mixed oxalates bearing chiral alcohol auxiliaries is
a quick and efficient method to synthesize a-keto esters
in good to excellent yields. It is crucial that the temper-
Table 1. Temperature studies on n-butyl Grignard addi-
tion to dimenthyl oxalate
Confident that optimum conditions were now defined, a
series of a-keto-esters was synthesized (Scheme 1).
These are shown in Table 2. Most notable from the
results is the generality of the reaction and the consis-
tent yields obtained, both with aliphatic and aromatic
Grignard reagents. In some instances it was difficult to
achieve complete separation of the product from start-
Temp (°C)
Yield (%) of 6 or ratio 6:5
0
−20
−40
−60
2.1:1
2.4:1
73
NR
Scheme 1. Reagents and conditions: (a) CH2Cl2, pyridine, DMAP, rt; (b) THF, n-BuMgCl, −40°C.

D. I. MaGee et al. / Tetrahedron: Asymmetry 14 (2003) 3177–3181
3179
Table 2. Synthesis of chiral a-keto esters via Grignard addition to symmetrical and mixed oxalates, (a) isolated as the
TBS-enol ether ester
ature be controlled or else spurious results will be
obtained. The use of this chemistry for the synthesis of
the fungal metabolite (−)-cryptosporiopsin 1 is cur-
rently being pursued and will be communicated in due
course.
toluene, were distilled over sodium, using benzophe-
none as an indicator, prior to use. Other solvents such
as dichloromethane, triethylamine and acetonitrile were
used freshly distilled from calcium hydride. Standard
techniques were used in handling air sensitive reagents.
All commercially available reagents and solvents were
purchased either from Aldrich, Fluka or Fisher and
used without further purification. 2-methoxy-1-
phenylethanol,13 1-(2,4,6-triisopropylphenyl)ethanol,14
4. General experimental procedures
2,2-diphenylcyclopentanol15
and
trans-2-phenyl-1-
All reactions except those stated otherwise were per-
formed under inert atmospheres of either argon or
nitrogen in flame dried glassware (pyrex). Solvents,
such as ether, tetrahydrofuran, xylenes, benzene and
cyclohexanol16 were synthesized according to literature
procedures. All preparative SiO2 (flash) chromatogra-
phy was done using Silicycle Ultra Pure Silica Gel for

3180
D. I. MaGee et al. / Tetrahedron: Asymmetry 14 (2003) 3177–3181
1
chromatography. All H and 13C NMR spectra were
recorded on a Varian UNITY 400 MHz spectrometer.
Optical rotations were performed on a Perkin–Elmer
241 Polarimeter using the Na lamp. All IR spectra were
done on a Bruker IFS 25 instrument and mass spectra
were run on a Kratos MS50 instrument.
1456, 1368, 1258, 1142, 834. MS: m=/z-C12H18=
186.07171 (calculated=186.07123), C8H9 (105.07053,
calculated=105.070425). [h]D=+2.2 (c=1.08, CH2Cl2).
4.5. (1R,2S,5R)-Menthyl 2-oxo-hexanoate
1
Colourless liquid. H NMR (CDCl3): l 0.77 (d, J=7.0
4.1. General procedure for the preparation of symmetri-
cal oxalates
Hz, 3H), 0.87 (t+2d, 9H), 1.06 (septet, J=12.1 Hz, 3H),
1.36 (m, 2H), 1.50 (m, 2H), 1.66 (m, 1H), 1.73 (d of d,
J=3.25, 6.15 Hz, 2H), 1.86 (m, 1H), 2.04 (d of pentet,
J=3.42, 10.25 Hz, 1H), 2.81 (t of d, J=1.54, 7.18 Hz,
2H), 4.82 (t of d, J=4.44, 10.94 Hz, 1H). 13C NMR
(CDCl3): l 13.8, 16.2, 20.6, 21.9, 22.1, 23.3, 25.1, 26.2,
31.4, 34.0, 39.1, 40.4, 46.7, 76.7, 161.1, 195.2. IR (NaCl
plates, cm−1): 2932, 1750, 1726, 1455, 1250, 1125, 1054.
MS: m=/z=268.20382 (calculated=268.203845). [h]D=
−64.6 (c=2.34, EtOH).
