Naturwissenschaften 83, 222-225 (1996) © Springer-Verlag 1996 Biosynthesis of the Solenopsins, Venom Alkaloids of the Fire Ants S. Leclercq, J.C. Braekman, D. Daloze Laboratory of Bio-Organic Chemistry (CP 160/7), Faculty of Sciences, University of Brussels, B-1050 Brussels, Belgium J.M. Pasteels Laboratory of Animal and Cellular Biology, Faculty of Sciences, University of Brussels, B-1050 Brussels, Belgium R.K. Van der Meer Laboratory of Medical and Veterinary Entomology Research, US Department of Agriculture, Gainesville, Florida 32604, USA Ants of the genus Solenopsis (Myrmici- nae) secrete a venom consisting of a mixture of 2-methyl-6-alkylpiperidines accompanied in some cases by N-meth- ylated, imino, or side-chain-unsaturat- ed derivatives [1-4]. These piperidine alkaloids have been assigned the trivial name solenopsins by MacConnell et al. [5]. The solenopsins (Fig. 1) differ from each other by the relative configuration of their substituents, the length, and unsaturation of the alkyl chain. The absolute configuration of the trans alkaloids is always (2R, 6R) while that of the cis alkaloids is (2R, 6S) (see 1 to 6 for examples [61). Although these alkaloids have been the subject of numerous synthetic [4, 7] and biological [8] studies, their biosyn- thesis remains, however, unknown. The aim of this paper is to report our first results on this topic, which clearly dem- 9 CH3-COOH onstrate that cis- and trans-solenopsin A (/ and 4) are acetate-derived. Based on our previous results on the biosynthesis of insect alkaloids (tetra- ponerine-8 [9], coccinelline [10l), we hypothesized that the solenopsins (1 to 6) are formed by the linear combination of 9, 10, or 11 acetate units. Loss of the carboxyl group from the resulting long- chain acid, followed by introduction of an amino group, intramolecular cycli- zation, and reduction of the imino group thus obtained, could afford the cis- and trans-solenopsins. The inter- mediate long-chain acid can be either a suitably functionalized fatty acid or a polyketo acid. Figure 2 illustrates this hypothesis for cis- and trans-solenopsin A. This biosynthetic pathway would therefore be similar to the well-estab- lished biosynthesis of the hemlock al- kaloid confine, which is formed by the linear combination of four acetate units [11, 12]. To test the acetate origin of the cis- and trans-solenopsin A, tracer experiments o COOH or COOH Route A/ CH~ .......... "' ( I H CH2~CH3 1: n = lO,cis-solenopsin A 2: n = 12,cis-solenopsin B 3." n = 14,cis-solenopsin C R ~ R (CH2) CH~'...... nCH3 I H 4: n = lO,trans-solenopsin A 5: n = 12,trans-solenopsin B 6: n = 14,trans-solenopsin C Fig. 1. Structure of natural solenopsins CH3~ C H B ~ CH~'""" 7 [ g 10 12 14 16 15 H cis" and trans-solanopsin A Fig. 2. Biosynthetichypothesis for cis- and trans-solenopsin A 222 Naturwissenschaften 83 (1996) © Springer-Verlag 1996