The synthesis of gem-cyclopentyl substituted glutarates via the oxidative ring contraction of 2-acetylcyclohexanones

Article abstract of DOI:10.1081/SCC-120012979

A two step synthesis of differentially protected gem-cyclopentyl glutarates has been developed from 2-acetylcyclohexanone and acrylates. The key step involves an oxidative ring contraction reaction with hydrogen peroxide. The methodology has been used to

Full text of DOI:10.1081/SCC-120012979

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THE SYNTHESIS OF GEM-CYCLOPENTYL SUBSTITUTED
GLUTARATES VIA THE OXIDATIVE RING CONTRACTION
OF 2-ACETYLCYCLOHEXANONES
Stephen Challenger a , Andrew Derrick a & Terry V. Silk a
a Pfizer Global Research & Development , Sandwich, Kent, CT13 9NJ, UK
Published online: 16 Aug 2006.
To cite this article: Stephen Challenger , Andrew Derrick & Terry V. Silk (2002) THE SYNTHESIS OF GEM-CYCLOPENTYL
SUBSTITUTED GLUTARATES VIA THE OXIDATIVE RING CONTRACTION OF 2-ACETYLCYCLOHEXANONES, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:19, 2911-2918, DOI:
10.1081/SCC-120012979
To link to this article: http://dx.doi.org/10.1081/SCC-120012979
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 19, pp. 2911–2918, 2002
THE SYNTHESIS OF
GEM-CYCLOPENTYL SUBSTITUTED
GLUTARATES VIA THE OXIDATIVE RING
CONTRACTION OF
2-ACETYLCYCLOHEXANONES
*
Stephen Challenger, Andrew Derrick,
and Terry V. Silk
Pfizer Global Research & Development,
Sandwich, Kent, CT139NJ, UK
ABSTRACT
A two step synthesis of differentially protected gem-cyclo-
pentyl glutarates has been developed from 2-acetylcyclo-
hexanone and acrylates. The key step involves an oxidative
ring contraction reaction with hydrogen peroxide. The
methodology has been used to prepare intermediates used in
the preparation of the atriopeptidase inhibitor candoxatril.
Key Words: Oxidative ring-contraction; Hydrogen perox-
ide; Preparation of cyclopentyl substituted glutarates
In the early stages of a programme directed at designing synthetic
routes to the atriopeptidase inhibitor candoxatril 1[1] (Sch. 1), we required
*Corresponding author. E-mail: stephen_challenger@sandwich.pfizer.com
2911
DOI: 10.1081/SCC-120012979
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2912
CHALLENGER,DERRICK,AND SILK
Scheme 1.
Scheme 2.
an efficient method for the preparation of the gem-cyclopentyl substituted
glutarates 2 and 3.
In the original synthesis of candoxatril, the key intermediate 2 was
prepared in less than 40% yield by the direct alkylation of the lithium
dianion of cyclopentanecarboxylic acid with tert-butyl 3-bromopropio-
nate.[2] We required a higher yielding, more economic synthesis of 2 and 3
that avoided the use of expensive dianion chemistry.
The oxidative rearrangement of 2-acylcyclohexanones with hydrogen
peroxide has been reported in the literature as a method for the preparation
of substituted cyclopentanecarboxylic acids.[3–6] This chemistry was used by
Payne[4] to prepare alkyl substituted cyclopentanecarboxylic acids and he
proposed a mechanism for the reaction involving ring contraction of the
cyclic peroxide intermediate 4 (Sch. 2). A literature survey of this reaction
revealed that the substrates reported to date have been either unsubstituted
2-acylcyclohexanones (R¼H, Sch. 2),[4] part of a spiro-diketone[3,5] or
substituted with an unfunctionalised alkyl group.[4,6] We were interested in
applying this reaction to substrates containing a carboxyethyl group
(R ¼ –CH2CH2CO2R, Sch. 2) to establish if this chemistry could be extended
to the preparation of differentially protected glutarate derivatives of types
2 and 3.
The availability of the required diketones 5 (Sch. 3)[7,8] through the
Michael reaction of commercially available 2-acetylcyclohexanone with

