The synthesis of S-(+)-2,2-dimethylcyclopropane carboxylic acid: A precursor for cilastatin

Article abstract of DOI:10.1016/S0957-4166(98)00421-2

S-(+)-2,2-Dimethylcyclopropane carboxylic acid, a precursor for cilastatin, was prepared from 2-methylpropene and chiral iron carbene in three steps. Asymmetric cyclopropanation reaction of 2-methylpropene with iron carbene complex having chirality at the carbene ligand, followed by exhaustive ozonolysis, produced S-(+)-2,2-dimethylcyclopropanecarboxylic acid of up to 92% ee. The absolute configuration of complexed chiral cyclopropane (-)-8 was determined by X-ray crystallographic analysis.

Full text of DOI:10.1016/S0957-4166(98)00421-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3971–3977
The synthesis of S-(+)-2,2-dimethylcyclopropane carboxylic acid:
a precursor for cilastatin
Qinwei Wang, Fukang Yang, Hong Du, M. Mahmun Hossain, Dennis Bennett and
∗
Desiree S. Grubisha
Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
Received 28 July 1998; accepted 4 October 1998
Abstract
S-(+)-2,2-Dimethylcyclopropane carboxylic acid, a precursor for cilastatin, was prepared from 2-methylpropene
and chiral iron carbene in three steps. Asymmetric cyclopropanation reaction of 2-methylpropene with iron
carbene complex having chirality at the carbene ligand, followed by exhaustive ozonolysis, produced S-(+)-
2
,2-dimethylcyclopropanecarboxylic acid of up to 92% ee. The absolute configuration of complexed chiral
cyclopropane (−)-8 was determined by X-ray crystallographic analysis. © 1998 Elsevier Science Ltd. All rights
reserved.
1. Introduction
The practical importance of S-(+)-2,2-dimethylcyclopropanecarboxylic acid (+)-10 comes from the
pharmaceutical field. Imipenem 1 (Fig. 1), one of the most promising β-lactam antibiotics, was found to
1
be deactivated by renal dipeptidase (dehydropeptidase-I). Cilastatin 2 (Fig. 1), an excellent inhibitor of
dehydropeptidase-I which increases the in vivo stability of imipenem, has the desired pharmacological
2
properties. The S-(+)-2,2-dimethylcyclopropane carboxylic acid (+)-10 is a key building block for the
synthesis of cilastatin. Several methods recently reported for the asymmetric synthesis of (+)-10 or its
esters were mainly based on: (1) the cyclopropanation of chiral alkenes;3 or (2) on the enantioselective
,4
5
,6
cyclopropanation of alkenes in the presence of chiral copper carbenoid by means of ethyl diazoacetate.
5
6
Aratani and Evans have obtained the ethyl ester of (+)-10 with an excellent ee by the second method.
Recently, we developed a novel method for the synthesis of an iron carbene having chirality at the carbene
7
ligand, and reported the first asymmetric cyclopropanation with styrene with 60% ee. Here we report the
asymmetric synthesis of S-(+)-2,2-dimethylcyclopropanecarboxylic acid via the same chiral iron carbene
complex.
∗
Corresponding author. Fax: (414) 229-5530; e-mail: mahmun@csd.uwm.ed
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00421-2

