Verrucarol synthesis, macrocyclization

There exist just a few total syntheses of macrocyclic trichothecenes. However, all of these deal with the synthesis of verrucarol (454), a hydrolysis product of the naturally occurring verrucarin A (380). Venucarol (454) represents the sesquiterpenoid moiety of most macrocyclic trichothecene derivatives. To date, there are several syntheses of this moiety. In 1998, the most recent total synthesis was published by Tadano et al. (327). 

The first report dealing with the synthesis of a macrocyclic tri-chothecene, albeit a non-natural product, originated from Tamm s laboratory in 1978 (22). Three years later, Still and Ohmizu synthesized the first naturally occurring macrocyclic trichothecene verrucarin A (37) (133). Since 1981, the increased availability of verrucarol (82) (150), the sesquiter-penoid backbone for most of the macrocycles, has stimulated work in this area and culminated in Still s recent syntheses (135) of baccharin B5 (59) and roridin E (47), the most complex trichothecenes synthesized to date. Sandwiched between these landmark syntheses have been equally exciting studies initiated by Tamm (verrucarin A and 3a-hydroxyverrucarin A (106), Fraser-Reid and Jarvis (verrucarin J) (42) and Roush (verrucarin J and... 

Historically, it is no coincidence that Tamm, who has had a long involvement with all aspects of trichothecene chemistry and, hence, had access to an ample supply of verrucarol, initially lead the field in the synthesis of the macrocycles. In 1978, Breitenstein and Tamm synthesized the model macrocycle tetrahydroverrucarin J (236) as shown in Scheme 27... 

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). 

Most synthetic work directed toward the macrocyclic trichothecenes has focused on the verrucarins, particularly verrucarin A (37) and verrucarin J (40). For verrucarin A there now exist two total syntheses 106, 133), starting from verrucarol (82), as well as innumerable reports on the synthesis of verrucarinic acid derivatives, a principal component of the macrocyclic ribbon (see Scheme 32). 

Extensive efforts toward the synthesis of the macrocyclic trichothecenes have been initiated by Roush and co-workers and culminated in the synthesis of verrucarin J (40) and related olefin isomers (121). The successful approach, outlined in Scheme 35, was one in which a growing side chain was ultimately cyclized onto the hydroxy group at C-4 of verrucarol (82). Initial efforts to attach an intact ribbon such as (281) (see Scheme 33) to verrucarol were frustrated by concomitant isomerization of... 

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