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GEM-CYCLOPENTYL SUBSTITUTED GLUTARATES
2913
Scheme 3.
Table 1. Reaction of Substituted 2-Acetylcyclohexanones with Hydrogen Peroxide
Entry
1
Substrate
Conditions
Products/Yielda
5a R1¼tBu, R2¼H
30% aqueous H2O2, H2SO4 2a 78% 6a 7%
(cat), t-BuOH rt 16 h
2
3
4
5b R1¼Bn, R2¼H
5c R1¼Et, R2¼H
5d R1¼tBu,
30% aqueous H2O2, H2SO4 2b 72%b
(cat), t-BuOH rt 20 h
30% aqueous H2O2, H2SO4 2c 67%b
(cat), t-BuOH rt 24 h
30% aqueous H2O2, H2SO4
3 72%c
R2¼ꢀ CH2OCH2CH2OMe (cat), t-BuOH rt 24 h
aAll yields correspond to purified material. bHeptanedioic acid major impurity in
c
reaction but not isolated. Product isolated as crystalline isopropylamine salt.
inexpensive acrylates was an attractive feature of this approach. It is note-
worthy that inexpensive hydroxide, carbonate or alkoxide bases can be used
in this reaction instead of expensive lithium diisopropylamide used in the
original dianion chemistry. A series of substituted 2-acetylcyclohexanones
(5a–d, Sch. 3and Table 1) were prepared using the method of Yanovskaya
et al.[9] The crude products 5a–d were obtained as oils and were used directly
in the next step without purification.
With the required substrates 5 in hand, we investigated the key oxida-
tive ring contraction reaction with hydrogen peroxide (CAUTION: all reac-
tions involving hydrogen peroxide and organo-peroxide intermediates

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2914
CHALLENGER,DERRICK,AND SILK
should be conducted behind a safety shield[10]) (Table 1). Acid or base
catalysis was used since this type of reaction has been reported to be slow
under neutral conditions.[4]
Treatment of substrate 5a with a 30% aqueous solution of hydrogen
peroxide and sulfuric acid catalyst in t-butanol gave the desired glutarate 2a
in 78% yield after chromatography (Entry 1). The heptanedioic acid 6a was
also isolated in 7% yield, and is believed to arise from the alternative frag-
mentation of the proposed peroxide intermediate 4.[4] This impurity can
readily be purged by selective extraction into aqueous base. The presence
of the ester side chain in substrates 5a–d did not interfere with oxidative ring
contraction chemistry and similar yields were obtained compared with those
reported for simple alkyl substituted 2-acylcyclohexanones.
A base-catalysed oxidative ring contraction reaction on substrate 5a
gave the desired product but in lower yield. Also, sodium perborate tetra-
hydrate in acetic acid and sodium percarbonate in t-butanol can be success-
fully used as alternative sources of hydrogen peroxide in this reaction,
although the yields are lower compared with the acid-catalysed process
using aqueous hydrogen peroxide. In this sequence of reactions the enolate
of 2-acetylcyclohexanone can be regarded as a synthetic equivalent of the
cyclopentanecarboxylic acid dianion.
The methodology has been successfully applied to the preparation of
the more highly substituted glutarate 3 (Table 1, Entry 4) containing a
2-methoxyethoxy methyl (MEM) side chain. A problem with this synthesis
was a low yielding Michael addition reaction to prepare diketone 5d (Sch. 4),
due to competing b-elimination of 2-methoxyethanol to give acrylate 8.
An extensive investigation of base and solvent combinations led to the
discovery of optimised conditions for this reaction involving catalytic
potassium t-butoxide in acetonitrile at ꢀ10ꢁC. The Michael adduct 5d
was obtained from 2-acetylcyclohexanone and acrylate 7[2b] in 55% yield
after chromatography.
Scheme 4.