3972
Q. Wang et al. / Tetrahedron: Asymmetry 9 (1998) 3971–3977
Figure 1.
2. Results and discussion
8
The enantiomerically pure O-anisaldehyde(tricarbonyl)chromium complex (+)-4 was reacted with the
Fp anion 3 in the presence of chlorotrimethylsilane, followed by extraction and column chromatography,
providing an enantiomerically pure bimetallic complex (−)-6 in 90% yield (Scheme 1).
Scheme 1.
In order to carry out the asymmetric cyclopropanation reaction, one equivalent of the enantiomerically
pure (−)-(α-siloxy-O-methoxybenzyl) bimetallic complex (−)-6 was dissolved in dichloromethane and
then treated with 1.1 equivalent of trimethylsilyl trifluoromethanesulfonate at −78°C in the presence of
an excess of 2-methylpropene. The corresponding complexed cyclopropane (−)-8 was obtained in 91%
yield (Scheme 2). The absolute configuration of (−)-8 was established by X-ray crystallographic analysis
as SS-(−)-2,2-dimethyl-1-O-methoxyphenyl (tricarbonyl chromium) cyclopropane (Fig. 2).
Decomplexation of the Cr(CO) moiety from (−)-8 under a sun lamp or natural sunlight in a solution
3
of pentane:ether provided the chiral cyclopropane (−)-9 with 97% yield. A >95% ee was indicated
for (−)-9 as measured by the proton NMR spectrum, utilizing a chiral shift reagent of ytterbium D-
3
-heptafluorobutyrylcamphorate Yb(hfc) .
3
Ozonolysis of the cyclopropane (−)-9 followed by oxidative workup with hydrogen peroxide and
subsequent fractional distillation gave a clear oil of S-(+)-2,2-dimethylcyclopropane carboxylic acid
(
+)-10 in 82% yield (Scheme 3). The enantiomeric excess of (+)-10 was determined by the proton
9,10
NMR spectrum of its S-methyl mandelate ester derivative.
The split mandelate methine proton of
11 indicated a 92% ee (Fig. 3a) when compared with the corresponding 1:1 diastereomeric mixture
(Fig. 3b).
In conclusion, the asymmetric synthesis of S-(+)-2,2-dimethylcyclopropane carboxylic acid was
carried out by using an iron carbene having a chiral carbene ligand in high yield with 92% ee. Extension
of the chiral cyclopropanation to other olefins in order to prepare other building blocks for the synthesis
of natural products and insecticides is being worked on.

Q. Wang et al. / Tetrahedron: Asymmetry 9 (1998) 3971–3977
3973
Scheme 2.
Figure 2. ORTEP drawing of SS-(−)-8. Ellipsoids are drawn at the 35% probability level
Scheme 3.

3974
Q. Wang et al. / Tetrahedron: Asymmetry 9 (1998) 3971–3977
1
Figure 3. 300 MHz H NMR spectrum of 11 (a) and the corresponding diastereomeric mixture (b)
3. Experimental
1
13
H NMR and C NMR spectra were recorded on a Bruker 250 or 300 MHz spectrometer, in deuterated
chloroform using the solvent signal as internal reference unless otherwise stated. Chemical shifts are
