ORGN 125

Oxazolomycin 1 and related compoundshave been isolated from Streptomyces and exhibit wide ranging and potent antiviral and antibacterial activity, as well as in vivo antitumour activity, coupled with low toxicity.  They possess an unusual spiro fused b-lactone/g -lactam linked via a triene and (E,E)-diene spacer to an oxazole terminal residue, and lend themselves to retrosynthetic disconnection at points a and b (Figure 1).  We have already reported on our work for the preparation of the left and middle fragments, and now wish to communicate some of our preliminary work to designed to address the remaining right hand side.

Our starting point has been the enantiopure tetramic acid 2, available using our previously published methodology by chemoselective Dieckmann cyclisation of an appropriately modified serine derivative, and for which we envisaged using one carbon extensions of the tetramic acid ketone function, in order to permit application of disconnection b (Figure 1).  We have earlier shown that ketone extension using Wittig reagents is possible under forcing conditions, leading to benzoindolone products. The density of functionality, along with the hindered bicyclic structure and acidity at C-7 of tetramic acid 2 make this a demanding step, but we report here that this can be achieved under mild conditions using the inexpensive TMSCN/ZnI₂ reagent combination at room temperature and in the absence of solvent, leading to silylcyanohydrins 3.  Other carbon nucleophiles (benzthiazole, 1,3-dithiane) are much less selective, giving multiple sites of attack (e.g. lactam 4).  The scope of this reaction in other hindered and multifunctional ketones has been investigated and will also be discussed.