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GEM-CYCLOPENTYL SUBSTITUTED GLUTARATES
2915
In summary, we have developed an efficient two step synthesis of the
differentially protected gem-cyclopentyl glutarates 2 and 3 from commer-
cially available and inexpensive 2-acetylcyclohexanone and acrylates.
The key step, involving an oxidative rearrangement of a substituted
2-acetylcyclohexanone, has been demonstrated in substrates with side
chains containing ester functionality. The methodology has been used to
prepare intermediates used in the preparation of the atriopeptidase
inhibitor candoxatril.
EXPERIMENTAL
Melting points were determined on a Electrothermal melting point
1
apparatus and are uncorrected. 300 MHz H NMR and 75 MHz 13C NMR
spectra were recorded in CDCl3. Chemical shifts are reported in ppm (ꢀ)
relative to residual protons in the deuterated solvent. Analytical thin-layer
chromatography (TLC) was carried out using commercial glass-backed
Merck, Silica gel 60, F254 plates. All materials obtained from commercial
suppliers were used without further purification.
General procedure for preparation of substituted 2-acetylcyclohexanones
5a–c:[7,8] To a suspension of 2-acetylcyclohexanone, potassium carbonate
(1.2 eq) and benzyltriethylammonium chloride (0.02 eq) in toluene
(2.8 mL/g) was added in one portion the appropriate acrylate (1.5 eq) at
room temperature. The suspension was stirred at 40ꢁC for 18 h, diluted
with distilled water (10 mL/g) and toluene (5 mL/g) and the layers separated.
The aqueous layer was extracted with toluene (3 ꢂ 5 mL/g), the combined
toluene extracts dried over magnesium sulfate, filtered and concentrated in
vacuo to give the desired substituted 2-acetylcyclohexanone 5a–c. The crude
products were used without further purification.
2-Acetyl-2-[2-(tert-butoxycarbonyl)-3-(2-methoxyethoxy)-propyl]cyclo-
hexanone (5d): To a suspension of 2-acetylcyclohexanone (3.5 g, 0.025 mol)
and tert-butyl 2-(2-methoxyethoxymethyl)acrylate (5.41 g, 0.025 mol) (see
Ref. [2b] for preparation) in acetonitrile (20 mL) was added in one portion,
potassium tert-butoxide (0.14 g, 0.0012 mol) at ꢀ10ꢁC. The mixture was
stirred at ꢀ10ꢁC for 24 h and at room temperature for 18 h. The mixture
was partitioned between ethyl acetate (15 mL) and distilled water (20 mL)
and the layers separated. The aqueous layer was extracted with ethyl acetate
(2 ꢂ 15 mL) and the combined ethyl acetate extracts concentrated in vacuo
to give a brown oil (7.52 g). The crude product was purified by chromatog-
raphy on silica by eluting with n-hexane/ethyl acetate (4 : 1) to give the
desired product 5d as a mixture of diastereoisomers, (4.98 g, 55.8%) IR

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2916
CHALLENGER,DERRICK,AND SILK
(neat) 2980, 2935, 2870, 1720, 1695, 1450 cmꢀ1. Anal. %. Found: C, 64.22;
H, 9.03. C19H32O6 requires: C, 64.02; H, 9.05.
General procedure for the oxidative ring contraction reaction illustrated
by the preparation of 2a: CAUTION: All reactions involving hydrogen
peroxide and organo-peroxide intermediates should be conducted behind
a safety shield.
1-[2-tert-Butoxycarbonyl)ethyl]-1-cyclopentanecarboxylic acid 2a: To a
solution of crude 2-acetyl-2-[2-(tert-butoxycarbonyl)ethyl]cyclohexanone 5a
(42 g, 0.15 mol) in tert-butanol (84 mL) was cautiously added a 30% aqueous
solution of hydrogen peroxide (21 mL, 0.187 mol) and concentrated sulfuric
acid (0.25 mL, 98% w/w) at room temperature, maintaining the reaction
temperature below 50ꢁC during the addition. The mixture was stirred at
room temperature for 18 h, partitioned between dichloromethane (100 mL)
and water (100 mL), and the layers separated. The dichloromethane layer was
washed with a 5% aqueous sodium sulfite solution (50 mL), dried over mag-
nesium sulfate, filtered and concentrated in vacuo to give the crude product.
The crude product partially crystallised on standing overnight to provide the
desired compound 2a (15.5 g), after collecting and washing with n-pentane.
Chromatographic purification of the mother liquors on silica (ethyl
acetate : n-hexane 1 : 10) provided a further 14.47 g of the desired compound
(combined yield 29.97 g, 78%), m.p. ¼ 89–93ꢁC. H NMR (CDCl3) ꢀ 1.45
1
(s, 9H), 1.45–1.60 (m, 2H), 1.62–1.78 (m, 4H), 1.92–1.99 (m, 2H), 2.11–2.21
(m, 2H), 2.21–2.33 (m, 2H) ppm. 13C NMR (CDCl3) ꢀ 25.30, 28.33, 32.45,
33.74, 36.29, 53.32, 80.57, 172.99, 184.23 ppm.
The following glutarates (shown in Table 1) were prepared using this
general procedure.
1-[2-(Benzyloxycarbonyl)ethyl]-1-cyclopentanecarboxylic acid 2b: IR
1
(neat) 3800–2400, 1735, 1695, 1450 cmꢀ1. H NMR (CDCl3) ꢀ 1.47–1.63
(m, 2H), 1.62–1.80 (m, 4H), 1.98–2.10 (m, 2H), 2.10–2.25 (m, 2H),
2.38–2.53 (m, 2H), 5.15 (s, 2H), 7.38–7.46 (m, 5H) ppm. 13C NMR
(CDCl3) ꢀ 25.02, 31.01, 33.72, 36.69, 53.38, 66.69, 128.38, 129.06, 136.35,
173.72, 183.72 ppm. Anal. %. Found: C, 69.70; H, 7.18. C16H20O4 requires:
C, 69.55; H, 7.29.
1-[2-(Ethyoxycarbonyl)ethyl]-1-cyclopentanecarboxylic acid 2c: 1H NMR
(CDCl3) ꢀ 1.31 (t, 3H), 1.47–1.62 (m, 2H), 1.62–1.82 (m, 4H), 1.92–2.08 (m,
2H), 2.10–2.27 (m, 2H), 2.32–2.46 (m, 2H), 4.19 (q, 2H) ppm. 13C NMR
(CDCl3) ꢀ 14.26, 25.15, 31.21, 33.56, 36.15, 53.21, 60.49, 173.38, 183.52 ppm.
1-[2-(tert-Butoxycarbonyl)-3-(2-methoxyethoxy)propyl]-1-cyclopentane
carboxylic acid (3) isopropylamine salt: To a solution of 2-acetyl-2-[2-(tert-
butoxycarbonyl)-3-(2-methoxyethoxy)propyl]cyclohexanone 5d (5.45 g,
0.015 mol) in tert-butanol (10.9 mL) and concentrated sulfuric acid (one
drop) was cautiously added a 30% aqueous solution of hydrogen peroxide