A solution of alcohol (20 mmol), pyridine (1.62 mL, 20
mmol) and DMAP (24 mg,
2
mmol) in
dichloromethane (100 mL) was allowed to stir at rt for
5 min then cooled in an ice bath. Oxalyl chloride (0.88
g, 10 mmol) was then added dropwise over 5 min, the
ice bath was removed and the mixture was stirred at rt
overnight. It was then diluted with ether (200 mL),
washed with aq. HCl (10%, 2×), H2O (1×), brine (1×),
dried over MgSO4 and the solvent removed in vacuo.
The residue was purified by SiO2 chromatography (hex-
anes:ethyl acetate) to provide the pure oxalates.
4.6. (1R)-Fenchyl 2-oxo-hexanoate
1
Colourless liquid. H NMR (CDCl3): l 0.81 (s, 3H),
0.93 (t, J=7.35 Hz, 3H), 1.07 (s, 3H), 1.25 (dd, J=1.54,
10.43 Hz, 1H), 1.37 (m, 2H), 1.48 (m, 1H), 1.65 (m,
3H), 1.76 (m, 3H), 2.81 (td, J=2.39, 7.18 Hz, 2H), 4.48
ppm (d, J=1.88 Hz, 1H). 13C NMR (CDCl3): l 13.7,
19.3, 20.1, 22.1, 25.1, 25.7, 26.5, 29.6, 39.3, 39.7, 41.3,
48.2, 48.5, 88.5, 161.9, 194.8. IR (NaCl plates, cm−1):
2936, 1750, 1728, 1464, 1280, 1244, 1120, 1054. MS:
m=/z=252.17249 (calculated=252.172545). [h]D=
+33.8 (c=0.34, EtOH).
4.2. General procedure for mixed oxalate formation
Methyl chlorooxoacetate (0.20 mL, 2.2 mmol) and
dichloromethane (15 mL) were cooled in an ice bath
and then the alcohol (1.9 mmol) in dichloromethane (5
mL) was added followed immediately by pyridine (0.24
mL, 3.0 mmol). The reaction mixture was allowed to
warm to rt and stir for 1 h. When complete, the
solution was diluted with ether, washed with 10% HCl
(2×), H2O (1×), brine (1×), dried over MgSO4 and
solvent evaporated. The crude product was purified by
SiO2 chromatography (hexanes: ethyl acetate) to yield
the mixed oxalate.
4.7. (R)-2-Methoxy-1-phenylethyl 2-oxohexanoate
1
Colourless liquid. H NMR (CDCl3): l 0.91 (t, J=7.2
Hz, 3H), 1.35 (m, 2H), 1.61 (m, 2H), 2.83 (dt, J=1.1,
7.4 Hz, 2H), 3.40 (s, 3H), 3.62 (dt, J=3.6, 11.1 Hz,
1H), 3.83 (m, 1H), 6.06 (dd, J=3.6, 8.5 Hz, 1H), 7.33
(m, 5H). 13C NMR (CDCl3): l 13.8, 22.1, 25.0, 39.1,
59.2, 75.0, 76.5, 126.8, 128.7, 128.8, 136.1, 160.5, 194.3.
IR (NaCl plates, cm−1): 2936, 2874, 1750, 1726, 1456,
1120, 702. MS: m=/z=264.136152 (calculated=
264.13617). [h]D=−55.4 (c=1.3, EtOH).
4.3. General procedure for the preparation of a-keto
ester via Grignard reaction
Oxalate (0.15 mmol) in THF was cooled to −40°C, then
n-butyl magnesium chloride (0.11 mL, 0.22 mmol) was
added dropwise over 1 h 20 min [in two examples
phenyl magnesium bromide and methyl magnesium
bromide were used in place of the butyl Grignard
reagent]. After complete addition the reaction mixture
was stirred for 2 h at the same temperature and then
diluted with ether, washed with cold HCl (5%, 2×),
brine (1×), dried over MgSO4. The solvent was removed
in vacuo and the residue was purified by SiO2 chro-
matography (hexane:ethyl acetate) to provide the a-
keto esters.