expressed in ppm. Optical rotations were recorded on a Jasco DIP-370 digital polarimeter at 20°C.
Infrared spectra were taken with a Nicolet FT-IR spectrometer. The CHN analyses were carried out
with a Perkin–Elmer 240C element analyzer. Mass spectra were obtained on a Hewlett Packard 5985B
(H/P), GC/MS system, operated in DIP, CI or EI-70 eV. X-Ray diffraction analysis was performed on
a Picker 4-circle autodiffractometer at 22(2)°C. The ozone in the ozonolysis was generated by a T-400
Welsbach ozonator.
All reactions and manipulations of transition metal complexes were performed under a dry nitrogen
atmosphere using standard Schlenk line and/or dry box techniques. All glassware required for the above
was either flamed under vacuum or dried in an oven prior to use.
Tetrahydrofuran, diethyl ether, dichloromethane, pentane and deuterated chloroform were purified
11
according to our previous procedure. Hydrogen peroxide was obtained from Mallinckrodt Co. Chloro-
trimethylsilane, trimethylsilyl triflate (CF SO SiMe ), L-(+)-valinol, ortho-anisaldehyde and ytterbium
3
3
3
D-3-heptafluorobutyrylcamphorate Yb(hfc) were obtained from Lancaster and used without treatment.
3
S-(+)-Methyl mandelate, 1,3-dicyclohexylcarbodiimide, 4-dimethylaminopyridine and benzene-d were
6
obtained from Aldrich and used without further purification unless otherwise stated.
5
12
Potassium cyclopentadienyldicarbonylferrate, K[(η -C H )Fe(CO) ] and enantiomerically pure S-
5
5
2
8
(
+)-O-anisaldehyde(tricarbonyl)chromium complex were prepared according to the literature methods.
5
6
3
.1. SS-(−)-(η -C H )(CO) FeCH(OSiMe )[(η -O-CH OC H )Cr(CO) ] (−)-6
5
5
2
3
3
6
4
3
A 3.6–4.2 mmol (1.2 equiv.) sample of FpK 3 was dissolved in 40–45 ml of THF and cooled to
78°C, and a 3.0–3.5 mmol (1 equiv.) sample of S-(+)-O-anisaldehyde(tricarbonyl)chromium complex
+)-4, which had been dissolved in 20 ml of THF and degassed twice, was transferred via a cannula
−
(
to this Fp anion solution under −78°C. After the reaction mixture was stirred for 4–4.5 h at −78°C,
3.6–4.2 mmol (1.2 equiv.) of chlorotrimethylsilane was added dropwise. Stirring was continued for 4 h,
and the temperature was maintained at −78°C. After warming the reaction mixture for 20 min to ambient
temperature, the solvent was removed under reduced pressure, and the crude product was separated with
a water-jacked column on silica gel (40–140 mesh) using a 0–2% dichloromethane/pentane mixture. The
1
precursor (−)-6 was isolated as a brown solid in 90% yield. H NMR (CDCl , 250 MHz) δ: 6.20 (s, 1H,
3
CH), 5.82 (d, 1H, J=6.4 Hz, Ph), 5.39 (t, 1H, J=6.0 Hz, Ph), 5.01 (d, 1H, J=7.3 Hz, Ph), 4.95 (t, 1H, J=7.3