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GEM-CYCLOPENTYL SUBSTITUTED GLUTARATES
2917
(2.1 mL, 0.018 mol) at room temperature. The mixture was stirred at room
temperature for 24 h, partitioned between dichloromethane (20 mL) and the
layers separated. The dichloromethane layer was washed with water
(10 mL), the combined aqueous extract acidified to pH 2 with aqueous
hydrochloric acid solution (5 M) and extracted with n-hexane (2 ꢂ 20 mL).
The combined n-hexane extracts were washed with water (5 mL), concen-
trated under reduced pressure and azeotropically dried with ethyl acetate to
give the title acid as an oil (3.99 g, 79% crude yield, 96% purity GC normal-
isation). Rf 0.44 (silica, ethyl acetate, 1% acetic acid). The crude acid (3.4 g,
0.01 mol) was dissolved in n-hexane (34 mL), and isopropylamine (0.61 g,
0.01 mol) was added at room temperature. The precipated salt was cooled to
0ꢁC, granulated for 2 h and collected to give the title compound (3.57 g, 92%
yield salt formation, 72% overall yield; HPLC main band assay 98.7%),
m.p. ¼ 84–87ꢁC. H NMR (CDCl3): ꢀ 1.23(d, 6H), 1.45 (s, 9H), 1.35–1.50
1
(m, 2H), 1.58–1.70 (m, 4H), 1.78 (dd, 1H), 1.88 (dd, 1H), 2.05–2.19 (m, 2H),
2.60–2.69 (m, 1H), 3.28 (heptet, 1H), 3.36 (s, 3H), 3.48–3.62 (m, 6H), 5.98
(br s, 3H) ppm. 13C NMR (CDCl3) ꢀ 21.99, 24.51, 24.97, 27.86, 34.64, 37.98,
43.05, 44.94, 54.57, 58.78, 69.91, 71.68, 73.48, 79.98, 174.79, 183.22 ppm.
Anal. %. Found: C, 61.64; H, 10.30; N, 3.46. C20H39NO6 requires: C, 61.67;
H, 10.09; N, 3.60.
ACKNOWLEDGMENT
We would like to thank Dr. Mike Williams (PGRD, Sandwich) for his
encouragement and helpful discussions during this work.
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2918
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Received in the Netherlands September 27, 2001