Synthesis of novel sterically demanding carbo- and heterocyclic β-ketoesters

Article abstract of DOI:10.3390/11050357

We present an easy method for the synthesis of β-ketoesters starting from various carbocyclic and heterocyclic carboxylic acids and esters. The β-ketoester side-chain was introduced by a sequence involving α-deprotonation and quenching with CO₂

Full text of DOI:10.3390/11050357

Molecules 2006, 11, 357-364
molecules
ISSN 1420-3049
http://www.mdpi.org
Full Paper
Synthesis of Novel Sterically Demanding Carbo- and
Heterocyclic β-Ketoesters
Marko D. Mihovilovic,* Thomas C. M. Fischer and Peter Stanetty
Vienna University of Technology – Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC,
A-1060 Vienna, Austria
* Author to whom correspondence should be addressed; E-mail: mmihovil@ioc.tuwien.ac.at
Received: 16 December 2005; in revised form: 10 February 2006 / Accepted: 12 February 2006 /
Published: 10 May 2006
Abstract: We present an easy method for the synthesis of β-ketoesters starting from various
carbocyclic and heterocyclic carboxylic acids and esters. The β-ketoester side-chain was
introduced by a sequence involving α-deprotonation and quenching with CO2, conversion to
the corresponding acid chloride and subsequent chain elongation using deprotonated ethyl
acetate.
Keywords: Chain elongation, β-ketoesters, ethyl acetate, heterocyclic esters
Introduction
β-Ketoesters incorporating sterically demanding structural motifs have previously received
attention as precursors for the synthesis of biologically active compounds such as CP-263,114
(Phomoidride B) and CP-225,917 (Phomoidride A), which were reported to inhibit ras-farnesyl
transferase and squalene synthase [1]. Such compounds were also used as intermediates for the
synthesis of bicyclononedionetetracarboxylic tetramethyl ester (BCN) metal chelates [2]. These
products are of significant value in various applications such as catalysts, paint dryers, and motor fuel
anti knock agents. A recent study demonstrated the applicability of β-ketoesters as key precursors for
the synthesis of the C13 side chain of Taxol in a bioreductive approach [3]. Taxol and derivatives are
currently used for the treatment of various kinds of cancer, such as ovarian, breast, and small cell lung
cancer as well as melanoma. We envisioned such a strategy to incorporate functional groups with

Molecules 2006, 11
358
increased polarity in combination with sterically demanding centers, which may improve the solubility
of modified taxoids by preventing the hydrophobic collapse of the bioactive species [4].
Results and Discussion
In this contribution we present a versatile, robust, and efficient method for the synthesis of
β-ketoesters with a quaternary center and a carbo- or heterocyclic structural core starting from various
cyclic carboxylic acids 1 and esters 2 (Scheme 1). In a straightforward strategy, compounds 3a-e were
prepared by lithiation, either starting from the corresponding acid 1 and incorporating an ester
functionality [5] with chloroacetic acid methyl ester (step a), or from the preceding ester 2 by
introducing the acid functionality [6] with CO2 (step b). Reaction conditions found in the literature
were optimized to ensure complete lithiation prior to quenching with the corresponding electrophile
(Table 1). For carbocyclic precursors introduction of the ester functionality via pathway a proved to
give better yields than pathway b. In the case of heterocyclic starting materials, the corresponding
esters were used as they are commercially available and introduction of the carboxylic acid
functionality gave satisfactory yields. Formation of the acid halide 4 (step c) was accomplished with
thionyl chloride using standard reaction conditions [7].
Scheme 1.
COOH
O
step a
COOEt
MeOOC
COOH
step c
MeOOC
COCl
X
MeOOC
step d
1a,b,c
COOMe
step b
X
X
X
3a-e
4a-e
5a-e
X
2b,d,e
X= - (a), -CH2- (b), -CH2-CH2- (c), -O- (d), -NCOOCH3- (e)
Table 1.
step a
step b
step c
SOCl2
step d
conditions
LDA/ClCOOMe
-75±5°C/THF
LDA/CO2
-15°C/THF
LDA/EtOAc
-80°C/THF
dry CH2Cl2/RT
X
-
Yields
83 %
92 %
83 %
-
-
99 %
96 %
99 %
97 %
91 %
58 %
85 %
72 %
82 %
93 %
-CH2-
68 %
-
-CH2-CH2-
-O-
72 %
84 %
-NCOOCH3
-

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A key transformation of this synthetic pathway is the introduction of the side chain by reaction
with deprotonated EtOAc to product 5 (step d) [8]. Following work-up protocols for related reactions
from the literature under basic conditions usually led to formation of lithium enolates of compounds 5,
which were difficult to isolate. Such problems could be circumvented by hydrolyzing the crude
reaction mixture with 2N HCl, which provided the required products usually in high yields.
