Synthesis of the 1-monoester of 2-ketoalkanedioic acids, for example, octyl α-ketoglutarate

Article abstract of DOI:10.1021/jo302308q

Oxidative cleavage of cycloalkene-1-carboxylates, made from the corresponding carboxylic acids, and subsequent oxidation of the resulting ketoaldehyde afforded the important 1-monoesters of 2-ketoalkanedioic acids. Thus ozonolysis of octyl cyclobutene-1-carboxylate followed by sodium chlorite oxidation afforded the 1-monooctyl 2-ketoglutarate. This is a cell-permeable prodrug form of α-ketoglutarate, an important intermediate in the tricarboxylic acid (TCA, Krebs) cycle and a promising therapeutic agent in its own right.

Full text of DOI:10.1021/jo302308q

Note
pubs.acs.org/joc
Synthesis of the 1‑Monoester of 2‑Ketoalkanedioic Acids, for
Example, Octyl α‑Ketoglutarate
Michael E. Jung* and Gang Deng
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
S
* Supporting Information
ABSTRACT: Oxidative cleavage of cycloalkene-1-carboxy-
lates, made from the corresponding carboxylic acids, and
subsequent oxidation of the resulting ketoaldehyde afforded
the important 1-monoesters of 2-ketoalkanedioic acids. Thus
ozonolysis of octyl cyclobutene-1-carboxylate followed by
sodium chlorite oxidation afforded the 1-monooctyl 2-ketoglutarate. This is a cell-permeable prodrug form of α-ketoglutarate, an
important intermediate in the tricarboxylic acid (TCA, Krebs) cycle and a promising therapeutic agent in its own right.
he citric acid cycle, also known as the tricarboxylic acid
(TCA) cycle or the Krebs cycle, is the mechanism
monoesters of α-ketodicarboxylic acids, all of which are
analogues of α-ketoglutarate. We believe that the guarantee of
obtaining only the desired 1-monoester in generally quite pure
form makes up for the additional number of steps that this
method employs versus the direct esterification.
T
whereby aerobic organisms generate energy via oxidation of
acetate ultimately into carbon dioxide (Figure 1).1 A key step in
Synthesis of 1-Monooctyl α-Ketoglutarate, 6. We
decided to use the ozonolysis7 of a cycloalkene-1-carboxylate
as the penultimate step in preparing the monoesters of the α-
ketodicarboxylic acids. This guarantees the formation of only
the mono ester and its regiochemistry. The resulting
ketoaldehyde would be oxidized to the acid in the last step.
Thus for monooctyl α-ketoglutarate 6, one would need the
cyclobutene-1-carboxylic acid 8 (Scheme 1). Although this
Figure 1. Part of the citric acid cycle.
Scheme 1. Synthesis of 1-Monooctyl α-Ketoglutarate
this pathway is the conversion of D-isocitrate 3 (formed from
citrate 1 via aconitate 2) into α-ketoglutarate 4 via the enzyme
isocitrate dehydrogenase in an oxidative decarboxylation
process. α-Ketoglutarate 4 is then converted into succinyl
CoA 5 and ultimately via oxaloaceate into citrate to complete
the cycle. α-Ketoglutarate 4 is also prepared by the deamination
of glutamate and is thus an important chemical substance.2
Indeed a recent patent claims its use as a treatment for cancer
and other diseases.3 Recently for another project,4 we needed
to prepare a reasonable amount of a cell-permeable form of α-
ketoglutarate and chose the 1-monooctyl ester. Although there
are many biological methods for preparing α-ketoglutarate,5
e.g., by carboxylation of succinate using enzymes, we wanted to
use a chemical method. Several chemical methods exist for the
synthesis of the 1-ester of α-ketoglutarate,6 especially direct
esterification of 2-oxopentanedioic acid or other methods, but
those methods gave very mixed results in our hands. Therefore
we developed a new method for the synthesis of the monooctyl
ester 6 of α-ketoglutarate 4 via oxidative cleavage of a
