Retrosynthetic disconnection cleavage

The initial retrosynthetic analysis of 1 resulted in the cleavage of the two amide bonds and a C-N bond leading to the four components oxadiazole carbonyl chloride 2, methyl iodide, 4-fluorobenzylamine (4-FBA) and the densely functionalized hydroxypyrimidinone 3 (Scheme 6.1). These synthetic disconnections were reasonable and should be applicable for long term route development. 

Some disconnections must have -in the retrosynthetic direction- high priority. For instance, the elimination (or modification) of protecting groups (especially, hydrolytic cleavages) or particularly unstable functional groups. 

The first three retrosynthetic cleavages are formation of the C7-C8 aldol by intramolecular chromium-Reformatsky reaction of linear precursor 51, esterification between northern and southern half building blocks and Wit-tig reaction of phosphonium salt 52 known from Mulzer s work [85] and northern half precursor 53. The final disconnections were placed at the C2-C3 aldol in 51 (again to be formed by chromium-Reformatsky reaction, here between bromoacetimide 56 and aldehyde 57) and the C14-C15 bond by alkylation of acetoacetate 54 with neryl bromide 55. 

Our retrosynthetic analysis of generalised pyridine 5.4 commences with an adjustment of the oxidation level to produce dihydropyridine 5.5. This molecule can now be disconnected very readily. Cleavage of the carbon-heteroatom bonds in the usual way leaves dienol 5.6 which exists as diketone 5.7. The 1,5-dicarbonyl relationship can be derived from a Michael reaction of ketone 5.8 and enone 5.9, which in turn can arise from condensation of aldehyde 5.10 and ketone 5.11. 

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