Conclusions
In this work we developed a facile synthetic pathway for the formation of β-ketoesters
incorporating a cyclic structural motif bearing a quaternary ester functionality. The reaction sequence
was accomplished involving commercially available starting materials and simple steps in very good
overall yields for both carbo- and heterocyclic systems.
Acknowledgements
The authors thank the Austrian Science Fund (FWF, project number P15781) for supporting this
project.
Experimental
General
Unless otherwise noted, chemicals were purchased from commercial suppliers and used without
further purification. All solvents were distilled prior to use. Flash column chromatography was
performed on silica gel 60 from Merck (40-63 µm). Melting points were determined using a Kofler-
type Leica Galen III micro hot stage microscope and are uncorrected. NMR spectra were recorded
from CDCl3 solutions on a Bruker AC 200 (200 MHz) and chemical shifts are reported in ppm using
TMS as internal standard. Combustion analyses were carried out in the Microanalytic Laboratory,
University of Vienna.
General procedure for the preparation of 1,1-dicarboxylic acid mono-methylesters introducing the
ester functionality
Diisopropylamine (2-2.5 equiv.) in dry THF was treated with n-BuLi (2.5M in hexane, 2-2.5 equiv.)
under nitrogen and stirred for 30 min at -40°C. Then carboxylic acid 1 (1 equiv.) was added and the
mixture was heated to 50-60°C (reaction time depending on the acid). The mixture was cooled to
-75±5°C, ethyl chloroformate (1 equiv.) was added, and the reaction was stirred for 30 min at this
temperature. The solution was poured into the same amount of deionized water. The aqueous phase
was washed three times with diethyl ether. Then the pH of the aqueous layer was adjusted to 2-3 with
2N HCl followed by triple extraction with diethyl ether. The combined organic layers were washed
once with brine, dried over Na2SO4, and concentrated. According to NMR the products were pure and
were used in the next step without further purification.

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Cyclopentane-1,1-dicarboxylic acid methylester (3a)
Yield: 12.46cg (83%) as a yellow oil from diisopropylamine (30.7 mL, 219 mmol), dry THF (200
mL), n-BuLi (92.5 mL, 219 mmol), cyclopentanecarboxylic acid 1a (10.0 g, 87.6 mmol in 30 mL dry
THF) and ethyl chloroformate (6.7 mL, 87.6 mmol in 15 mL dry THF) with a deprotonation time of 3
1
hours at 50-60°C. H-NMR δ: 1.36-2.35 (m, 8H, -(CH2)4-), 3.72 (s, 3H, -OCH3), 11.36 (s, 1H, -
COOH); 13C-NMR δ: 25.4 (t, C3/C4), 34.6 (t, C2/C5), 52.7 (q, -OCH3), 60.3 (s, C1), 172.8 (s, -
COOMe), 178.8 (s, -COOH)
Cyclohexane-1,1-dicarboxylic acid methylester (3b)
Yield: 13.35 g (92%) as yellow crystals [6] from diisopropylamine (21.9 mL, 156 mmol), dry THF
(150 mL), n-BuLi (64.7 mL, 156 mmol), cyclohexanecarboxylic acid 1b (10.0 g, 78 mmol in 30 mL
dry THF) and ethyl chloroformate (6 mL, 78 mmol in 15 mL dry THF) with a deprotonation time of 2
hours at 50-60°C. Mp: 74-77°C; 1H-NMR δ: 1.39–2.06 (m, 10H, -(CH2)5-), 3.75 (s, 3H, -OCH3), 10.17
13
(s, 1H, -COOH); C-NMR δ: 22.6 (t, C3/C5), 24.9 (t, C4), 31.2 (t, C2/C6), 52.5 (q, -OCH3), 55.0 (s,