cyclobutene-1-carboxylate, which guaranteed the formation of
the desired 1-monoester. We have further shown that this new
method can be applied to the synthesis of a variety of 1-
compound is commercially available, it was easily prepared in
72% yield by treatment of the readily available ethyl 1-
bromocyclobutane-1-carboxylate 7 with potassium hydroxide in
toluene.8 Formation of the ester was carried out using 1-octanol
and dicyclohexyl carbodiimide (DCC) with DMAP as base to
give the ester 9 in 96% yield. Ozonolysis of the cyclobutene was
carried out at −78 °C and dimethyl sulfide (DMS) was used to
Received: October 22, 2012
© XXXX American Chemical Society
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The Journal of Organic Chemistry
Note
Scheme 2. Synthesis of Other Monoesters of α-Ketoalkanedioic Acids
literature procedures. H NMR and 13C NMR spectra were obtained
at 300 or 500 MHz for proton and 75 or 125 MHz for carbon and are
so indicated. The chemical shifts are reported in parts per million
(ppm, δ). The coupling constants are reported in hertz (Hz), and the
resonance patterns are reported with notations as the following: br
(broad), s (singlet), d (double), t (triplet), q (quartet), and m
(multiplet). The peak assignments in the 13C NMR spectra for 6 and 9
were determined by DEPT experiments. High-resolution mass spectra
were measured on a time-of-flight LC−MS. Thin-layer chromatog-
raphy (TLC) was carried out using precoated silica gel sheets. Visual
detection was performed with ultraviolet light, p-anisaldehyde stain,
potassium permanganate stain, or iodine. Flash chromatography was
performed using silica gel P60 (60 A, 40−63 μm) with compressed air.
Ethyl 1-Bromo-cyclobutanecarboxylate, 7. N-Bromosuccini-
mide (0.198 g, 1.1 mmol) and AIBN (8.0 mg, 0.05 mmol) were added
to a solution of ethyl cyclobutanecarboxylate (0.12 mL, 0.885 mmol)
in dry carbon tetrachloride (4.0 mL) at 21 °C. The mixture was heated
to reflux for 4 h. After the mixture was cooled to 21 °C, ethyl acetate
(3 × 40 mL) was added to the mixture. The combined organic phases
were washed with water and brine and dried over anhydrous Na2SO4.
Flash column chromatography on silica gel eluting with 20/1 hexanes/
ethyl acetate gave the known ethyl 1-bromocyclobutanecarboxylate 710
(0.169 g, 93%) as a clear oil. 1H NMR (500 MHz, CDCl3): δ 4.20 (q, J
= 5.0 Hz, 2H), 2.86 (m, 2H), 2.57 (m, 2H), 2.17 (m, 1H), 1.82 (m,
1H), 1.26 (t, J = 5.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 171.3,
61.8, 54.2, 37.1, 37.0, 16.6, 13.8.
1
destroy the ozonide to give the ketoaldehyde 10. This aldehyde
was not purified but was immediately oxidized via the Pinnick
conditions9 using sodium chlorite to give the desired product,
1-monooctyl α-ketoglutarate 6, in 84% yield for the last two
steps. Thus the acid 8 can be converted into the desired
monoester of α-ketoglutarate 6 in two operations and an overall
yield of 80%.
Synthesis of Monoesters of α-Ketoalkanedioic Acids,
13a−d. We decided to see how general this new method for
the synthesis of monoesters of α-ketoalkanedioic acids was
(Scheme 2). For this reason we prepared several cycloalkene-1-
carboxylic acids 11a−d by known methods, including the
indene-1- and 2-carboxylic acids. Each of these acids were
converted into their monoesters using the alcohol and DCC as
before to give the esters 12a−d. Ozonolysis and immediate
Pinnick oxidation of the resulting ketoaldehyde afforded the
desired monoesters of the α-ketodioic acids 13a−d. The overall
yields are comparable to those obtained for the monooctyl α-
ketoglutarate 6. Thus this method should be generally
applicable for the preparation of a variety of monoesters of
α-ketoalkanedioic acids.