4.8. (S)-1-(2-Naphthyl)ethyl 2-oxohexanoate
1
Colourless liquid. H NMR (CDCl3): l 0.89 (t, J=7.3
Hz, 3H), 1.32 (p, J=7.5 Hz, 2H), 1.59 (p, J=7.9 Hz,
2H), 1.72 (d, J=6.5 Hz, 3H), 2.80 (t, J=7.4 Hz, 2H),
6.14 (q, J=6.6 Hz, 1H), 7.47 (m, 3H), 7.83 (m, 4H). 13
C
NMR (CDCl3): l 13.8, 22.1, 25.1, 39.1, 60.5, 75.0,
123.9, 125.5, 126.4, 126.5, 127.8, 128.2, 128.7, 133.2,
133.3, 137.7, 160.8, 194.75. IR (NaCl plates, cm−1):
3054, 2948, 2928, 2864, 1714, 1601, 1454, 1264, 1050,
814. MS: m=/z=284.14124 (calculated=284.141245).
[h]D=−39.3 (c=1.37, CH2Cl2).
4.4. (R)-1-Phenylethyl Z-tert.butyldimethylsilyloxy-2-
hexenoate
1
Colourless liquid. H NMR (CDCl3): l 0.09 (s, 3H),
0.13 (s, 3H), 0.95 (t, J=7.5 Hz, 3H), 0.95 (s, 9H), 1.43
(sextet, J=7.5 Hz, 2H), 1.58 (d, J=5.0 Hz, 3H), 2.17
(dq, J=0.9, 7.2 Hz, 2H), 5.94 (q, J=6.3 Hz, 1H), 6.08
(t, J=7.5 Hz, 1H), 7.25–7.4 (m, 5H). 13C NMR
(CDCl3): l −3.98, −3.93, 14.3, 18.9, 22.4, 22.5, 26.2,
28.2, 73.2, 123.5, 126.5, 128.2, 128.8, 141.2, 141.9,
164.6. IR (NaCl plates, cm−1): 2946, 2855, 1720, 1640,
4.9. (S)-2,2-Diphenyl-1-cyclopentyl 2-oxohexanoate
Colourless liquid. 1H (CDCl3): l 0.81 (t, J=7.4 Hz,
3H), 1.16 (m, 2H), 1.34 (m, 2H), 1.58 (m, 1H), 1.89 (m,
3H), 2.26 (m, 3H), 2.52 (m, 3H), 2.66 (m, 1H), 6.22 (d,
J=5.5 Hz, 1H), 7.20 (m, 10H). 13C (CDCl3): l 13.6,
20.6, 22.0, 24.7, 30.7, 38.9, 59.8, 82.0, 126.1, 126.4,

D. I. MaGee et al. / Tetrahedron: Asymmetry 14 (2003) 3177–3181
3181
126.5, 127.8, 128.1, 128.5, 144.4, 144.7, 160.5, 194.8. IR
(NaCl plates, cm−1): 2958, 1750, 1728, 1442, 1280, 1156,
696. MS: m+/z=350.18813 (calcd=350.18820). [h]D=
+117.9 (c=1.1, EtOH).
IR (NaCl plates, cm−1): 2958, 2912, 2664, 1738, 1678,
1596, 1454, 1300, 1204, 1170, 754. MS: m+/z−C10H19=
149.02369 (calculated=149.023870), C10H19 (139.14824,
calculated=139.14868). [h]D=−54.9 (c=1.38, CH2Cl2).
4.10. (1R,2S)-trans-Phenylcyclohexyl 2-oxohexanoate
Acknowledgements
1
Colourless liquid. H NMR (CDCl3): l 0.81 (t, J=7.2
Hz, 3H), 1.18 (m, 2H), 1.34 (m, 3H), 1.57 (m, 3H), 1.81
(dd, J=2.6, 12.6 Hz, 1H), 1.94 (m, 2H), 2.15 (dd,
J=5.5, 8.7 Hz, 1H), 2.43 (td, J=2.7, 7.3 Hz, 2H), 2.77
(m, 1H), 5.08 (m, 1H), 7.19 (m, 3H), and 7.26 (m, 2H).
