A New and Expedient Total Synthesis of Ochratoxin A and d ₅-Ochratoxin A

Abstract

A new total synthesis of the mycotoxin ochratoxin A (OTA) is presented, in which it is prepared in 9% overall yield from commercially available substrates. The key step consists of the condensation reaction between protected l-phenylalanine and 5-chloro­-8-hydroxy-3-methyl-1-oxoisochromane-7-carboxylic acid (ochratoxin α, OTα). The same strategy could be successfully applied to l-d ₅-phenylalanine, leading to the first total synthesis of d ₅-OTA, a molecular tracer for the detection and analytical quantification of the natural mycotoxin in food samples by means of stable isotope dilution assay (SIDA).

heterocycles - natural products - ochratoxin A - stable isotope dilution assay - total synthesis

References

1a Bouras N. Mathieu F. Coppel Y. Strelkov SE. Lebrihi A. J. Agric. Food Chem.  2007,  55:  8920 

1b Battilani P. Pietri A. Eur. J. Plant Pathol.  2002,  108:  639 

1c Cabañes FJ. Accensi F. Bragulat MI. Abarca MI. Castella G. Minguez S. Pons A. Int. J. Food Microbiol.  2002,  79:  213 

1d Jodlbauer J. Maier NM. Lindner W. J. Chromatogr., A  2002,  945:  45 

1e Galvano F. Piva A. Ritieni A. Galvano G. J. Food Prot.  2001,  64:  120 

1f Sweeny MJ. Dobson AD. Int. J. Food Microbiol.  1998,  43:  141 

1g MacDonald S. Wilson P. Barnes K. Damant A. Massey R. Mortby E. Shepherd MJ. Food Addit. Contam.  1999,  16:  253 

1h Visconti A. Pascale M. Centone G. J. Chromatogr., A  1999,  864:  89 

1i Blank R. Hohler D. Wolffram S. Uebers. Tierernaehr.  1999,  27:  123 

1j Richard JL. Plattner RD. Mary J. Liska SL. Mycopathologia  1999,  146:  99 

1k Valenta H. J. Chromatogr., A  1998,  31:  75 

1l Jørgensen K. Food Addit. Contam.  1998,  15:  550 

1m Ramos AJ. Labernia N. Marin S. Sanchis V. Magan N. Int. J. Food Microbiol.  1998,  44:  133 

1n Hohler D. Z. Ernaehrungswiss.  1998,  37:  2 

1o Stegen G. Jrissen U. Pittet A. Saccon M. Steiner W. Vincenzi M. Winkler M. Zapp J. Schlatter CHR. Food Addit. Contam.  1997,  14:  211 

1p Trucksess MW. Giler J. Young K. White KD. Page SW. J. AOAC Int.  1997,  82:  85 

1q Teren J. Varga J. Hamari Z. Rinyu E. Kevei F. Mycopathologia  1996,  134:  171 

1r Varga J. Kevei E. Rinyu E. Téren J. Kozakiewicz Z. Appl. Environ. Microbiol.  1996,  62:  4461 

1s Zimmerli B. Dick R. Food Addit. Contam.  1996,  13:  655 

1t Pittet A. Tornare D. Huggett A. Viani R. J. Agric. Food Chem.  1996,  44:  3564 

1u Majerus P. Otteneder H. Dtsch. Lebensmitt. Rundsch.  1996,  92:  388 

1v Scott PM. Kanhere S. Food Addit. Contam.  1995,  12:  591 

1w Studer-Rohr I. Dietrich DR. Schlatter J. Schlatter C. Food Chem. Toxicol.  1995,  33:  341 

1x Abarca ML. Bragulat MR. Castella G. Cabanes FJ. Appl. Environ. Microbiol.  1994,  60:  2650 

1y Breitholtz-Emanuelson A. Olsen M. Oskarsson A. Hult IK. J. Assoc. Off. Anal. Chem.  1993,  76:  842 

1z Kuiper-Goodman T. Scott PM. Biomed. Environ. Sci.  1989,  2:  179 

2a Pohland AE. Nesheim S. Friedman L. Pure Appl. Chem.  1992,  64:  1029 

2b Micco C. Grossi M. Miraglia M. Brera C. Food Addit. Contam.  1989,  6:  333 

2c Van der Merwe KJ. Steyn PS. Fourie L. J. Chem. Soc.  1965,  7083 

For recent reviews, see:

3a Pfol-Leszkowicz A. Manderville RA. Mol. Nutr. Food Res.  2007,  51:  61 

3b Clark HA. Snedeker SM. J. Toxicol. Environ. Health B Crit. Rev.  2006,  9:  265 

3c O’Brien E. Dietrich DR. Crit. Rev. Toxicol.  2005,  35:  33 

3d Dai J. Park G. Perry JL. Il’ichev YV. Bow DAJ. Pritchard JB. Faucet V. Pfohl-Leszkowicz A. Manderville RA. Simon JD. Acc. Chem. Res.  2004,  37:  874 

3e Peraica M. Radić B. Lucić A. Pavlović M. Bull. World Health Organ.  1999,  77:  754 

4 Ochratoxin A. In Some Naturally Occurring Substances: Food Items and Constituents, Heterocyclic Aromatic Amines and Mycotoxins   IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 56:  IARC and WHO; Lyon: 1993. 489-521

For leading examples, see:

5a Lindenmeier M. Schieberle P. Rychlik M. J. Chromatogr., A  2004,  1023:  57 

5b Dell’Asta C. Galaverna G. Dossena A. Marchelli R. J. Chromatogr., A  2004,  1024:  275 

5c Monaci L. Palmisano F. Anal. Bioanal. Chem.  2004,  378:  96 

5d Soleas GJ. Yan J. Goldberg DM. J. Agric. Food Chem.  2001,  49:  2733 

5e Becker M. Degelmann P. Herderich M. Schreier P. Humpf H.-U. J. Chromatogr., A  1998,  818:  260 

6 For a review, see: Rychlik M. Asam S. Anal. Bioanal. Chem.  2008,  390:  617 

7a Kraus GA. J. Org. Chem.  1981,  46:  201 

7b Kraus GA. inventors; US Patent  4346039.  ; Chem. Abstr. 1983, 98, P4438v

8 Covarrubias-Zúñiga A. Ríos-Barrios E. J. Org. Chem.  1997,  62:  5688 

9 Betzer J.-F. Pancrazi A. Synthesis  1999,  629 

10 Sibi MP. Chttopadhyay S. Dankwardt JW. Snieckus V. J. Am. Chem. Soc.  1985,  107:  6312 

11 Donner CD. Gill M. Aust. J. Chem.  2002,  213 

12 It is worth noting that the coupling reaction between 8 and 9 has been carried out previously, in the presence of 2-ethoxy-1-(ethoxycarbonyl)-1,2-dihydroquinoline (EEDQ), to give, after deprotection, a mixture of 1a and 1b in a total yield of 35-50%, depending on the crystallization conditions. See: Roberts JC. Woollven P. J. Chem. Soc. C  1970,  278 

13

The only method reported in the literature so far for the synthesis of d ₅-OTA (2a) was based on a semi-synthetic sequence involving: (a) acid hydrolysis of OTA to give (R)-OTα; (b) conversion of (R)-OTα into the corresponding acyl chloride by reaction with SOCl₂; (c) reaction between the acyl chloride and l-d ₅-phenylalanine methyl ester to give methyl-protected d ₅-OTA; (d) deprotection of the latter with NaOH in MeOH to give d ₅-OTA (2a). The overall yield based on starting OTA was 5% over 4 steps. See ref. 5a.