C1), 171.9 (s, -COOMe), 178.1 (s, -COOH)
Cycloheptane-1,1-dicarboxylic acid methylester (3c)
Yield: 11.67g (83%) as a yellow oil from diisopropylamine (29.6 mL, 210.9 mmol), dry THF (200
mL), n-BuLi (89.1 mL, 210.9 mmol), cycloheptanecarboxylic acid 1c (10.0 g, 70.3 mmol in 30 mL dry
THF) and ethyl chloroformate (5.4 mL, 70.3 mmol in 15 mL dry THF) with a deprotonation time of 4
1
hours at 50-60°C. H-NMR δ: 1.36-2.19 (m, 12H, -(CH2)6-), 3.66 (s, 3H, -OCH3), 9.97 (s, 1H, -
COOH); 13C-NMR δ: 23.8 (t, C4/C5), 29.8 (t, C3/C6), 33.6 (t, C2/C7), 52.5 (q, -OCH3), 57.7 (s, C1),
172.9 (s, -COOMe), 178.9 (s, -COOH)
General procedure for the preparation of 1,1-dicarboxylic acid monomethylesters by introducing the
acid functionality
n-BuLi (2.5M in hexane, 1.5-2 equiv.) was added to a stirred solution of diisopropylamine (1.5-2
equiv.) in dry THF (N2, -10 to -15°C). After 15 min this mixture was treated dropwise (during 30 min)
with a solution of methyl ester 2 (1 equiv.), followed by passing a fast and dry stream of CO2 through
the mixture for 15 min. The solution was then poured into the same amount of deionized water. The
aqueous phase was separated and washed three times with diethyl ether. Then the pH of the aqueous
layer was adjusted to 2-3 with 2N HCl and it was extracted three times with diethyl ether. The organic
layer was washed once with brine, dried over Na2SO4 and evaporated. According to NMR the products
were pure and were used in the next step without purification.
Cyclohexane-1,1-dicarboxylic acid methylester (3b)
Yield: 4.55 g (68%) as yellow crystals [6] from diisopropylamine (5.9 mL, 42 mmol), dry THF (50
mL), n-BuLi (25.2 mL, 42 mmol), and 2b (5.09 g, 36 mmol).

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Tetrahydropyran-4,4-dicarboxylic acid methylester (3d)
Yield: 9.5 g (72%) as colorless crystals from diisopropylamine (19.7 mL, 140.8 mmol), dry THF
(200 mL), n-BuLi (59.5 mL, 140.8 mmol), and 2d (10.0 g, 70.4 mmol).. Mp: 113-116°C; 1H-NMR δ:
2.01-2.18 (m, 4H, H3/H5), 3.57-3.76 (m, 4H, H2/H6), 3.72 (s, 3H, -OCH3), 10.25 (s, 1H, -COOH);
13C-NMR δ: 30.8 (t, C3/C5), 52.2 (s, C4), 52.9 (q, -OCH3), 64.6 (t, C2/C6), 170.9 (s, -COOMe), 175.1
(s, -COOH)
1,4,4-Piperidinetricarboxylic acid 1,4-dimethylester (3e)
Yield: 4.22 g (84%) as colorless crystals from diisopropylamine (5.8 mL, 41.1 mmol), dry THF (60
mL), n-BuLi (17.4 mL, 41.1 mmol), and 2e (4.14 g, 20.55 mmol). Mp: 123-126°C; 1H-NMR δ: 2.02 (t,
J=6Hz, 4H, H3/H5), 3.43 (t, J=7Hz, 4H, H2/H6), 3.63 (s, 3H, -OCH3), 3.69 (s, 3H, -NCOOCH3),
10.15 (bs, 1H, -COOH); 13C-NMR δ: 30.3 (t, C3/C5), 40.9 (t, C2/C6), 52.8 (q, -OCH3), 52.9 (q, -
OCH3), 53.0 (s, C4), 156.1 (s, -NCOOMe), 170.1 (s, -COOMe), 173.9 (s, -COOH)
General procedure for the formation of acid chlorides
Thionyl chloride (2 equiv.) was added to a 10% solution of the corresponding dicarboxylic acid
monomethyl ester (1 equiv.) and stirred for 2-6 days at room temperature. The crude material was
isolated after evaporation of the volatiles in vacuo. According to NMR the products were pure and
were used in the next step without further purification.