Conclusion. In summary, we have developed a reliable
high-yielding method for the synthesis of the 1-monoesters of
α-ketoalkanedioic acids, which involves the ozonolysis and
Pinnick oxidation of alkyl cycloalkene carboxylates. The utility
of the method has been demonstrated by the facile synthesis of
1-monooctyl α-ketoglutarate 6 in two steps and 80% overall
yield from the commercially available acid 8.
1-Cyclobutene-1-carboxylic Acid, 8. Potassium hydroxide
(3.024 g, 54 mmol) was dissolved in hot toluene (50 mL), and then
the bromoester 7 (2 mL, 0.0124 mol) was added. The mixture was
refluxed for 1 h. After the mixture was cooled to 21 °C, water (50 mL)
was added, and the mixture was extracted with diethyl ether (30 mL)
and ethyl acetate (30 mL). The aqueous phase was acidified with 1.0
M aqueous HCl to pH 1. The acidified aqueous layer was extracted
with ethyl acetate (3 × 60 mL), and the combined organic phases were
washed with water and brine and dried over anhydrous Na2SO4. Flash
column chromatography on silica gel, eluting with 5/1 hexanes/ethyl
acetate, gave the known 1-cyclobutene-1-carboxylic acid 810 (0.873 g,
72%), which solidified to give a pale solid when stored in the
refrigerator. 1H NMR (500 MHz, CDCl3): δ 11.30 (br s, 1H), 6.92 (t,
J = 1.8 Hz, 1H), 2.73 (t, J = 5.0 Hz, 2H), 2.48 (td, J = 5.0, 1.8 Hz, 2H).
13C NMR (125 MHz, CDCl3): δ 167.3, 149.9, 138.1, 28.8, 27.2.
Octyl Cyclobut-1-enecarboxylate, 9. 1-Octanol (0.95 mL, 6.0
mmol), (4-dimethylamino)pyridine (DMAP, 37 mg, 0.3 mmol), and
EXPERIMENTAL SECTION
■
General. All reactions were carried out under an argon atmosphere
unless otherwise specified. Tetrahydrofuran (THF) and diethyl ether
were distilled from benzoquinone ketyl radical under an argon
atmosphere. Dichloromethane, toluene, benzene, pyridine, triethyl-
amine, and diisopropylethylamine (DIPEA) were distilled from
calcium hydride under an argon atmosphere. Dimethyl sulfoxide
(DMSO) was distilled over calcium hydride and stored over 4 Å
molecular sieves. Diisopropylamine was distilled from NaOH, and
methanol was distilled from magnesium turnings under an argon
atmosphere. All other solvents or reagents were purified according to
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Note
13
1
dicyclohexyl carbodiimide (DCC, 0.743 g, 3.6 mmol) were added to a
solution of 1-cyclobutene-1-carboxylic acid 8 (0.295 g, 3.0 mmol) in
dry dichloromethane (6.0 mL) at 0 °C. After it had stirred for 1 h, the
solution was allowed to warm to 21 °C and was stirred for another 8 h.
The precipitate was filtered and washed with ethyl acetate (3 × 100
mL). The combined organic phases were washed with water and brine
and dried over anhydrous Na2SO4. Flash column chromatography on
silica gel eluting with 80/1 hexanes/ethyl acetate gave octyl cyclobut-
1-enecarboxylate 9 as a clear oil (0.604 g, 96%). 1H NMR (500 MHz,
CDCl3): δ 6.71 (bs, 1H), 4.07 (t, J = 7.0 Hz, 2H), 2.68 (t, J = 3.5 Hz,
2H), 2.42 (td, J = 3.5, 1.0 Hz, 2H), 1.61 (m, 2H), 1.24 (m, 10H), 0.84
(t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 162.3, 146.0,
138.8, 64.1 (CH2), 31.7 (CH2), 29.1 (CH2), 29.1 (CH2), 29.0 (CH2),
28.5 (CH2), 26.9 (CH2), 25.8 (CH2), 22.5 (CH2), 14.0 (CH3). HRMS
(ESI) calcd for [C13H22O2H]+ 211.1698, found 211.1696.
