Identification and Synthesis of Macrolide Pheromones of the Grain Beetle Oryzaephilus Surinamensis and the Frog Spinomantis Aglavei

Abstract

Macrolide lactones, the so called cucujolides derived from unsaturated fatty acids, are aggregation pheromones of cucujid grain beetles. Thirty years ago, Oehlschlarger et al. showed that (3Z,6Z)-dodeca-3,6-dien-11-olide (4) and the respective 12-olide (7) attract the sawtoothed grain beetle Oryzaephilus surinamensis, whereas (5Z,8Z,13R)-tetradeca-5,8-dien-13-olide (5) increases the response synergistically. The frass of this beetle is attractive for its parasitoid Cephalonomia tarsalis, which potentially can be used for pest control. A GC/MS analysis of attractive frass showed the presence of 5, together with an unknown isomer. Cucujolide V was tentatively identified also in the femoral glands, pheromone-releasing structures, of the Madagascan mantelline frog Spinomantis aglavei. Therefore, a new route to synthesize doubly unsaturated macrolides allowing the flexible attachment of the side chain was developed. A straightforward method to obtain Z configured macrolides involves ring-closing alkyne metathesis (RCAM) followed by Lindlar-catalyzed hydrogenation. This methodology was extended to homoconjugated diene macrolides by using RCAM after introduction of one Z configured double bond in the precursor by Wittig reaction. A tungsten benzylidyne complex was used as the catalyst in the RCAM reaction, which afforded the products in high yield at room temperature. With the synthetic material at hand, the unknown isomer was identified as the new natural product (5Z,8Z,12R)-tetradeca-5,8-dien-12-olide, cucujolide X (8). Furthermore, the route also allowed the synthesis of cucujolide V in good yield. The natural products were identified by the synthesis of enantiomerically pure or enriched material and gas chromatography on chiral phases. The new macrolide (R)-8 proved to be biologically active, attracting female O. surinamensis, but no males. The synthetic material allowed the identification of (R)-5 in both the beetle and the frog.

Well‐Defined Alkyne Metathesis Catalysts: Developments and Recent Applications

“…Amongt he most efficient well-defined catalysts are certainly Fürstner's trisilanol molybdenum alkylidyne 22 b [8,61,75] and Ta mm's MoF6 [60] and WF3 [64] complexes, respectively ( Figure 8). Catalyst 22 b has mainly been studied in natural product synthesis in the presence of variousf unctional groups, [8,100] whereas MoF6 proved active not only in the cross-metathesis of terminal alkynes [59,62] but also in efficient ROAMP reactions [170,171] and hase ven been immobilized onto partially dehydroxylated silica. [62,65] The tool box of alkyne metathesis catalysts is complementedb y Zhang'ss ystems with multidentatel igandss uch as 30, [84,85] which found use especially in supramolecular chemistry.…”

“…Ethynylenebridged BODIPYD YEmers could be prepared with catalyst 9a [58] as well as multiple cycloalkynes including the macrolide pheromone of ag rain beetle. [52,59] The metal-carbon tripleb ond is ah ighly reactive structure motif andt hose complexes must be handled under vigorously dry and air-free conditions. To generate inherently stable alkyne metathesis catalysts, as trategy was pursued to increase the steric demand of the alkylidynem oiety by using 2,4,6-trimethylbenzylidyne ligands.…”

“…[116] To tal synthesis of marine oxylipinsh ybridalactone and the ecklonialactones A, B, and Cw as achieved withoutt he need for protecting groups. [117] More recent examples of natural product syntheses, in whicha lkyne metathesis plays as key role, include the potential antibiotic and unusual a-pyrone neurymenolide A, [118] macrolide pheromones cucujolide Va nd X, [59] the 1,3-diyne Ivorenolide B, [119] and cytotoxic amphidinolides Ca nd F. [120] At the same time, both Fürstner and Ta mm togetherw ith Schulz demonstrated the effective RCAM of precursors carrying one terminal and one internal alkyne unit. Fürstner reportedt he preparation of mandelalide A, [121] while Ta mm and Schulz synthesized cucujolide XI, ag rain beetle pheromone (Scheme 15).…”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…Ring closing alkyne metathesis to afford cycloalkyne lactones (e.g. 1565) was a key step in the total synthesis of frog and grain beetle pheromones [1327]. Ring closing alkyne metathesis was employed for the preparation of a macrocyclic alcohol used in the preparation of the E and Z stereoisomers of the cycloalkenone aurelione [1328].…”

Identification, synthesis and mass spectrometry of a macrolide from the African reed frog Hyperolius cinnamomeoventris

“…Macrocyclic lactones such as phoracantholide I ( 3 ), phoracantholide J ( 4 ) or gephyromantolide A ( 5 ), are released by males from femoral glands to serve as signals, often accompanied by secondary alcohols (Fig. 1) [2–4]. Another frog family most likely using volatile compounds during courtship are the African reed frogs, Hyperoliidae.…”