Synthetic studies on polyether antibiotics: New approaches to oligo-tetrahydrofurans and complex spiroketals

The polyether antibiotics have received considerable attention from synthetic chemists because of their scarce availability, biological activity and structural complexity. Monensin and kijimicin are two renowned members of the polyether antibiotics. Their ability to transport ion across hydrophobic membranes have attracted the attention of researchers to investigate their structure activity relationship. As a result, the synthesis of less substituted analogs have received considerable attention.; The work reported in this thesis involves the development of novel approaches for the synthesis of the spiroketal and poly-tetrahydrofuran (THF) segments of the polyether antibiotics. The first spiroketal methodology is based on a metathesis-haloetherification silver mediated sequence of reactions. The key intermediate is a hydroxy iodo-THP, which is converted to a spiroketal when treated with silver triflate. A second spiroketal strategy involves the synthesis of a hydroxy glycal precursor. The key reaction in this synthesis is an oxocarbenium ion cyclization on a 1,2-O-isopropylidene enol ether substrate. The key concept in the synthesis of the poly-THF segment is the iodocyclization of C5 allylated furanoside or 1,2-O-isopropylidene-5-alkene template, to afford a trans-2,5-disubstituted THF's in high stereoselectivity and yield. Subsequent elaboration of these intermediates via Sharpless asymmetric dihydroxylation led to oligo-THF's in high diastereoselectivity. These methodologies are highlighted by the synthesis of a spiroketal-oligo-THF analog of monensin and a truncated oligo-THF system of kijimicin.