ketoheptanedioic ester 13b (0.156 g, 78%) as a clear oil. H NMR
(500 MHz, CDCl3): δ 5.38 (m, 1H, major enol), 5.16 (m, 1H, minor
enol), 4.23 (t, J = 6.8 Hz, 2H, keto), 4.22 (t, J = 6.8 Hz, minor enol),
4.15 (t, J = 6.8 Hz, major enol), 2.82 (m, 2H), 2.35 (m, 2H), 1.94 (m,
2H), 1.66 (m, 2H), 1.43 (m, 4H), 1.36−1.20 (m, 20H), 0.85 (t, J = 7.1
Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 193.9, 179.2, 167.9 (enol),
161.1, 105.9 (enol), 105.0 (enol), 66.5, 66.0 (enol), 38.8, 33.5, 31.6,
29.03, 29.02, 28.3, 28.2 25.62, 25.55, 22.5, 14.0. HRMS (ESI) calcd for
[C15H26O5 − H]− 285.1702, found 285.1715.
Octyl 1H-Indene-3-carboxylate, 12c. Prepared from 1-octanol
and 1H-indene-3-carboxylic acid14 11c (0.389 g, 2.4 mmol) by the
procedure described for the preparation of 9 to give octyl 1H-indene-
1
3-carboxylate 12c (0.655 g, 99%) as a clear oil. H NMR (300 MHz,
CDCl3): δ 8.10 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.4 Hz, 1H), 7.47 (s,
1H), 7.38 (t, J = 7.4 Hz, 1H), 7.28 (dt, J = 7.4, 1.5 Hz, 1H), 4.34 (t, J =
6.7 Hz, 2H), 3.51 (s, 2H), 1.81 (pentet, J = 6.9 Hz, 2H), 1.55−1.25
(m, 10H), 0.94 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
164.0, 144.1, 143.3, 140.7, 136.4, 126.5, 125.4, 123.6, 122.3, 64.5, 38.2,
31.7, 29.13, 29.09, 28.6, 26.0, 22.5, 14.0. HRMS (ESI) calcd for
[C18H24O2 − H]− 271.1698, found 271.1691.
Octyl 2-(2-(Carboxymethyl)phenyl)-2-oxoacetic Ester, 13c.
Prepared from octyl 1H-indene-3-carboxylate, 12c (0.136 g, 0.5
mmol), by the procedure described for the preparation of 6 to give
octyl 2-(2-(carboxymethyl)phenyl)-2-oxoacetic ester 13c (0.135 g,
1-Monooctyl α-Ketoglutarate, 6. Into a solution of the oil 9
(0.211 g, 1.0 mmol) in dichloromethane (10 mL) cooled to −78 °C
was bubbled ozone (in a stream of oxygen) until the solution turned
blue. The residual ozone was discharged by bubbling with oxygen, and
the reaction mixture was warmed to 21 °C and stirred for another 1 h.
Dimethyl sulfide (0.11 mL, 1.5 mmol) was added to the mixture,
which was stirred for another 2 h. The dichloromethane was removed
in vacuo, and the crude product 10 was dissolved in a solution of 2-
methyl-2-butene (0.8 mL) in tert-butyl alcohol (3.0 mL). To this was
added dropwise a solution containing sodium chlorite (0.147 g, 1.3
mmol) and sodium dihydrogen phosphate monohydrate (0.179 g, 1.3
mmol) in water (1.0 mL). The mixture was stirred at 21 °C overnight
and then extracted with ethyl acetate (3 × 50 mL). The combined
organic phases were washed with water and brine and dried over
anhydrous Na2SO4. Flash column chromatography on silica gel eluting
with 5/1 hexanes/ethyl acetate gave 1-monooctyl α-ketoglutarate 6,6
which became a pale solid when stored in the refrigerator (0.216 g,
1
85%) as pale solid. Mp 63−64 °C. H NMR (500 MHz, CDCl3): δ
7.76 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.43 (dt, J = 7.7, 0.85
Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 4.34 (t, J = 6.9 Hz, 2H), 4.00 (s,
2H), 1.74 (quint, J = 7.2 Hz, 2H), 1.40−1.21 (m, 10H), 0.88 (t, J = 6.9
Hz, 3H). 13C NMR (125 MHz, DMSO-d6): δ 188.3, 171.8, 163.8,
137.4, 134.1, 133.2, 132.6, 130.8, 127.4, 66.0, 39.5, 31.2, 28.6, 28.5,
27.9, 25.2, 22.1, 13.9. HRMS (ESI) calcd for [C18H24O5 − H]−
319.1545, found 319.1557.
