Stereoselective Total Synthesis of (±)-Ptilocaulin and its 7-Epimer. A Strategy Based On the Use of an Intramolecular Nitrile Oxide Olefin Cycloaddition (INOC) Reaction†‡

A stereoselective total synthesis of (±)-ptilocaulin 1, an antimicrobial anticancer agent as well as of its 7-epimer 23 is described. The strategy involves an aldol condensation of the dilithio dianion of the Z-aldoxime (13) with a ketone 6 to produce 11 and the stereospecific intramolecular cycloaddition of the nitrile oxide 5, generated in situ from 11. The resulting isoxazoline 4 was converted to hydroxy ketone 3 which serves as a starting point for introduction of the fourth stereocenter at C-7. Lithium in ethylamine reduction of 3 produces stereospecifically the 7β-methyl compound which leads to ptilocaulin 1, while catalytic hydrogenation of 3 introduces the 7α-methyl substituent and finally 7-epiptilocaulin 23. H- and C NMR analysis permits differentiation between isomers of intermediates. When, in the last step of the synthesis of 1 or 23 from 19 or 22 and guanidine, a higher temperature (>130 °C) was applied, an interesting disproportionation to aminopyrimidine 25 or 28 and cyclic guanidine 24 or 27 was observed.