Oxazolomycin A and neooxazolomycin originally isolated from a strain of Streptomyces by Uemura et al. in 1985, constitute a family of structurally unique oxazole polyene lactam-lactone antibiotics together with seven other congeners identified to date. These oxazolomycins were found to exhibit wide ranging and potent antibacterial and antiviral activities as well al in vivo antitumor activity. The intriguing molecular architectures and biological activities make these compounds attractive targets for synthesis. However, the total synthesis is limited to neooxazolomycin achieved by Kende's group and our group, and other oxazolomycins having a spiro γ-lactam-β-lactone core have not been synthesized yet. We report here the highly stereoselective synthesis of the oxazolomycin core 3 based on In(OTf)_3-catalyzed Conia-ene type cyclization. Our synthesis of 3 started from a seven-step transformation of known propargyl alcohol 7 to amide 13. By taking advantage of In(OTf)_3-catalyze cyclization, which we have recently developed, 13. By taking advantage of In(OTf)_3-catalyzed cyclization, which we have recently developed, 13 was then converted to lactam 11 in good yield. Stereoselective dihydroxylation accompanied by lactonization and chemoselective reduction of the methyl ester converted 14 to bicyclic lactone 2. Successive methoxymethylation, LiBH_4 reduction, and silylation gave diol 20. We gratifyingly found that methylation of 20 with Me_3O^+BF_4^- in the presence of proton sponge afforded 5 in good yield. After conversion of 5 to carboxylic acid 6, Mitsunobu reaction afforded β-lactone 3. Now, the fully functionalized left hand core of the oxazolomycins was successfully synthesized for the first time.