1
84%) but was a clear oil at room temperature. H NMR (300 MHz,
Octyl 1H-Indene-2-carboxylate, 12d. Prepared from 1-octanol
and 1H-indene-2-carboxylic acid15 11d (0.2661 g, 1.66 mmol) by the
procedure described for the preparation of 9 to give octyl 1H-indene-
CDCl3): δ 4.25 (t, J = 7.0 Hz, 2H), 2.95 (m, 2H), 2.72 (t, J = 7.1 Hz,
2H), 1.71 (m, 2H), 1.29 (m, 10H), 0.87 (t, J = 7.0 Hz, 3H). 13C NMR
(75 MHz, DMSO-d6): δ 192.8, 173.3, 160.2, 65.6 (CH2), 33.9 (CH2),
31.2 (CH2), 28.6 (CH2), 28.5 (CH2), 27.8 (CH2), 27.4 (CH2), 25.2
(CH2), 22.1 (CH2), 13.9 (CH3). HRMS (ESI) calcd for [C13H21O5 −
H]− 257.1389, found 257.1394.
Octyl Cyclopent-1-enecarboxylate, 12a. Prepared from 1-
octanol and cyclopent-1-enecarboxylic acid 11a (0.15 g, 1.34 mmol)
by the procedure described for the preparation of 9 to give octyl
cyclopent-1-enecarboxylate 12a (0.284 g, 95%) as a clear oil.11 1H
NMR (500 MHz, CDCl3): δ 6.73 (t, J = 2.4 Hz, 1H), 4.09 (t, J = 6.7
Hz, 2H), 2.53 (m, 2H), 2.46 (m, 2H), 1.92 (pentet, J = 7.6 Hz, 2H),
1.62 (t, J = 7.6 Hz, 2H), 1.38−1.20 (m, 10H), 0.85 (t, J = 7.1 Hz, 3H).
13C NMR (125 MHz, CDCl3): δ 165.4, 143.3, 136.7, 64.2, 33.2, 31.7,
31.3, 29.2, 29.1, 28.6, 25.9, 23.0, 22. 6, 14.0.
1-Monooctyl α-Ketohexanedioic Ester, 13a. Prepared from
octyl cyclopent-1-enecarboxylate, 12a (0.202 g, 0.9 mmol) by the
procedure described for the preparation of 6 to give 1-monooctyl α-
ketohexanedioic ester 13a (0.216 g, 89%) as a pale solid. Mp 39−40
°C. 1H NMR (500 MHz, CDCl3): δ 4.23 (t, J = 6.8 Hz, 2H), 2.93 (t, J
= 7.1 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 1.95 (pentet, J = 7.2 Hz, 2H),
1.71 (pentet, J = 7.2 Hz, 2H), 1.40−1.20 (m, 10H), 0.86 (t, J = 7.1 Hz,
3H). 13C NMR (125 MHz, CDCl3): δ 193.6, 179.0, 160.9, 66.6, 38.2,
32.5, 31.7, 29.1, 29.0, 28.3, 25.7, 22.6, 17.8, 14.0. HRMS (ESI) calcd
for [C14H24O5 − H]− 271.1545, found 271.1552.
