An Improved Synthesis of Petromyzonamine Disulfate
Jones, Dorian T.
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Sea lampreys (petromyzon marinus) are a parasitic, invasive species threatening large fish in the great lakes. Traditionally, their population has been controlled by use of the lampricide 4-nitro-3-(trifluoromethyl) phenol (TFM) to destroy the larva before they had entered the parasitic life stage. Despite the problems with the treatment, it was effective in reducing adult populations. Sea lampreys release multicomponent steroidal pheromones. One isolated compound is petromyzonamine disulfate (PADS). Male sea lampreys release the bile acid 7a, 12 a, 24-trihydroxy-5a-cholan-3-one-24-sulfate (3 keto-petromyzonol sulfate, 3ketoPZS). Ovulating female sea lampreys are attracted to this sex pheromone. The use ofthese pheromones to control the sea lamprey population in the Great Lakes could include either the use of Petromyzonol Sulfate (PS) to disrupt spawning migration behavior or to build traps utilizing petromyzonamine disulfate (PADS). Petromyzonamine disulfate is structurally similar to the cationic steroid squalamine. Synthesis of squalamine has been accomplished in nine steps from methyl chenodeoxycholate. Based on the initial steps of the synthesis of squalamine, it was hypothesized that the synthesis of petromyzonamine disulfate could be shortened using a direct oxidation, greatly shortening the method. Further work with squalamine produced greater yields, but in thirteen steps utilizing stereospecific epoxidation and isopropylation as key steps. Improving the synthesis of PADS involved modifying bile acids and working to maintain the proper stereochemistry. The Bridge Organics Chemical Company has accepted contracts from the Great Lakes Fishery Commission to synthesize small amounts of PADS. Trials with synthetic PADS were successful, and the company believes that the Great Lakes Fishery Commission will request another large quantity of PADS to further test the possibility of using the pheromone to bait a trap to capture adult, migrating lampreys. In order to prepare for this large shipment, it was necessary to improve the method for producing PADS in order to save money and time. Reduction of the steps necessary to create the compound while maintaining an acceptable yield was the goal of these experiments. Using the methods outlined, PADS was synthesized in five fewer steps with an overall yield of 20%, saving $22,000 for each run on a kilogram scale.