1-Chlorocarbonylcylopentane-1-carboxylic acid methyl ester (4a)
Yield: 4.22 g (84%) as a red brown oil from compound 3a (12.46 g, 72.4 mmol) and thionyl
1
chloride (10.5 mL, 144.8 mmol). H-NMR δ: 1.36-2.35 (m, 8H, -(CH2)4-), 3.72 (s, 3H, -OCH3); 13C-
NMR δ: 25.3 (t, C3/C4), 34.9 (t, C2/C5), 53.1 (q, -OCH3), 70.4 (s, C1), 170.6 (s,-COOMe), 173.1 (s, -
COCl)
1-Chlorocarbonylcyclohexane-1-carboxylic acid methyl ester (4b)
Yield: 15.9 g (96%) as a red brown oil from compound 3b (14.032 g, 75.35 mmol) and thionyl
1
13
chloride (10.9 mL, 150.7 mmol). H-NMR δ: 1.33–2.15 (m, 10H, (CH2)5), 3.72 (s, 3H, -OCH3); C-
NMR δ: 22.5 (t, C3/C5), 24.8 (t, C4), 31.8 (t, C2/C6), 52.9 (q, -OCH3), 64.7 (s, C1), 169.9 (s, -
COOMe), 173.2 (s, -COCl)
1-Chlorocarbonylcycloheptane-1-carboxylic acid methyl ester (4c)
Yield: 11.35 g (99%) as a red brown oil from compound 3c (10.47 g, 52.3 mmol) and thionyl
1
13
chloride (7.6 mL, 104.6 mmol). H-NMR δ: 1.41-2.21 (m, 12H, -(CH2)6-), 3.71 (s, 3H, -OCH3); C-
NMR δ: 23.5 (t, C4/C5), 29.6 (t, C3/C6), 33.9 (t, C2/C7), 52.9 (q, -OCH3), 67.7 (s, C1), 170.9
(s, -COOMe), 173.7 (s, -COCl)

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4-Chlorocarbonyltetrahydopyran-4-carboxylic acid methyl ester (4d)
Yield: 10.02 g (97%) as a red brown oil from compound 3d (9.438 g, 50.2 mmol) and thionyl
1
chloride (7.3 mL, 100.4 mmol). H-NMR δ: 2.09-2.20 (m, 4H, H3/H5), 3.62-3.68 (m, 4H, H2/H6),
3.76 (s, 3H, -OCH3); 13C-NMR δ: 31.4 (t, C3/C5), 53.3 (q, -OCH3), 61.9 (s, C4), 64.0 (t, C2/C6),
168.8 (s, -COOMe), 172.4 (s, -COCl)
4-Chlorocarbonylpiperidine-1,4-dicarboxylic acid dimethyl ester (4d)
Yield: 4.13 g (91%) as a red brown oil from compound 3d (4.22 g, 17.2 mmol) and thionyl chloride
(2.5 mL, 34.4 mmol). As the reaction was not complete after 3 days another 2 equiv. of thionyl
1
chloride were added and stirring was continued for another 3 days. H-NMR δ: 2.11-2.25 (m, 4H,
13
H3/H5), 3.50-3.58 (m, 4H, H2/H6), 3.70 (s, 3H, -NCOOCH3), 3.83 (s, 3H, -COOCH3); C-NMR δ:
30.9 (t, C3/C5), 40.4 (t, C2/C6), 52.8 (q, -OCH3), 53.4 (q, -OCH3), 62.8 (s, C4), 155.6 (s, -NCOOMe),
168.8 (s, -COOMe), 172.4 (s, -COCl)
General procedure for the formation of the β-ketoesters
To a solution of diisopropylamine (2 equiv.) in dry THF (N2, -20°C) n-BuLi (2.5M in hexane, 2
equiv.) was added and stirred for 15 min. Then the mixture was cooled to -80°C and dry ethyl acetate
was added and stirred for 15 min at this temperature. Afterwards, the corresponding acid chloride (1
equiv, in dry THF) was added dropwise and the resulting mixture was stirred for further 2 hours. The
reaction mixture was hydrolyzed by adding saturated NH4Cl-solution and stirring for another 15 min.
The mixture was then poured into the same amount of 2N HCl. The aqueous phase was extracted three
times with diethyl ether. The combined organic layers were washed once with brine, dried over
Na2SO4 and concentrated. Purification was carried out by column chromatography.
