Bidirectional Synthesis of 6-Acetoxy-5-hexadecanolide, the Mosquito Oviposition Pheromone of Culex quinquefasciatus, from a C₂-Symmetric Building Block Using Olefin Metathesis Reactions

Abstract

(5R,6S)-6-Acetoxy-5-hexadecanolide (MOP) is the oviposition pheromone of the mosquito Cx. quinquefasciatus, a vector of pathogens causing a variety of tropical diseases. We describe and evaluate herein three syntheses of MOP starting from mannitol-derived (3R,4R)-hexa-1,5-diene-3,4-diol. This C-symmetric building block is elaborated through bidirectional olefin metathesis reactions into 6-epi-MOP, which was converted into MOP via Mitsunobu inversion. The shortest of the three routes makes use of two sequential cross-metathesis reactions and an assisted tandem catalytic olefin reduction, induced by an in situ conversion of a Ru-carbene to a Ru-hydride.

Total Synthesis and Structure Revision of Palmarumycin B6

“…The retro-synthetic analysis of palmarumycin B 6 (2) is shown in Scheme 1. Palmarumycin B 6 can be synthesized from ketal (9) by oxidation with pyridinium dichromate (PDC) and t-BuOOH, followed by a demethylation of the methoxy group.…”

“…The outbreak of the Zika fever epidemic in Brazil in 2015 has raised concerns that the mosquitoes of the genus Aedes (such as A. aegypti and A. albopictus ) might be the vectors of the Zika virus. This issue has stimulated a renewed interest to develop sustainable vector control systems. , The resistance of the mosquitoes to traditional insecticides has developed quickly in recent years; − therefore a search for novel drugs, especially those derived from natural products, to overcome this serious problem is important. Palmarumycins CP 17 , B 6 , and C 8 (Figure ) were isolated from the endophytic fungus Berkleasmium sp., which was purified from the medicinal plant Dioscorea zingiberensis C. H. Wright.…”

Synthesis of Semiochemicals via Olefin Metathesis

“…The total synthesis of (−)-6-acetoxy-5-hexadecanolide [(5 R ,6 S )- 56 ], the pheromone of the mosquitoes Culex pipiens fatigans and Culex quinquefasciatus, was carried out by ring-closing metathesis (RCM) and CM reactions in one pot (Scheme ) , based on the general method of Piva and co-workers. , …”

“…55 Biological testing of each stereoisomer indicated that the (3R,13R,3′S) isomer 52 is the bioactive one (Scheme 16). 56 The total synthesis of (−)-6-acetoxy-5-hexadecanolide [(5R,6S)-56], the pheromone of the mosquitoes Culex pipiens fatigans and Culex quinquefasciatus, was carried out by ringclosing metathesis (RCM) and CM reactions in one pot (Scheme 17) 57,58 based on the general method of Piva and coworkers. 59,60 The total synthesis of 65, the female sex pheromone of Macrodiprion nemoralis, via CM using a second-generation Hoveyda−Grubbs catalyst was reported by Loh and coworkers (Scheme 18).…”

Enantioselective synthesis of (-)-(5R,6S)-6-acetoxyhexadecan-5-olide via tandem α-aminooxylation-Henry reaction

“…Owing to the potential of (-)-(5R,6S)-6-acetoxy-5-hexadecanolide 1a in controlling mosquito populations, several enantioselective synthetic approaches for 1a and its unnatural isomer (+)-6-acetoxy-5-hexadecanolide 1b (Figure 1) have been disclosed in the literature. [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] As part of our research program aimed at developing the asymmetric synthesis of bioactive natural compounds, [30][31][32][33][34][35][36][37] we turned our attention to developing a flexible and simple approach for the asymmetric synthesis of functionalized δ-lactones and its application to asymmetric synthesis of (-)-(5R,6S)-6-acetoxyhexadecan-5-olide 1a. Herein, we report a new enantioselective synthesis of (-)-(5R,6S)-6-acetoxyhexadecanolide 1a employing tandem α-aminooxylation-Henry reaction as the source of chirality.…”