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Synthesis of the 1‑Monoester of 2‑Ketoalkanedioic Acids, for Example, Octyl Α‑Ketoglutarate Michael E

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Synthesis of the 1‑Monoester of 2‑Ketoalkanedioic Acids, for Example, Octyl Α‑Ketoglutarate Michael E 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 monoesters of α-ketodicarboxylic acids, all of which are T (TCA) cycle or the Krebs cycle, is the mechanism analogues of α-ketoglutarate. We believe that the guarantee of whereby aerobic organisms generate energy via oxidation of obtaining only the desired 1-monoester in generally quite pure acetate ultimately into carbon dioxide (Figure 1).1 A key step in form makes up for the additional number of steps that this method employs versus the direct esterification. 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 compound is commercially available, it was easily prepared in use a chemical method. Several chemical methods exist for the 72% yield by treatment of the readily available ethyl 1- α 6 bromocyclobutane-1-carboxylate 7 with potassium hydroxide in synthesis of the 1-ester of -ketoglutarate, especially direct 8 esterification of 2-oxopentanedioic acid or other methods, but toluene. Formation of the ester was carried out using 1-octanol those methods gave very mixed results in our hands. Therefore and dicyclohexyl carbodiimide (DCC) with DMAP as base to give the ester 9 in 96% yield. Ozonolysis of the cyclobutene was we developed a new method for the synthesis of the monooctyl − ° fi ester 6 of α-ketoglutarate 4 via oxidative cleavage of a carried out at 78 C and dimethyl sul de (DMS) was used to cyclobutene-1-carboxylate, which guaranteed the formation of the desired 1-monoester. We have further shown that this new Received: October 22, 2012 method can be applied to the synthesis of a variety of 1- Published: November 19, 2012 © 2012 American Chemical Society 11002 dx.doi.org/10.1021/jo302308q | J. Org. Chem. 2012, 77, 11002−11005 The Journal of Organic Chemistry Note Scheme 2. Synthesis of Other Monoesters of α-Ketoalkanedioic Acids destroy the ozonide to give the ketoaldehyde 10. This aldehyde literature procedures. 1H NMR and 13C NMR spectra were obtained was not purified but was immediately oxidized via the Pinnick at 300 or 500 MHz for proton and 75 or 125 MHz for carbon and are conditions9 using sodium chlorite to give the desired product, so indicated. The chemical shifts are reported in parts per million δ 1-monooctyl α-ketoglutarate 6, in 84% yield for the last two (ppm, ). The coupling constants are reported in hertz (Hz), and the steps. Thus the acid 8 can be converted into the desired resonance patterns are reported with notations as the following: br (broad), s (singlet), d (double), t (triplet), q (quartet), and m monoester of α-ketoglutarate 6 in two operations and an overall (multiplet). The peak assignments in the 13C NMR spectra for 6 and 9 yield of 80%. α were determined by DEPT experiments. High-resolution mass spectra Synthesis of Monoesters of -Ketoalkanedioic Acids, were measured on a time-of-flight LC−MS. Thin-layer chromatog- − 13a d. We decided to see how general this new method for raphy (TLC) was carried out using precoated silica gel sheets. Visual the synthesis of monoesters of α-ketoalkanedioic acids was detection was performed with ultraviolet light, p-anisaldehyde stain, (Scheme 2). For this reason we prepared several cycloalkene-1- potassium permanganate stain, or iodine. Flash chromatography was carboxylic acids 11a−d by known methods, including the performed using silica gel P60 (60 A, 40−63 μm) with compressed air. indene-1- and 2-carboxylic acids. Each of these acids were