Submitted to: Journal of Agricultural and Food Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/25/2007
Publication Date: 2/24/2007
Citation: Petroski, R.J., Bartelt, R.J. Direct aldehyde homologation utilized to construct a conjugated-tetraene hydrocarbon insect pheromone. Journal of Agricultural and Food Chemistry. 55:2282-2287.
Interpretive Summary: The sap beetle pheromones can be used to control a group of insect pests that cause damage to a wide variety of crops and spread oak wilt disease and other harmful microorganisms. The pheromones are being sold commercially, but continued production was uncertain because of the length and high cost of synthesis. We designed and developed new synthetic reagents that were used to shorten the synthetic pathway from seven steps to just five steps and nearly double the overall yield of pheromone. The viability of commercial pheromone production was enhanced. This more concise chemistry could also be applied to the practical synthesis of a variety of natural products, pharmaceuticals, and other compounds.
Technical Abstract: New phosphonate reagents were developed for the two-carbon homologation of aldehydes to methyl- or ethyl-branched unsaturated aldehydes and used in the practical synthesis of (2E,4E,6E,8E)-7-ethyl-3,5-dimethyl-2,4,6,8-undecatetraene (1), a pheromone of the beetle, Carpophilus lugubris. The phosphonate reagents, diethyl ethylformyl-2-phosphonate dimethylhydrazone and diethyl 1-propylformyl-2-phosphonate dimethylhydrazone contained a protected aldehyde group instead of the usual ester group. A homologation cycle entailed condensation of the reagent with the starting aldehyde followed by removal of the dimethylhydrazone protective group with a biphasic mixture of dilute HCL and petroleum ether. This robust two-step process replaces the standard three-step aldehyde homologation route using ester-based Horner-Wadsworth-Emmons reagents. The new synthesis of 1 from (2E)-2-methyl-2-butenal was run on a 10-gram scale and required just five steps (two cycles of condensation and deprotection followed by a final Wittig olefination) instead of the usual seven. In addition, the Wittig olefination step was simplified, and its E-isomer selectivity was improved. The overall yield for the entire synthetic pathway was increased from 20 percent to 37 percent, enhancing the commercial potential of Carpophilus pheromones.