Q. Wang et al. / Tetrahedron: Asymmetry 9 (1998) 3971–3977
3975
13
Hz, Ph), 4.69 (s, 5H, C H ), 3.70 (s, 3H, OCH ), 0.28 (s, 9H, Si(CH ) ); C NMR (CDCl , 250 MHz)
5
5
3
3 3
3
δ: 234.6 (Cr(CO) ), 216.7, 215.2 (Fe(CO) ), 135.2 (COCH ), 120.1, 92.1, 89.5, 86.7 (C H ), 85.7, 84.9,
3
2
3
5
5
−1
7
3.7 (FeCH), 54.8 (OCH ), 0.47 (Si(CH ) ). IR (CH Cl ) ν : 2007, 1953, 1872 cm . Anal. calcd for
FeC H O CrSi: C, 48.29; H, 4.24. Found: C, 48.12; H, 4.21. [α]
3
3 3
2
2
CO
20
−335 (c, 0.226, CHCl3).
21
22
7
D
3.2. SS-(−)-2,2-Dimethyl-1-O-methoxyphenyl(tricarbonyl chromium)cyclopropane (−)-8
A 2.5–3.0 mmol (1 equiv.) sample of the bimetallic complex (−)-6 was dissolved in 25 ml of CH Cl
2
2
and cooled to −78°C, and an excess of 2-methylpropene, which had been condensed to liquid at −78°C,
was introduced. After adding 3.0–3.6 mmol (1.1 equiv.) of trimethylsilyl triflate, the solution was stirred
for 4 h at −78°C and warmed to room temperature over 0.5 h. The color of the reaction mixture changed
to purple after several minutes of stirring. After the treatment of the reaction mixture with a short-wash
column of neutral alumina (activity IV) under nitrogen, the solvent was removed under reduced pressure.
The crude product was then separated with a chromatography column on neutral alumina (activity IV)
1
and a bright yellow solid of (−)-8 was isolated in 91% yield. H NMR (CDCl , 250 MHz) δ: 5.36–5.42
3
(
m, 2H, Ph), 5.13 (d, 1H, J=6.6 Hz, Ph), 4.90 (t, 1H, J=6.2 Hz, Ph), 3.77 (s, 3H, OCH ), 1.85 (t, 1H,
3
J=7.2 Hz, CH), 1.19 (s, 3H, CH ), 0.82 (s, 3H, CH ), 0.81 (t, 1H, J=5.4 Hz, CH ), 0.64 (t, 1H, J=5.5
3
3
2
1
3
Hz, CH2); C NMR (CDCl , 250 MHz) δ: 232.4 (Cr(CO) ), 163.9, 142.2, 95.7, 92.7, 85.8, 74.8 (Ph),
6.0 (OCH ), 26.7, 19.8, 20.2 (cyclopropane), 24.8 (CH ), 18.2 (CH ). Anal. calcd for C H O Cr: C,
7.69; H, 5.16. Found: C, 57.74; H, 5.25. m/z: 312 (22%, M ). [α]D −191 (c, 0.273, CHCl3).
3
3
5
5
3
3
3
20
15 16
4
+
3.3. S-(−)-2,2-Dimethyl-1-O-methoxyphenylcyclopropane (−)-9
A 2.2–2.8 mmol sample of (−)-8 was dissolved in 200–250 ml solvent (pentane:ether, 50:50), and
stirred under a sun lamp or natural sunlight for 3 days while air was bubbled through the solution. The
solution became colorless. After gravity filtration, the solvent was removed by a rotavapor and a clear oil
of (−)-9 was obtained in 97% yield. The enantiomeric excess of the product was determined by adding
1
4
0 mg of Yb(hfc) into 4 mg of (−)-9 in 0.5 ml CDCl and the split peaks of the methoxy proton in H
3
3
1
NMR spectrum were used to determine the ee of (−)-9. A >95% ee of (−)-9 was indicated. H NMR
(
6
(
1
CDCl , 250 MHz) δ: 7.16 (t, 1H, J=7.7 Hz, Ph), 7.01 (d, 1H, J=6.4 Hz, Ph), 6.86 (t, 1H, J=7.4 Hz, Ph),
3
.83 (d, 1H, J=8.0 Hz, Ph), 3.83 (s, 3H, OCH ), 1.83 (t, 1H, J=7.3 Hz, CH), 1.24 (s, 3H, CH ), 0.75
3
3
13
d, 2H, J=7.3 Hz, CH ), 0.70 (s, 3H, CH ); C NMR (CDCl , 250 MHz) δ: 159.7, 129.4, 129.0, 126.7,
20.1, 110.0 (Ph), 55.5 (OCH ), 27.1 (CH ), 25.6 (CH), 20.1 (C(CH ) ), 18.2 (CH ), 17.8 (CH ). Anal.
calcd for C H O: C, 81.77; H, 9.15. Found: C, 81.80; H, 9.46. m/z: 176 (46%, M ), 161 (94, M−Me)
2
3
3
3 2 3 2 3 3
+
12
16
20
and 146 (16, M−2Me). [α]D −51 (c, 0.548, CHCl ).
3
3.4. S-(+)-2,2-Dimethylcyclopropane carboxylic acid (+)-10
A 2.0–2.5 mmol sample of (−)-9 was dissolved in 60 ml of CH Cl and cooled to −78°C, and a stream
2
2
of ozone was bubbled through the solution for 0.5 h. Bubbling was continued for 8 h, and the temperature
was maintained at −20 to −30°C. The reaction mixture was then poured into a solution of 20 ml 30%
H O in 60 ml 10% NaOH, and stirred overnight at room temperature. After acidifying the solution to pH
2
2
3
, the reaction mixture was extracted with CH Cl , and dried over MgSO . After fractional distillation
2 2 4
the final product of S-(+)-2,2-dimethylcyclopropane carboxylic acid (+)-10 was obtained in 82% yield.
1
H NMR (CDCl , 250 MHz) δ: 1.51 (dd, 1H), 1.24 (s, 3H), 1.15 (s, 3H), 1.11 (dd, 1H), 0.93 (dd, 1H);
3

