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acid 4. Due to their novelty, for both routes a Brazilian patent has
been filed.24 These syntheses of enantiomerically pure (R)-ochra-
toxin
cally pure ochratoxin
reactions6,9,11,15 of OT
and also of the isotopically labeled analogs of OTA by coupling
OT with isotopically labeled reagents
13C]-, 15N]- or
[2H]-
-phenylalanine. In addition to these analogs derived from
OT 2, both synthetic routes presented here can easily be adapted
a
2 constitute also the formal total synthesis of enantiomeri-
by means of known coupling
2 with the amino acid -phenylalanine
A
1
a
L
a
2
[
[
L
a
for the preparation of non-chlorinated analogs (R)-ochratoxin b
and ochratoxin B (OTB) starting from non-chlorinated analogic
reagents.
18. (a) Mortier, J.; Moyroud, J. J. Org. Chem. 1994, 59, 4042–4044; (b) Nguyen, T.-H.;
Chan, N. T. T.; Castanet, A.-S.; Nguyen, K. P. P.; Mortier, J. J. Org. Chem. 2007, 72,
3419–3429.
19. Gohier, F.; Mortier, J. J. Org. Chem. 2003, 68, 2030–2033.
20. Dean, F. M.; Goodchild, J.; Houghton, L. E.; Martin, J. A.; Morton, R. B.; Parton,
B.; Price, A. W.; Somvichien, N. Tetrahedron Lett. 1966, 35, 4153–4159.
21. (a) Rieche, A.; Gross, H.; Höft, E. Chem. Ber. 1960, 93, 88–94; (b) Garcia, O.;
Nicolás, E.; Albericio, F. Tetrahedron Lett. 2003, 44, 4961–4963.
22. Chakraborty, D.; Gowda, R. R.; Malik, P. Tetrahedron Lett. 2009, 50, 6553–6556.
23. Procedure for synthesis of (3R)-5-chloro-8-methoxy-3-methyl-1-oxo-3,4-
dihydro-1H-isochromene-7-carboxylic acid 14. Lithium 2,2,6,6-tetram-
ethylpiperidide (LTMP) was generated by adding tetramethylpiperidine
Acknowledgments
We thank the division BIOANALYTIK Weihenstephan for host-
ing one of the authors (C.A.L.) for the synthetic studies. Moreover,
one of the authors (C.A.L.) gratefully thanks the Brazilian National
Council for Scientific and Technological Development (CNPq) for
the financial support in the form of a CNPq fellowship.
(5.6 mL, 33 mmol) to
a solution of n-butyl lithium 2.5 mol/L (13.4 mL,
33.5 mmol) in 300 mL of THF at À20 °C under argon atmosphere with
agitation, and was maintained at this temperature for 15 min. Then, the
mixture was cooled to À50 °C, and a solution of 5-chloro-2-methoxybenzene-
1,3-dicarboxylic acid (4) (2.31 g, 10 mmol) in 20 mL of THF was added
dropwise, and the mixture was stirred at this temperature for 4 h. (R)-
Propylene oxide (5) was added in one portion (2.4 mL, 34.3 mmol) and the
temperature was allowed to rise slowly to room temperature, and thereafter,
HCl (4 mol/L) was added until a pH below 1 was obtained. The mixture was
extracted with ethyl acetate (4 Â 50 mL), the combined organic phases were
extracted with aqueous sodium hydroxide (4 Â 50 mL, 10%), the latter of which
was extracted with dichloromethane to clean it from organic by-products. The
aqueous alkaline solution was acidified with HCl (4 mol/L) until a pH below 1
and extracted again with ethyl acetate, which was washed with water and
saturated NaCl solution, and dried over Na2SO4. After filtration and evaporation
of the solvents, the crude material was purified by crystallization from acetone
or by dry column vacuum chromatography (DCVC) using mixtures of ethyl
acetate and methanol with polarity gradient elution, providing 0.623 g of
product 14 as a white solid (23%). LC–MS, ESI positive mode (DP = 50 V):
m/z = 293.1 (82) [M+Na]+, 271.1 (100) [M+H]+. LC–MS/MS [M+H]+ (ESI positive
mode, CE = 21 V): m/z = 253.1 (100), 223.1 (20), 195.1 (2).
Rapid derivatization for further confirmation by GC–MS: preparation of methyl
(3R)-5-chloro-8-methoxy-3-methyl-1-oxo-3,4-dihydro-1H-isochromene-7-
carboxylate (methyl ester of 14). About 2 mg of the carboxylic acid 14 was
dissolved in a vial with 1 mL of ether and 0.5 mL of methanol, followed by
addition of an ether solution (2 mol/L) of trimethylsilyldiazomethane
((CH3)3SiCHN2) until persistent yellow color. The vial was shaken for 5 min
and the GC-MS spectrum of the derivative product was obtained: GC-MS
(70 eV, IE): m/z = 284 [M]+ (12) (cluster of Cl containing [M]+ and [M+2]+), 266
(35), 253 (40), 239 (58), 208 (57), 180 (67), 103 (70), 75 (100).
Supplementary data
Supplementary data associated with this article can be found,
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