A new two-step synthetic approach toward 3-(chloromethyl)cyclobutanone is described and used in the synthesis of 2,4-methanoproline analogues. The key step consists of a reversible addition of hydrogen cyanide onto the imines 12 in 50-74% yield under conditions that allow ring closure. 2-Alkyl-2-azabicyclo[2.1.1]hexane-1-carbonitriles 19, synthesized in four steps, can also be converted to the corresponding amines.
2,4-Methanoproline, a supposed non-proteinogenic anti-feedant, was synthesised in 5 steps starting from allyl benzyl ether 3 in 10% overall yield with an intramolecular nucleophilic substitution as the key step for the formation of the bicyclic skeleton.
2,4-methanoproline is a natural product isolated from the seeds of Ateleia herbert smithii Pittier that was formerly suggested to have insect repellent/antifeedant activity; however, this was not tested quantitatively. In this study the insect repellent/antifeedant potency of methanoproline was measured against larvae of the cotton leafworm, Spodoptera littoralis (Boisd.), and adults of the cowpea weevil, Callosobruchus maculatus (F.). In addition, several N-alkyl, amino, and nitrile derivatives of methanoproline with varying stereodemanding substituents were synthesized and also tested. It was shown that in S. littoralis methanoproline itself did not show any significant activity but that derivatives 5, 7, 8, and 10 did show a reasonable repulsive/antifeedant activity that was comparable to the commercial repellent DEET. A significant repellent activity was scored for methanoproline in adults of C. maculatus that was similar to DEET.
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