Ethyl 1-Bromo-cyclobutanecarboxylate, 7. N-Bromosuccini- converted into their monoesters using the alcohol and DCC as mide (0.198 g, 1.1 mmol) and AIBN (8.0 mg, 0.05 mmol) were added before to give the esters 12a−d. Ozonolysis and immediate to a solution of ethyl cyclobutanecarboxylate (0.12 mL, 0.885 mmol) ff in dry carbon tetrachloride (4.0 mL) at 21 °C. The mixture was heated Pinnick oxidation of the resulting ketoaldehyde a orded the fl ° desired monoesters of the α-ketodioic acids 13a−d. The overall to re ux 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 yields are comparable to those obtained for the monooctyl α- were washed with water and brine and dried over anhydrous Na2SO4. ketoglutarate 6. Thus this method should be generally Flash column chromatography on silica gel eluting with 20/1 hexanes/ applicable for the preparation of a variety of monoesters of ethyl acetate gave the known ethyl 1-bromocyclobutanecarboxylate 710 α 1 δ -ketoalkanedioic acids. (0.169 g, 93%) as a clear oil. H NMR (500 MHz, CDCl3): 4.20 (q, J Conclusion. In summary, we have developed a reliable = 5.0 Hz, 2H), 2.86 (m, 2H), 2.57 (m, 2H), 2.17 (m, 1H), 1.82 (m, 13 δ high-yielding method for the synthesis of the 1-monoesters of 1H), 1.26 (t, J = 5.0 Hz, 3H). C NMR (125 MHz, CDCl3): 171.3, α-ketoalkanedioic acids, which involves the ozonolysis and 61.8, 54.2, 37.1, 37.0, 16.6, 13.8. Pinnick oxidation of alkyl cycloalkene carboxylates. The utility 1-Cyclobutene-1-carboxylic Acid, 8. Potassium hydroxide of the method has been demonstrated by the facile synthesis of (3.024 g, 54 mmol) was dissolved in hot toluene (50 mL), and then α the bromoester 7 (2 mL, 0.0124 mol) was added. The mixture was 1-monooctyl -ketoglutarate 6 in two steps and 80% overall fl ° yield from the commercially available acid 8. re uxed 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 ■ EXPERIMENTAL SECTION M aqueous HCl to pH 1. The acidified aqueous layer was extracted × General. All reactions were carried out under an argon atmosphere with ethyl acetate (3 60 mL), and the combined organic phases were unless otherwise specified. Tetrahydrofuran (THF) and diethyl ether washed with water and brine and dried over anhydrous Na2SO4. Flash column chromatography on silica gel, eluting with 5/1 hexanes/ethyl were distilled from benzoquinone ketyl radical under an argon 10 atmosphere. Dichloromethane, toluene, benzene, pyridine, triethyl- acetate, gave the known 1-cyclobutene-1-carboxylic acid 8 (0.873 g, amine, and diisopropylethylamine (DIPEA) were distilled from 72%), which solidified to give a pale solid when stored in the 1 δ calcium hydride under an argon atmosphere. Dimethyl sulfoxide refrigerator. H NMR (500 MHz, CDCl3): 11.30 (br s, 1H), 6.92 (t, (DMSO) was distilled over calcium hydride and stored over 4 Å J = 1.8 Hz, 1H), 2.73 (t, J = 5.0 Hz, 2H), 2.48 (td, J = 5.0, 1.8 Hz, 2H). 13 δ molecular sieves. Diisopropylamine was distilled from NaOH, and C NMR (125 MHz, CDCl3): 167.3, 149.9, 138.1, 28.8, 27.2. methanol was distilled from magnesium turnings under an argon Octyl Cyclobut-1-enecarboxylate, 9. 1-Octanol (0.95 mL, 6.0 atmosphere. All other solvents or reagents were purified according to mmol), (4-dimethylamino)pyridine (DMAP, 37 mg, 0.3 mmol), and 11003 dx.doi.org/10.1021/jo302308q | J. Org. Chem. 2012, 77, 11002−11005 The Journal of Organic Chemistry Note dicyclohexyl carbodiimide (DCC, 0.743 g, 3.6 mmol) were added to a ketoheptanedioic ester 13b (0.156 g, 78%) as a clear oil. 1H NMR13 δ solution of 1-cyclobutene-1-carboxylic acid 8 (0.295 g, 3.0 mmol) in (500 MHz, CDCl3): 5.38 (m, 1H, major enol), 5.16 (m, 1H, minor dry dichloromethane (6.0 mL) at 0 °C.
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