13C NMR (CDCl3): l 13.6, 22.0, 24.7, 24.8, 25.6, 31.9,
33.4, 39.0, 49.7, 78.6, 126.7, 127.6, 128.4, 142.3, 160.6,
195.1. IR (NaCl plates, cm−1): 2936, 2854, 1750, 1728,
1450, 1274, 1046, 696. MS: [m+/z−C9H9O3]=159.1187
(calculated=159.11737). [h]D=−41.8 (c=1.41, EtOH).
We wish to thank the Natural Sciences and Engineering
Research Council of Canada (NSERC) for a Discovery
grant to carry out this research. M.E. would like to
thank NSERC for a summer research assistantship
(NSERC USRA) and T.C.M. would like to thank the
New Brunswick Women’s Doctoral Fellowship for
financial support. We would like to thank Mr. Gilles
Vautour with assistance in running the mass spectra
and Dr. Larry Calhoun for assistance in some NMR
experiments.
4.11. (R)-1-(2,4,6-Triisopropylphenyl)ethyl 2-oxohex-
anoate
1
Colourless liquid. H NMR (CDCl3): l 0.84 (t, J=7.2
References
Hz, 3H), 1.18 (d, J=6.7 Hz, 6H), 1.19 (d, J=6.8 Hz,
6H), 1.25 (d, J=6.8 Hz, 6H), 1.30 (p, J=7.7 Hz, 2H),
1.51 (p, J=7.5 Hz, 2H), 1.65 (d, J=6.8 Hz, 3H), 2.79
(t, J=7.2 Hz, 2H), 2.84 (heptet, J=7.0 Hz, 1H), 3.49
(heptet, J=6.7 Hz, 2H), 6.5 (q, J=6.8 Hz, 1H), 7.02 (s,
2H). 13C NMR (DMS0-d6, 80°C): l 13.8, 21.8, 22.2,
24.0, 24.1, 24.4, 24.9, 25.1, 29.2, 33.8, 38.6, 122.1, 131.6,
147.2, 148.5, 160.9, 194.8. IR (NaCl plates, cm−1): 2950,
2905, 2876, 1726, 1608, 1466, 1382, 1276, 1240, 1050,
1002. MS: m+/z=360.26645 (calculated=360.266495).
[h]D=−25.6 (c=1.7, CH2Cl2).
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4.12. (S)-1-(2,4,6-Triisopropylphenyl)ethyl 2-oxoproan-
oate
White solid. Mp=55–56.5°C. 1H NMR (CDCl3): l 1.22
(d, J=6.9 Hz, 6H), 1.24 (d, J=6.9 Hz, 6H), 1.30 (d,
J=6.9 Hz, 6 H), 1.72 (d, J=7.2 Hz, 3H), 2.43 (s, 3H),
2.86 (septet, J=6.9 Hz, 1H), 2.52 (br, 2H), 6.60 (q,
J=6.9 Hz, 1H), 7.02 (bs, 2H). 13C NMR (DMS0-d6,
80°C): l 21.3, 23.2, 23.23, 23.6, 24.1, 25.9, 28.0, 28.4,
32.9, 69.9, 121.3, 130.8, 146.3, 147.6, 159.5, 191.2. IR
(NaCl plates, cm−1): 2936, 2854, 1750, 1728, 1450, 1274,
1046, 696. MS: m+/z=318.21948 (calculated=
318.219495). [h]D=+20.6 (c=2.7, CH2Cl2).
4.13. (1R,2S,5R)-Menthyl oxophenylacetate
1
Colourless oil. H NMR (CDCl3): l 0.84 (d, J=7.0 Hz,
3H), 0.90, (d, J=7.0 Hz, 3H), 0.96 (d, J=6.5 Hz, 3H),
1.03–1.27 (m, 5H), 1.46–1.62 (m, 3H), 1.64–1.80 (m,
3H), 1.83–2.01 (m, 1H), 2.19 (dt, J=Hz, 1H), 5.01 (dt,
J=4.5, 10.9 Hz, 1H), 7.51 (t, J=8.2 Hz, 2H), 7.66 (dt,
J=1.2, 7.5 Hz, 1H), 7.98 (dd, J=1.4, 8.5 Hz, 2H). 13C
NMR (CDCl3): l 16.3, 20.8, 22.1, 23.4, 26.3, 31.7, 34.2,
40.7, 46.9, 77.1, 129.0, 130.0, 132.7, 134.9, 164.0, 186.9.