SYNTHESIS OF LEUCONOLIDE VIA BORONIC ESTERS

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Our recently discovered method of asymmetric synthesis based on boronic ester chemistry will be applied to the synthesis of leuconolide, the aglycone of the macrolide antibiotic leucomycin. All seven chiral centers can be constructed via the reaction of a boronic ester of a chiral diol with a (dihalomethyl)lithium, which inserts a CHX group into the carbon- boron bond with >99% control of absolute configuration. Boron facilitates the displacement of the neighboring halide by a variety of nucleophiles, and kinetic resolution during this process provides additional improvement of the already excellent diastereoselection. The planned synthesis builds the molecule in three major segments, and two of these will be joined by a stereospecific coupling of halo boronic ester with an alkoxy lithium reagent derived from another boronic ester. The remaining segment will be connected via esterification at one end and Suzuki coupling of vinyl halide to boronic ester to provide the diene at the other. The esterification is already known as a means of macrolide closure. The Suzuki diene synthesis will also be tested as a means of ring closure. This new chemistry offers a major opportunity for the efficient controlled synthesis of intricate chiral structures such as leuconolide or other macrolide or ionophore antibiotics.