Verrucarin acetate

The successful synthesis of optically active 7 then led to the first synthesis of verrucarin A (8), a macrotrilactone with significant cytostatic activity. The synthesis involved esterification of the primary alcohol of verrucarol (the tricyclic fragment) with the acetate of 7 (DCC, 4-pyrrolinopyridine) and then with a protected derivative of (E, Z)-muconic acid. After deprotection (Bu4NF), lactonization was effected by the Mitsunobu procedure (7,405-406). 

The strucure-activity response is even more subtly expressed in the etiolated wheat coleoptile (Triticum aestivum L. Wakeland) that has been described in detail elsewhere (13) Subtle modifications in structure cause marked changes in the inhibitory responses induced (Table I). With the exception of 15-acetoxy-T- 2-tetraol, neosolaniol and isoneosolaniol which are inactive at lO M (Fig. 2l, all of the trichothecenes so far tested are active at 10" M. A further one-third are active at 10"°M and the most potent, which are active at 10" M, are verrucarins A and J, and trichoverrin B, Neosolaniol, which inhibits 100% at 10" and 61% at 10" M has an acetate at C15 while isonesolaniol, which has an hydroxyl group at C15 inhibits coleoptiles 80 and 51% at 10" and 10"3, respectively. 

Figure 5. Specificity of different antibodies against T-2 toxin metabolites and selected trichothecenes. Reference numbers are given In the parenthesis for each Immunogen used. Abbreviations are given In Table I except MAS, MEOS, 4Ac and VA which represent monoacetoxysclrpenol, neosolanlol, tetra-acetate, and verrucarin A respectively.

The synthesis of another macrocyclic model compound was communicated by Notegen, Tori and Tamm in 1981 and is summarized in Scheme 28 (109). Selective protection (72%) of the C-4 hydroxy moiety as the acetal (237) allowed esterification with acid (238) to take place at C-15. The hydroxy acid (239), devoid of protecting groups, was then lactonized, this time onto the C-4 hydroxy group of verrucarol, to yield the model macrocycle (240). These early examples established that macrolactonization, either at C-4 (Scheme 28) or at the primary hydroxy group of the side chain (Scheme 27) would be equally valid approaches to the naturally occurring verrucarins, a fact which has since been substantiated by synthesis of the natural products 121, 133). 

These authors have given several procedures for the preparation of the antibiotic from cultures of M. verrucaria S 118. One liter of medium contained 20 g of glucose, 2 g of malt extract, 2 g of yeast extract, 2 g of peptone, 2 g of potassium dihydrogen phosphate, 2 g of magnesium sulfate heptahydrate and 0.2 g of ferrous sulfate heptahydrate. After 63 hours, 501 of broth was extracted with ethyl acetate, and the extract concentrated to 41. The crude product was washed with dilute sodium hydroxide solution and water and recrystalhzed to give 2.31 g of verrucarin A contaminated with small amounts of verrucarin B. Silica gel... 

Verrucarin A (32) obtained after the incorporation of [l- " C]acetate was hydrolyzed with K2CO3 in aqueous methanol to afford, after acidification,... 

Incorporation of [ 2]acetate into verrucarin E (130) by cultures of Myrothecium verrucaria indicates its formation by condensation of two molecules of acetoacetate as shown in Scheme 29. ... 

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