1-(2-Ethoxycarbonylacetyl)cyclopentanecarboxylic acid methyl ester (5a)
Yield: 10.00 g (57%) as a yellow oil from diisopropylamine (20.2 mL, 144 mmol), dry THF (150
mL), n-BuLi (60.6 mL, 144 mmol), dry ethyl acetate (7 mL, 72 mmol), and 4a (13.69 g, 72 mmol),
followed by hydrolysis with saturated NH4Cl-solution (8 mL). Product purification was achieved by
chromatography on silica gel (300 g, 20:1 LP-EtOAc). Elemental analysis: calculated: C 59.49%, H
7.49% found: C 59.67%, H.7.32%; 1H-NMR keto δ: 1.18 (t, J=7.18Hz, 3H, -CH3), 1.48-2.18 (m, 8H, -
(CH2)4-), 3.43 (s, 2H,-CH2-), 3.65 (s, 3H, -OCH3), 4.11 (q, J=7.16Hz, 2H, -OCH2-); enol δ: 1.18 (t,
J=7Hz, 3H, -CH3), 1.48-2.18 (m, 8H, -(CH2)4-), 3.65 (s, 3H, -OCH3), 4.11 (q, J=7Hz, 2H, -OCH2-),
5.03 (s, 1H, =CH-), 12.29 (s, 1H, -OH); 13C-NMR keto δ: 13.9 (q, -CH3), 25.5 (t, C3/C4), 32.9 (t,
C2/C5), 45.7 (t, C-α), 52.5 (q, -OCH3), 61.2 (t, -OCH2), 66.9 (s, C1), 166.7 (s, -COOMe), 173.2 (s, -
COOEt), 198.3 (s, C=O); enol δ: 13.9 (q, -CH3), 25.5 (t, C3/C4), 32.9 (t, C2/C6), 52.5 (q, -OCH3),
61.2 (t, -OCH2-), 66.9 (s, C1), 88,1(d, C-α), 166.7 (s, -COOMe), 173.2 (s, -COOEt), 178.1 (s, =C-OH)

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1-(2-Ethoxycarbonylacetyl)cyclohexanecarboxylic acid methyl ester (5b)
Yield: 14.2 g (80%) as a yellow oil from diisopropylamine (20.2 mL, 143.8 mmol), dry THF (150
mL), n-BuLi (60.6 mL, 143.8 mmol), dry ethyl acetate (7 mL, 71.9 mmol), and 4b (15.88 g, 71.9
mmol), followed by hydrolysis using saturated NH4Cl-solution (8 mL). Product purification was
achieved by chromatography on silica gel (300 g, 10:1 LP-EtOAc). Elemental analysis: calculated: C
1
60.92%, H 7.80% found: C 61.12%, H.7.62%; H-NMR keto δ: 1.23 (t, J=7Hz, 3H, -CH3), 1.17-2.12
(m, 10H, -(CH2)5-), 3.45 (s, 2H, -CH2-), 3.71 (s, 3H, -OCH3), 4.14 (q, J=7Hz, 2H, -OCH2-); enol δ:
1.23 (t, J=7Hz, 3H, -CH3), 1.17-2.12 (m, 10H, -(CH2)5), 3.71 (s, 3H, -OCH3), 4.14 (q, J=7Hz, 2H, -
OCH2-), 5.09 (s, 1H, =CH-), 12.38 (s, 1H, -OH); 13C-NMR keto δ: 13.9 (q, -CH3), 22.6 (t, C3/C5),
25.1 (t, C4), 30.4 (t, C2/C6), 44.9 (t, C-α), 52.5 (q, -OCH3), 61.3 (t, -OCH2), 61.4 (s, C1), 166.8 (s, -
COOMe), 171.9 (s, -COOEt), 199.9 (s, C=O); enol δ: 13.9 (q, -CH3), 22.6 (t, C3/C5), 25.1 (t,C4), 30.4
(t,C2/C6), 52.5 (q,-OCH3), 61.3 (t, -OCH2-), 61.4 (s, C1), 88.5 (d, C-α), 166.8 (s, -COOMe), 171.9 (s,
-COOEt), 176.2 (s, =C-OH)
1-(2-Ethoxycarbonylacetyl)cycloheptanecarboxylic acid methyl ester (5c)
