Epipolythiodiketopiperazines

Fig. 9.1 Representative dimeric hexahydropyrroloindole alkaloids, (a) Dimeric epipolythiodiketopiperazine alkaloids, (b) Calycanthaceous alkaloids, (c) Dimeric diketopiperazine alkaloids...

These epipolythiodiketopiperazine alkaloids, together with the calycanthaceous alkaloids (Fig. 9.1b), form a superfamily of natural products termed the dimeric hexahydropyrroloindole alkaloids [6-8]. The main dichotomy within this superfamily arises from the biogenetic elaboration of tryptamine versus tryptophan building blocks. The tryptamine-based calycanthaceous alkaloids, boasting members such as chimonanthine (7), calycanthine (9), and folicanthine (8), are largely plant derived and have a long and rich history in the context of natural product synthesis [7, 9]. 

Scheme 9.1 Postulated biosynthetic pathway for dimeric epipolythiodiketopiperazine alkaloids...

L-tryptophan is compulsory, the biosynthetic machinery displays wide latitude in its ability to condense a second auxiliary amino acid—L-alanine in the case of (+)-ll,ll -dideoxyverticillin A (1)—to afford a tryptophan-derived diketopiperazine intermediate 13. Mirroring Woodward and Robinson s biogenetic hypothesis for the calycanthaceous alkaloids, single-electron oxidation of the electron-rich tryptophan residue would likely initiate an oxidative dimerization of the diketopiperazine precursor with concomitant cyclization to yield the octacyclic intermediate 17. Subsequent A-methylation of the amides would then yield an unembellished skeletal core of the dimeric epipolythiodiketopiperazine alkaloids. The first step en route... 

Our retrosynthesis for the epipolythiodiketopiperazine alkaloids by and large observes the basic strategic framework laid out in the synthesis of (+)-11,11 dideoxyverticillin A (1) the main deviation is aptly in the final stages of thiol incorporation (Scheme 9.11). 

Numerous attributes make G, virens an ideal fungus for mycoherbicide formulations. It is readily cultured, grows rapidly and is long-lived in dried preparations. A unique feature of G. virens is the production of chemical compounds in addition to the phytotoxin viridiol. The two main compounds are the epipolythiodiketopiperazines gliotoxin and gliovirin (15,16). 

Later in 2010, Movassaghi et al. proposed an alternative synthesis for (+)-chaetocin A (677) as well as syntheses for the epipolythiodiketopiperazines (+)-chaetoxin C (693) and (+)-12,12 -dideoxychetracin A (694) (432). These were the first reports on the preparation of high-order polysulfides. Studies have shown that the polysulfide bridge is important for the biological activity of these compotmds and that potency increases with the number of sulfur atoms incorporated (433). Therefore, the versatile construction of this scaffold might lead to highly active substrates. 

Iwasa E, Hamashima Y, Sodeoka M (2011) Epipolythiodiketopiperazine Alkaloids Total Syntheses and Biological Activities. Isr J Chem 51 420... 

---