Total synthesis of the structure of the putative landomycin aglycone, revision of the structure and studies directed toward the synthesis of the proposed structure of the landomycin aglycone

As an extension of our program towards the total synthesis of carbohydrate natural products, we became interested in landomycin A almost ten years ago. Landomycin A is the largest anti-tumor antibiotic of the angucycline family and has been shown to interact with DNA and inhibit cell cycle progression from the G₀ to S phase as well as to possess activity against 60 cancerous cell lines. Our interest in this molecule stems both from the complex nature of the hexasaccharide chain, which features six 2,6-di-deoxysugars, as well as the delicate tetracyclic aglycone. Our synthesis of the hexasaccharide was completed in 1999, at which time, work on the aglycone began. The synthesis of the reported structure of the landomycin aglycone featured a late stage, intramolecular Michael addition to a quinone to generate the desired tetracycle. The substrate for this reaction was generated by a Dötz benzannulation reaction of a Fischer carbene derived from hydroquinone and a functionalized, mono-substituted alkyne. Upon completion of the synthesis, spectral data from the synthetic material failed to match that reported for the natural aglycone. After investigating any possible issues of conformational isomerism being responsible for the spectral disparity, we concluded the structure of the natural product had been mis-assigned. Based on examination and comparison of the spectral data for the synthetic and natural material, as well as a derivative of each, an alternate structure was proposed. The alternate structure differs from the reported structure only by the regiochemistry of a single alcohol.; Four approaches towards the synthesis of the alternate structure have been investigated. Dötz benzannulation was again used to provide advanced intermediates to attempt an intramolecular Michael addition, however in this case the Michael closure was not successful. Another approach involved late-stage epoxidation followed by reductive oxirane opening. This scheme proved untenable due to side oxidations undergone by the electron rich aromatic substrate in lieu of epoxidation. Radical mediated closure was attempted, but failed owing to the demanding steric environment around the radical precursor. A final approach entailed an intramolecular Heck reaction to close the tetracyclic aglycone. This route failed to provide the desired product of simple ring closure, producing instead a structurally interesting pentacyclic ketone.