A total synthesis of (±)-sirenin and analogs for the biological study of sexual pheromone activity in Allomyces

Abstract

The synthesis and biological evaluation of structural analogs of the potent fungal (Allomyces) sex pheromone sirenin (1) is described. A new total synthesis of the pheromone itself is also presented. In addition, the biological activity displayed by sirenin is compared to the activities exhibited by the analogs. Several 1,5-diols were prepared by allowing the lithium dianion of tiglic acid (40) to react with aldehyde substrates. The resulting hydroxy acids were exclusively of the (E)-configuration. Hydride reduction of the acids (or esters after esterification) yielded the corresponding diols. Additional analogs were prepared by structural modification of the initial diols by standard chemical methods. Many of the materials subjected to biological evaluation exhibited biological activity at concentrations of 10⁻³ M to 10⁻⁵ M. Alcohol 41 was synthesized to provide a monohydroxy analog of sirenin that maintained the basic structural features of the pheromone. The bicyclic acid 39 was formed by lithium hydroxide initiated ring contraction of the 1,3-cyclohexadiene/chloromethylketene adduct 31. Alcohol 41 was prepared from acid 39 through a side chain homologation sequence of the corresponding aldehyde 49. Horner-Emmons reactions were employed to introduce the requisite five-carbon unit in two sections. Analog 41 exhibited strong biological activity at concentrations as low as 10⁻¹⁰ M. Sirenin (1) was synthesized by methods that parallel those used for the preparation of alcohol 41. Benzylation of the readily available alcohol 42 gave ether 93. Cycloaddition of diene 93 with chloromethylketene yielded a 3.6:1 mixture of endo-methyl adduct 95 and exo-methyl isomer 96, respectively. The endo-isomer 95 was ring contracted with silver nitrate in methanol to give bicyclic ester 97. A series of reactions analogous to those used to prepare alcohol 41 from acid 39 was employed to convert ester 97 to alcohol 106. Cleavage of the benzyl ether of 106 under dissolving metal conditions produced (±)-sirenin. The synthetic sirenin showed strong biological activity at concentrations as low as 10⁻¹⁰ M. Sirenin and analog 41 are much more potent chemotactic agents than any of the other analogs.