The class of natural products known as 2,5-diketopiperazines is both broad and synthetically well-trodden. An important sub-class of these targets are found with a sprinkling of sulfur atoms, and seem particularly well-suited to pathogen-bashing – and in particular the nefarious malaria protist and poliovirus. Needless to say, their intriguing chemistry and biology has busied many a chemist, with much ongoing research (including the pioneering work of Mohammad Movassaghi). However, a simple, safe and robust method for sulfenylating 2,5-diketopiperazines has not yet been identified, preventing commercialisation of this chemistry – something that a team from the Scripps Research Institute in La Jolla, US, led by K C Nicolaou, hopes to resolve.1
In its most simple form, sulfur exists as eight-membered rings of sulfur atoms. However, elemental sulfur is quite reactive, and when treated with a base, this ring can easily be fragmented. The team in California did just this, reacting S8 with sodium hexamethyldisilazide (NaHMDS) to isolate a tetrasulfide species that could then be used as a sulfenylating reagent.
The reaction proceeds by forming an S4 bridge across the diketopiperazine, which can easily be fragmented to provide the pair of sulfide groups required (figure?1). The team demonstrated the efficacy of this reaction in various highly functionalised substrates, but there really is no alternative to featuring this in the synthesis of a thiodiketopiperazine natural product. However, and perhaps unsurprisingly given the renown of the Scripps team in this field, they actually showcase the synthesis of seven members of that family – but I’ll keep this brief, and stick to one – epicoccin G.
Paul Docherty is a science writer and blogger based in Reading, UK