Sulfinylnorvaline moiety

With the successful synthesis of ustiloxin D in hand, it would seem sensible to extend our method to the preparation of the most complex and most active member of the family, ustiloxin A. In fact, my first forays into the ustiloxins involved studies of the preparation of the sulfinylnorvaline moiety. During my ARC postdoctoral fellowship (my first stint at Melbourne) I had been awarded funding to study the biosynthesis of lysobactin, ° another highly functionalized cyclic peptide natural product. Unfortunately, I was not able to reproduce the biosynthetic production of lysobactm through incubation of the lysobacter species, which makes it difficult to undertake a biosynthetic analysis So I needed another project that would deliver results. 

Forays into Early vs Late Incorporation of the Sulfinylnorvaline Moiety... 

However, these findings were before the development of our current method to perform AAA reaction and complete the macrocycle. Hence, after Aaron had completed the synthesis of ustiloxin D, it seemed the most obvious route to ustiloxin A was to introduce iodine functionality on the dopa moiety at a late stage in the ustiloxin D synthesis, then incorporate the sulfinylnorvaline moiety. However, iodination of protected ustiloxin D 58 or the acyclic precursor 57 resulted in degradation through a retro-aldol reaction and destruction of the p-hydroxydopa residue and/or other pathways. 

Ultimately, after many years we have come to the conclusion that introduction of the sulfinylnorvaline moiety at a late stage is fraught with functional group incompatibilities, and that in order to synthesize ustiloxin A we most likely need to constmct a dopa-sulfinylnorvaline adduct similar to 74, then incorporate our AAA-Ugi method employed for ustiloxin D with the sulfinyl-norvaline side chain aheady installed. Will we ever embark on this It depends if 1 can wait long enough for the ustiloxin project to fade from the students corporate memory yet again, and have the right student arrive at my door. 

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