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A new unnatural macrocyclic trichothecene, an analogue of verrucarine A (l), which was named 3-Isoverrucarin A (( 1"-0 )(3+4)ubeo -verrucarin A; 3) was synthesized starting from anguidine (5). The two key reactions were the removal of the 4b-acetoxy group of anguidine (5) by a Barton deoxygenation and the final macrolactonization. During the cyclization procedure, two unexpected new macrocyclic by-products, which were named verrucinol(l9) and verrucene (20), were formed. They represent novel types of macrocyclic trichothecenes, the macrolidic moiety of verrucene (20) consisting only of the (Z,E)-muconic-acid residue. The formation of the analogous macrolide 26 of verrucene (20) was not possible, probably because the ring strain is too strong.

~~~~~~ ~The 4-epiverrucarin A (24), a new unnatural macrocyclic trichothecene, was synthesized starting from 4-epiverrucarol(20). The latter was obtained by metal-hydride reduction of the 4-0x0 derivative 19. Subsequent conversion of 20 into the monoester 30 and then the diester 32 followed by macrolactonization of the latter yielded 4-epiverrucarin A (24). Attempts to invert the configuration of the naturally occuring 3a-OH group of a tricholhecene were unsuccessful. The cytostatic (P-8 15) and immunosuppressive (MLR) activity of several natural and unnatural trichothecenes was determined in v i m .Introduction. -In the preceeding communication [ 11, first results of our programme directed to the synthesis of new unnatural macrocyclic trichothecenes were described, namely the synthesis of 3-isoverrucarin (( 1"-0 )(4+3)abeo-verrucarin A; 1) and the two novel macrocyclic by-products verrucinol and verrucene (2). In continuation of these efforts, the next goal was the preparation of 3-and 4-hydroxytrichothecenes possessing unnatural configurations and to use them for the synthesis of additional macrocyclic analogues of verrucarin A (3). Such compounds will give more detailed information on the relationship between chemical structure and biological activity.

The synthesis of the title compounds is envisaged in order to obtain trichothecene analogues which possess the antibiotic, antifungal and cytotoxic activity of the natural trichothecenes but are less toxic than these compounds.