Synthesis of a Dimethylfuran-Containing Macrolide Insect Pheromone.

Abstract The synthetic pathway to the furan-containing macrolide pheromone (1) of Galerucella beetles was shortened from 13 steps in the original synthesis to 10 steps, and the overall yield was increased greater than six-fold. A concise Reformatsky-based sequence of reactions was utilized to construct the key precursor, 2,3-dimethyl-2-butenolide. Reduction of the butenolide with diisobutylaluminum hydride afforded 3,4-dimethylfuran. A one-pot sequence of lithiation, alkylation by a tetrahydropyranyl (THP)-containing iodide, a second lithiation, and, finally, formylation gave the required tetrasubstituted furan intermediate, 3,4-dimethyl-5-[5-(tetrahydrofuran-2-yloxy)pentyl]-2-furaldehyde. To continue construction of the three-carbon acyl side chain, the aldehyde was converted to an unsaturated ester by a Horner–Wadsworth–Emmons (HWE) condensation with triethyl phosphonoacetate. After reduction of the double bond in the ester side chain and removal of protective groups, the lactone ring was closed using t...