Aflatoxins racemic

Scheme 15. Trost s approach to aflatoxin B involves the Pd-catalyzed dynamic asymmetric transformation of chiral racemic 103 to optically pure 104 (1999).

This methodology has been expanded to geranyl methyl carbonate for the synthesis of the vitamin E nucleus, and to tiglyl methyl carbonate for the synthesis of (—)-calanolide A and B. In the latter example, the anthracenyldiamine -based ligand was required for optimum selectivity. The synthesis of (—)-aflatoxin B lactone utilizes a dynamic kinetic asymmetric transformation, whereby a suitably functionalized phenol reacts with a racemic 5-acyloxy-2-(5//)-furanone to provide a single product in 89% yield. One final example of phenol as a nucleophile is for the deracemization of Baylis-Hillman adducts." ... 

Thus, the total syntheses of the racemic aflatoxins B, (/), B2 (5) [since this can be prepared by the controlled catalytic hydrogenation of aflatoxin B, (l)51,63)], and B2a (11) were accomplished in a rather elegant carbon rearrangement fashion. 

The phenolic constituent required for a synthesis of aflatoxin Gt (9) is the same as that previously employed in the Bj (I) synthesis, namely (70). Indeed, from the reaction of phenol (70) and vinyl bromide (83), in the presence of zinc carbonate and lithium iodide (a minor modification designed to increase the electrophilicity even more), there was obtained a modest amount of racemic aflatoxin Gj(9), which was spectroscopically shown to be identical with the natural material. 

The conversion fix>m averufin (AVF) to versiconal hemiacetal acetate (VHA) is catalyzed by an averufin oxidase encoded by afll (oyfA) (41). VHA was converted to versiconal (VAL) by an esterase (29, 63, 64, 65). VAL is converted to Versicolorin B (VERB) by a VERB synthase (31). The gene, qflK (ybs), was cloned, characterized and expressed (66,67,68). It was demonstrated that the versicolorin B synthase catalyzes the side chain cyclodehydration of racemic VHA to VERB. This is a key step in the aflatoxin formation since it closed the bisfuran ring of aflatoxin for binding to DNA. VERB is converted to versicolorin A (VERA) by a desaturase encoded by qflL (verB) (31). 

The group of Biichi, who also determined the structure and absolute configuration of several aflatoxins (20-22), achieved the first total synthesis of racemic aflatoxin Bi (1) in 1966 (34, 35). They started from phloroacetophenone (17), which was converted in two steps into its monomethyl ether 18 (see Scheme 2.2). Selective monobenzylation, followed by Wittig condensation and selenium dioxide oxidation gave the bicyclic aldehyde 19 in good yield. 

In 1969, Biichi et al. published the first total synthesis of racemic aflatoxin Ml (5) (36). They started with the diol 24, which was first dimethylated with dimethyl sulfate, then mono deprotected by aluminum chloride, and finally benzylated to afford species 25 (see Scheme 2.3). 

One year later, in 1970, Biichi and Weinreb presented a total synthesis of racemic aflatoxin Gi (3) and an improved synthesis of aflatoxin Bi (1) (37). The synthesis of 1 involved the same coupling with a cyclopentenone as described above for the total synthesis of aflatoxin Mi (5) (see last step in Scheme 2.3). Accordingly, this group was able to increase the overall yield to 2.5% with the same number of reaction steps. 

Scheme 2.4 Total synthesis of racemic aflatoxin Gi (3). Reagents and conditions ...

Biichi G, Foulkes DM, Kurono M, Mitchell GF (1966) The Total Synthesis of Racemic Aflatoxin Bl. J Am Chem Soc 88 4534... 

The hemiacetal of aflatoxin Bi racemizes readily in basic solution. Suggest an explanation. 

The Pechmann condensation also played a key role in the Biichi group s efforts toward the total synthesis of aflatoxin Bi (44). In this work, the central coumarinic ring system of aflatoxin was prepared by condensing the racemic tricyclic phenol 40 with ethyl methyl-3-oxoadipate (41) in methanolic HCl at 5 °C to provide tricycle 42 in 57% yield. The use of methanol as a solvent was crucial to the success of this reaction, as attempts to perform this reaction in sulfuric acid led to the rapid isomerization of 40 to the corresponding benzofuran-3-acetic acid, which could be converted to the analogous coumarin product only in very poor yield. Subsequent cyclization of the pendant ester moieties of 42 afforded pentacyclic lactone 43. Treatment of 43 with disiamylborane resulted in selective reduction of the dihydrofuranone to the corresponding hemiaminal, which was then acetylated and pyrolyzed (240 °C) to provide ( )-aflatoxin Bi (44). 

Dutton and Anderson (1978) removed the cell walls of A. flavus by enzymatic digestion with Trichoderma viride. The formed protoplasts are capable of de novo aflatoxin biosynthesis. Versicolorin A added to the protoplasts was incorporated into aflatoxin B. The racemic versicolorin C is formed by aflatoxin-producing strains of A. flavus (Heathcote and Dutton, 1969). Although Heathcote et al. (1976) reported that versicolorin C was not converted into the aflatoxins hy A.flavus CMI91019B, Dutton and Anderson (1978) reported its apparent conversion into aflatoxin by protoplast preparations. 

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