3976
Q. Wang et al. / Tetrahedron: Asymmetry 9 (1998) 3971–3977
1
3
C NMR (CDCl , 250 MHz) δ: 179.2 (COOH), 27.0 (CH), 26.6 (CH ), 24.5 (C(CH ) ), 22.9 (CH ),
3
3
3 2
2
2
0
1
8.6 (CH ). [α]
+114 (c, 1.13, CHCl3).
.5. Determination of enantiomeric excess of (+)-10
S-methyl mandelate (0.2 mmol) and dicyclohexylcarbodiimide (0.2 mmol) were added to a solution
3
D
3
of acid (+)-10 (0.2 mmol) and 4-dimethylaminopyridine (0.04 mmol) in 5 ml CH Cl at −10°C, and
2
2
the mixture was stirred for 3 h at −10°C. After filtration of the precipitated urea, the solvent was
1
removed with a rotavapor. Without further purification, H NMR was obtained in C D and the split peak
6
6
(
around δ 6.1) of mandelate methine proton was used to calculate the ee of (+)-10. The corresponding
diastereomeric mixture of S-methyl mandelate ester derivative was prepared from the racemic 2,2-
dimethylcyclopropane carboxylic acid in the same way.
3
.6. X-Ray structure determination of SS-(−)-2,2-dimethyl-1-O-methoxyphenyl (tricarbonyl chro-
mium)cyclopropane
(
−)-8 A yellow crystal (0.3×0.15×0.15 mm) of compound (−)-8, which was obtained by slow
evaporation of an ethyl ether solution, was anchored with epoxy in a quartz capillary tube and mounted
on the autodiffractometer for data collection. A summary of crystallographic data (collected at room
temperature) and structure refinement is given in Table 1. Cell constants were determined by least-
squares refinement of 10 reflections. Data were sorted and collected using PCXTL.13 Orientation and
crystal decay were monitored by measuring the intensities of three standard reflections at intervals of
1
20 min. Minimal intensity losses were observed. Data reduction, handling and analysis were performed
14
using NRCVAX. The locations of non-hydrogen atoms were determined by direct methods using
15
16
SHELXS-86. The structure was refined against F using SHELX-76. All heavy atoms were refined
anisotropically. Hydrogen atoms were allowed to ride on the heavy atom to which they were attached,
with hydrogen atom thermal parameters fixed at 1.2 times the equivalent isotropic thermal parameter of
the heavy atom. The Flack x parameter was 0.019 with an esd of 0.042. The expected value is 0 (within
3
esds) for the correct enantiomer, and +1 for the inverted enantiomer.
Acknowledgements
Support for this research was provided by the PRF. We thank Dr. Alexander Blumenfeld for technical
assistance in NMR.
References
1
2
. Kropp, H.; Sundelof, J. G.; Hajdu, R.; Kahan, F. M. Antimicrob. Agents Chemother. 1980, 17, 993.
. Graham, D. W.; Ashton, W. T.; Barash, L.; Brown, J. E.; Brown, R. D.; Canning, L. F.; Chan, A.; Springer, J. P.; Rogers,
E. F. J. Med. Chem. 1987, 30, 1074.
3
4
5
6
7
8
. Mori, A.; Arai, I.; Yamamoto, H. Tetrahedron 1986, 42, 6447.
. Kang, J.; Lim, G. J.; Yoon, S. K.; Kim, M. Y. J. Org. Chem. 1995, 60, 564.
. Aratani, T. Pure & Appl. Chem. 1985, 57, 1839.
. Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726.
. Theys, R. D.; Hossain, M. M. Tetrahedron Lett. 1995, 36, 5113.
. Davies, S. G.; Goodfellow, C. L. J. Chem. Soc., Perkin Trans. 1 1989, 192.

Q. Wang et al. / Tetrahedron: Asymmetry 9 (1998) 3971–3977
3977
Table 1
Crystallographic data for SS-(−)-2,2-dimethyl-1-O-methoxyphenyl(tricarbonyl chromium)cyclopro-
pane (−)-8
9. Park, D. Chem. Rev. 1991, 91, 1411 and references cited therein.
1
1
1
1
1
1
1
0. Park, D. J. Chem. Soc., Perkin Trans. 2 1983, 83.
1. Theys, R. D.; Vargas, R. M.; Wang, Q.; Hossain, M. M. Organometallics 1998, 17, 1333.
2. Plotking, J. S.; Shore, S. G. Inorg. Chem. 1981, 20, 284.
3. Weinrach, J. B.; Bennett, D. W. J. Appl. Cryst. 1991, 24, 91.
4. Gabe, E. J.; Le Page, Y.; Charland, J. P.; Lee, F. L.; White, P. S. J. Appl. Cryst. 1989, 22, 384.
5. Sheldrick, G. M. Acta. Cryst. 1990, A46, 467.
6. Sheldrick, G. M. A Program for Crystal Structure Solution, University of Cambridge, Cambridge, England, 1976.