FULL PAPERS
ture for 8 h. Water (7.5 mL) was added and the pH was ad-
justed to 8.0 by the addition of ca. 1.2 mL of 2.0N NaOH.
The reaction mixture was then poured into ice-cold sodium
sulfite solution (0.34 g in 4.4 mL of water), maintained
below 208C with an ice/water bath. After stirring for 15 min
at room temperature, 8 mL of methyl tert-butyl ether
(MTBE) was added and the resulting mixture was stirred
for 15 min. The organic layer was separated and discarded.
More MTBE (8 mL) was added and the rapidly stirred mix-
ture was acidified with 2.0N HCl to pH 3–4. The organic
layer was separated and the aqueous layer was extracted
with 2ꢁ8 mL portions of MTBE. The combined organic
phases were washed with two 6 mL portions of water and
6 mL of brine, and then concentrated to give almost pure
azelaic acid (7) as a white solid without further recrystalliza-
tion; yield: 131 mg (94%).
mixture was poured into a saturated sodium bicarbonate so-
lution (5.0 mL) and extracted three times with ethyl acetate.
The combined organic layers, which contained the dibutyltin
oxide as a fine white precipitate, were filtered through
celite, dried over sodium sulfate, and filtered. After removal
of the solvent under vacuum, methyl nonanoate (8) was pu-
rified by vacuum distillation as a colorless liquid; yield:
110 mg (80%); bp 728C (10 mmHg) (lit.[20] bp 1228C
1
(45 mmHg)); H NMR (300 MHz, CDCl3): d=3.62 (s, 3H),
2.26 (t, J=7.5 Hz, 2H), 1.60–1.56 (m, 2H), 1.29–1.20 (m,
10H), 0.84 (t, J=6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=173.84, 51.03, 33.83, 31.68, 29.10, 29.02, 29.00, 24.79,
22.49, 13.82.
Azelaic acid (7), Method C:[13b] A 10% aqueous solution
of NaHCO3 (2.25 mL) was added to a solution of compound
6 (0.13 g, 0.74 mmol) in acetone (8 mL) at 08C, followed by
solid NaBr (7.6 mg, 10 mol) and TEMPO (2,2,6,6-tetrameth-
yl-piperidin-1-yl oxyl) (2.3 mg, 0.015 mmol, 2 mol%). Tri-
chloroisocyanuric acid (TCCA) (0.258 g, 1.11 mmol) was
then slowly added within 20 min at 08C. The resulting mix-
ture was warmed to room temperature and stirred for the
required time (4 h) until the completion of the reaction, and
then 2-propanol (0.4 mL) was added. The mixture was fil-
tered on celite, concentrated under vacuum, and treated
with 2.7 mL of a saturated solution of Na2CO3. The aqueous
phase was washed with two portions of 8 mL of MTBE,
treated with 1N HCl, and extracted twice with 10 mL of
10% MeOH-ethyl acetate. The organic layers were dried
(Na2SO4), and the solvent was evaporated to yield almost
pure azelaic acid (7) as a white solid without further recrys-
tallization; yield: 130 mg (93%).
Acknowledgements
This study was supported by the R&D Program of MOTIE/
KEIT, Republic of Korea [10044604 and 10044647]. J.-H.
Seo was partially supported by Ewha Womans University
(RP-Grant 2015).
References
[1] a) A. Kçckritz, A. Martin, Eur. J. Lipid Sci. Technol.
2011, 113, 83–91; b) K. Kroha, Inform 2004, 15, 568–
571.
[2] G. Liu, X. Kong, H. Wan, S. Narine, Biomacromole-
cules 2008, 9, 949–953.
[3] U. Schorken, P. Kempers, Eur. J. Lipid Sci. Technol.
2009, 111, 627–645.
Azelaic acid (7): Mp 109–1108C (lit.[19] mp 105–1078C);
1H NMR (300 MHz, DMSO-d6): d=2.17 (t, J=7.5 Hz, 4H),
1.47 (m, 4H), 1.24 (m, 6H); 13C NMR (75 MHz, DMSO-d6):
d=174.95 (2C), 34.07 (2C), 28.90, 28.86 (2C), 24.89 (2C).