Octyl Cyclohex-1-enecarboxylate, 12b. Prepared from 1-
octanol and cyclohex-1-enecarboxylic acid 11b (0.19 g, 1.5 mmol)
by the procedure described for the preparation of 9 to give octyl
cyclohex-1-enecarboxylate 12b (0.325 g, 91%) as a clear oil.12 1H
NMR (500 MHz, CDCl3): δ 6.93 (tt, J = 4.0, 1.5 Hz, 1H), 4.07 (t, J =
6.7 Hz, 2H), 2.22 (m, 2H), 2.15 (m, 2H), 1.65−1.53 (m, 6H), 1.37−
1.19 (m, 10H), 0.84 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ 167.6, 139.3, 130.5, 64.3, 31.8, 29.22, 29.17, 28.7, 26.0, 25.7,
24.1, 22.6, 22.1, 21.5, 14.0.
1
2-carboxylate 12d (0.437 g, 97%) as a clear oil. H NMR (300 MHz,
CDCl3): δ 7.71 (td, J = 1.9, 0.6 Hz, 1H), 7.53−7.47 (m, 2H), 7.35−
7.28 (m, 2H), 4.24 (t, J = 6.7 Hz, 2H), 3.67 (d, J = 3.0 Hz, 2H), 1.73
(pentet, J = 6.6 Hz, 2H), 1.36−1.25 (m, 10H), 0.89 (t, J = 6.9 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 165.0, 144.7, 142.7, 140.8, 137.4,
127.4, 126.7, 124.1, 123.2, 64.5, 38.2, 31.7, 29.2, 29.1, 28.7, 26.0, 22.6,
14.0. HRMS (ESI) calcd for [C18H24O2 − H]− 271.1698, found
271.1694.
2-(3-(Octanyloxy)-2,3-dioxopropyl)benzoic Acid, 13d. Pre-
pared from octyl 1H-indene-2-carboxylate, 12d (0.137 g, 0.5 mmol) by
the procedure described for the preparation of 6 to give 2-(3-
(octanyloxy)-2,3-dioxopropyl)benzoic acid 13d (0.125 g, 78%) as a
pale solid. Mp 67−68 °C. 1H NMR of keto form (500 MHz, CDCl3):
δ 8.09 (bd, J = 7.8 Hz, 1H), 7.55 (dt, J = 7.6, 1.2 Hz, 1H), 7.38 (t, J =
7.4 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 4.23 (t, J = 6.7 Hz, 2H), 3.67
(bs, 1H), 3.24 (bs, 1H), 1.63 (pentet, J = 7.0 Hz, 2H), 1.31−1.18 (m,
10H), 0.85 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, DMSO-d6): δ
190.6, 168.1, 163.3, 136.1, 134.1, 128.9, 128.5, 127.7, 124.2, 66. 7, 35.7,
31.2, 28.5, 28.5, 27.9, 25.1, 22.1, 13.9. HRMS (ESI) calcd for
[C18H24O5 − H]− 319.1545, found 319.1556.
ASSOCIATED CONTENT
■
S
* Supporting Information
Proton and carbon NMR data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jung@chem.ucla.edu.
1-Monooctyl α-Ketoheptanedioic Ester, 13b. Prepared from
octyl cyclohex-1-enecarboxylate, 12b (0.165 g, 0.7 mmol) by the
procedure described in preparation of 6 to give 1-monooctyl α-
Notes
The authors declare no competing financial interest.
C
dx.doi.org/10.1021/jo302308q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(15) Varnavas, A.; Lassiani, L.; Valenta, V.; Berti, F.; Tontini, A.;
Mennuni, L.; Makovec, F. Eur. J. Med. Chem. 2004, 39, 85.
ACKNOWLEDGMENTS
■
The LC−MS used in this project was supported by grant no.
S10RR025631 from the National Center for Research
Resources. The content is solely the responsibility of the
authors and does not necessarily represent the official views of
the National Center for Research Resources or the National
Institutes of Health. This NMR spectrometers were supported
by the National Science Foundation under equipment grant no.
CHE-1048804.
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