Yield: 10.02 g (72%) as a yellow oil from diisopropylamine (14.4 mL, 103 mmol), dry THF (100
mL), n-BuLi (43.5 mL, 103 mmol), dry ethyl acetate (5 mL, 51.5 mmol), and 4c (11.26 g, 51.5 mmol)
followed by hydrolysis using saturated NH4Cl-solution (7 mL). Product purification was achieved by
chromatography on silica gel (300g, 10:1 LP:EtOAc). Elemental analysis: calculated: C 62.20%, H
1
8.20% found: C 62.45%, H.7.93%; H-NMR keto δ: 1.29 (t, J=7Hz, 3H, -CH3), 1.39-2.12 (m, 12H, -
(CH2)6-), 3.39 (s, 2H,-CH2-), 3.66 (s, 3H, -OCH3), 4.12 (q, J=7Hz, 2H, -OCH2-); enol δ: 1.29 (t, J=7Hz,
3H, -CH3), 1.39-2.12 (m, 12H -(CH2)6), 3.66 (s, 3H, -OCH3), 4.12 (q, J=7.11Hz, 2H, -OCH2-), 5.03 (s,
13
1H, =CH-), 12.33 (s, 1H, -OH); C-NMR keto δ: 13.9 (q, -CH3), 23.5 (t, C4/C5), 29.9 (t, C3/C6)),
32.1 (t, C2/C7), 45.1 (t, C-α), 52.4 (q, -OCH3), 61.2 (t, -OCH2-), 63.8 (s, C1), 166.7 (s, -COOMe),
173.3 (s, -COOEt), 199.4 (s, C=O); enol δ: 13.9 (q, -CH3), 23.5 (t, C4/C5), 29.9 (t, C3/C6), 32.1 (t,
C2/C7), 52.4 (q,-OCH3), 61.2 (t, -OCH2-), 63.8 (s, C1), 87.9 (d, C-α), 166.7 (s, -COOMe), 173.3 (s, -
COOEt), 179.6 (s, =C-OH)
4-(2-Ethoxycarbonylacetyl)tetrahydropyran-4-carboxylic acid methyl ester (5d)
Yield: 9.39g (82%) as a yellow oil from diisopropylamine (12.56 mL, 89.6 mmol), dry THF (100
mL), n-BuLi (37.9 mL, 89.6 mmol), dry ethyl acetate (4.4 mL, 44.8 mmol), and 4d (9.26 g, 44.8 mmol)
followed by hydrolysis using saturated NH4Cl-solution (6 mL). Product purification was achieved by
chromatography on silica gel (300g, 20:1 LP:EtOAc). Elemental analysis: calculated: C 55.81%, H
1
7.02% found: C 55.65%, H.6.74%; H-NMR keto δ: 1.18 (t, J=7Hz, 3H, -CH3), 1.81-2.14 (m, 4H,
H3/H5), 3.41-3.75 (m, H2/H6), 3.44 (s, 2H, -CH2-), 3.69 (s, 3H, -OCH3), 4.11 (q, J=7Hz, 2H, -OCH2-);
enol δ: 1.18 (t, J=7Hz, 3H, -CH3), 1.81-2.14 (m, 4H, H3/H5), 3.41-3.75 (m, H2/H6), 3.69 (s, 3H, -
OCH3), 4.11 (q, J=7Hz, 2H, -OCH2-), 5.04 (s, 1H, =CH), 12.35 (s, 1H, -OH); 13C-NMR keto δ: 13.9 (q,
-CH3), 29.9 (t, C3/C5), 44.5 (t, C-α), 52.8 (q, -OCH3), 58.8 (s, C4), 61.4 (t, -OCH2-), 64.4 (t, C2/C6),
166.4 (s, -COOMe), 170.9 (s, -COOEt), 198.5 (s, C=O); enol δ: 13.9 (q, -CH3), 29.9 (t, C3/C5), 52.8

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(q, -OCH3), 58.8 (s, C4), 61.4 (t, -OCH2-), 64.4 (t, C2/C6), 88.9 (d, C-α), 166.4 (s, -COOMe), 170.9 (s,
-COOEt), 176.5 (s, =C-OH)
4-(2-Ethoxycarbonylacetyl)piperidine-1,4-dicarboxylic acid dimethyl ester (5e)