[4] a) J.-W. Song, E.-Y. Jeon, D.-H. Song, H.-Y. Jang, U. T.
Bornscheuer, D.-K. Oh, J.-B. Park, Angew. Chem. 2013,
125, 2594–2597; Angew. Chem. Int. Ed. 2013, 52, 2534–
2537; b) J.-W. Song, J.-H. Lee, U. T. Bornscheuer, J.-B.
Park, Adv. Synth. Catal. 2014, 356, 1782–1788.
[5] a) E.-Y. Jeon, J.-H. Lee, K.-M. Yang, Y.-C. Joo, D. K.
Oh, J.-B. Park, Process Biochem. 2012, 47, 941–947;
b) S.-M. Jung, J.-H. Seo, J.-H. Lee, J.-B. Park, J.-H. Seo,
Biotechnol. J. 2015, 10, 1887–1893.
Direct Chemical Conversion of the Ester
Intermediate (4) to Azelaic Acid (7)
The final product, azelaic acid (7), was directly synthesized
without column chromatography through a two-step reac-
tion of the crude ester. The crude ester (4) (approximately
430 mg, calculated amount of the ester: 290 mg), which was
obtained by extraction using organic solvents after biotrans-
formation, was subjected to hydrolysis [1N NaOH in
MeOH-H2O (4/1) at 608C for 3 h], followed by direct oxida-
tion [NaClO2 (1.2 equiv.), TEMPO (4 mol%) and NaOCl
(2 mol%) in acetonitrile at room temperature for 8 h). Aze-
laic acid (7) was isolated by recrystallization in the final
step; yield: 100 mg (58% overall yield over two steps based
on the measured concentration of the crude ester).
[6] J.-H. Seo, S.-M. Lee, J. Lee, J.-B. Park, J. Biotechnol.
2015, 216, 158–166.
[7] a) M. K. Julsing, M. Schrewe, S. Cornelissen, I. Her-
mann, A. Schmid, B. Bꢂhler, Appl. Environ. Microbiol.
2012, 78, 5724–5733; b) M. Schrewe, A. O. Magnusson,
C. Willrodt, B. Bꢂhler, A. Schmid, Adv. Synth. Catal.
2011, 353, 3485–3495.
[8] H.-Y. Jang, K. Singha, H.-H. Kim, Y.-U. Kwon, J.-B.
Park, Green Chem. 2016, 18, 1089–1095.
[9] C. J. Delebecque, A. B. Lindner, P. A. Silver, F. A.
Aldaye, Science 2011, 333, 470–474.
[10] S. Schmidt, C. Scherkus, J. Muschiol, U. Menyes, T.
Winkler, W. Hummel, H. Grçger, A. Liese, H.-G. Herz,
U. T. Bornscheuer, Angew. Chem. 2015, 127, 2825–
2828; Angew. Chem. Int. Ed. 2015, 54, 2784–2787.
[11] C. Willrodt, A. Hoschek, B. Bꢂhler, A. Schmid, M. K.
Julsing, Biotechnol. Bioeng. 2015, 112, 1738–1750.
[12] a) H.-Y. Jang, E.-Y. Jeon, A. H. Baek, S.-M. Lee, J.-B.
Park, Process Biochem. 2014, 49, 617–622; b) J.-M.
Woo, J.-W. Kim, J.-W. Song, L. M. Blank, J.-B. Park,
Methanolysis of the Ester Intermediate (4) to Methyl
Nonanoate (8)
The ester intermediate (4) (150 mg, 0.75 mmol) was dis-
solved in methanol (5 mL). After the addition of dibutyltin
oxide (20 mg, 0.075 mmol), the mixture was heated under
reflux for 12 h. After the completion of the reaction, the
Adv. Synth. Catal. 0000, 000, 0 – 0
8
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!