Yield: 4.54 g (93%) as a yellow oil from diisopropylamine (4.34 mL, 31 mmol), dry THF (150 mL),
n-BuLi (13.1 mL, 31 mmol), dry ethyl acetate (1.5 mL, 15.5 mmol), and 4e (4.08 g, 15.5 mmol)
followed by hydrolysis using saturated NH4Cl-solution (4 mL). Product purification was achieved by
chromatography on silica gel (150 g, 7:1 LP:EtOAc). Elemental analysis: calculated: C 53.33%, H
1
6.71%, N 4.44% found: C 53.61%, H.6.78%, N 4.33%; H-NMR keto δ: 1.27 (t, J=7Hz, 3H, -CH3),
1.78-2.27 (m, 4H, H3/H5), 3.15-3.35 (m, H2/H6), 3.53 (s, 2H, -CH2), 3.68 (s, 3H, -OCH3), 3.79 (s, 3H,
-NCOOCH3), 4.19 (q, J=7Hz, 2H, -OCH2-); enol δ: 1.27 (t, J=7Hz, 3H, -CH3), 1.78-2.27 (m, 4H,
H3/H5), 3.15-3.35 (m, H2/H6), 3.68 (s, 3H, -OCH3), 3.79 (s, 3H, -NCOOCH3), 4.19 (q, J=7Hz, 2H, -
13
OCH2-), 5.12 (s, 1H, =CH-), 12.47 (s, 1H, -OH); C-NMR keto δ: 13.9 (q, -CH3), 29.3 (t, C3/C5),
40.6 (t, C2/C6), 44.7 (t, C-α), 52.5 (q,-OCH3), 52.8 (q, -NCOOCH3), 59.5 (s, C4), 61.3 (t, -OCH2-),
155.5 (s, -NCOOMe), 166.3 (s, -COOMe), 170.7 (s, -COOEt), 198.5 (s, C=O); enol δ: 13.9 (q, -CH3),
29.3 (t, C3/C5), 40.6 (t, C2/C6), 52.5 (q, -OCH3), 52.8 (q, -NCOOCH3), 59.5 (s, C4), 61.3 (t, -OCH2-),
88.9 (d, C-α), 155.5 (s, -NCOOMe), 166.3 (s, -COOMe), 170.7 (s, -COOEt), 176.2 (s, =C-OH).
References
1. a) Spiegel, D. A.; Njardson, J. T.; Wood, J. L. Tetrahedron 2002, 58, 6545-6554; b) Yoshimitsu,
T.; Sasaki, S.; Arano, Y.; Nagaoka, H. J. Org. Chem. 2004, 69, 9262-9268
2. Swigar, A. A.; Nesquehoning; Walde, R. A. U.S. Pat. 3,429,906; [Chem. Abstr. 1970, 70, 89282]
3. Feske, B. D.; Kaluzna, I.A.; Stewart, J. D. J. Org. Chem. 2005, 70, 9654-9657
4. a) Gao, Q.; Chen, S.-H. Tetrahedron Lett. 1996 37, 3425-3428; b) Vander Velde, D. G.; Georg, G.
I.; Grunewald, G. L.; Gunn, C. W.; Mitscher, L.A. J. Am. Chem. Soc. 1993, 115, 11650-11651; c)
Gao, Q.; Parker, W. L. Terahedron 1996, 52, 2291-2300; d) Boge, T. C.; Wu, Z.-H.; Himes, R. H.,
Vander Velde, D. G., Georg, G. I. Bio. Med. Chem. Lett. 1999, 3047-3052
5. Krapcho, P. A.; Jahngen, E. G. E.; Kashdan, D. S. Tetrahedron Lett. 1974, 32, 2721-2723
6. Reiffers, S.; Wynberg, H., Srating, J. Tetrahedron Lett. 1971, 32, 3001-3004
7. Toma, L.; Giovannoni, M. P.; Dal Piaz, V.; Kwon, B.-M.; Kim, Y.-K.; Gelain, A.; Barlocco, D.
Heterocycles 2002, 57, 39-46
8. Baraldi, P. T.; Zarbin, P. H. G.; Viera, P. C.; Corrêa, A. G. Tetrahedron Asym. 2002, 13, 621-624.
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