Introduction

The red flour beetle, Tribolium castaneum Herbst (Coleoptera: Tenebrionidae), is a cosmopolitan, destructive stored product pest , which has been found to damage 246 grain commodities, especially starchy products . In addition, the adult T. castaneum secretes carcinogenic methyl-1,4-benzoquinone and ethyl-1,4-benzoquinone to inhibit the microorganisms and the predators . Therefore, T. castaneum infected stored products are harmful to human health and this became a significant challenge to food security . Long-term synthetic pesticide applications to control the red flour beetle has resulted in the development of resistance to organophosphates, pyrethroids, methyl carbamates, and neonicotinoids . It became critical for devising a more effective and environmentally friendly strategy to control this pest .

Pheromone-based pest management is one of most environment benign, effective, and promising solutions . The aggregation pheromone of T. castaneum was first reported by Ryan in 1976, secreted by the male, is attractive to both sexes . Later, Suzuki identified the compound as 4,8-dimethyldecanal . Mori synthesized four possible stereoisomers of 4,8-dimethyldecanal, and found that the response of T. castaneum to the (4R,8R)-isomer was identical to the natural pheromone . In 2011, Mori and Phillips achieved the complete separation of the derivatives from the four stereoisomers by reversed-phase HPLC at −54 °C, and revealed that the natural pheromone consists of four stereoisomers of 4,8-dimethyldecanal (Figure 1) . Previous syntheses mainly focused on chiral sources of (R)-citronellic acid , methyl (S)-3-hydroxy-2-methylpropanoate, (S)-2-methyl-1-butanol , (R)-2,3-O-isopropylideneglyceraldehyde , (R)- and (S)-citronellol , (R)-4-methyl-δ-valerolactone , porcine pancreatic lipase (PPL)-catalyzed acetylation of racemic citronellol , and Evan′s inductive methylation .

Figure 1: The aggregation pheromone of Tribolium castaneum.

To research further the bioactivity of the pheromone, herein, we report an effective synthesis of the aggregation pheromone of T. castaneum, which uses the cheap (R)- and (S)-2-methyloxirane as chiral sources, connects two chiral building blocks through Li2CuCl4-catalyzed coupling, and finally leads to the target pheromones by olefin oxidation with RuCl3/NaIO4.

Results and Discussion

The retrosynthetic analysis of the aggregation pheromone (4R,8R)-1 is shown in Scheme 1. Obviously, the target pheromone (4R,8R)-1 could be synthesized via an oxidation of chiral terminal olefine (5R,9R)-12, which could be obtained through Li2CuCl4-catalyzed coupling of chiral tosylate (S)-10 with a Grignard reagent derived from (R)-1-bromo-2-methylbutane ((R)-11). The key chiral building block (S)-10 was envisaged to be prepared through a sequence of hydrolyzation, decarboxylation, borane-amine reduction and tosylation from diethyl (S)-2-(hex-5-en-2-yl)malonate ((S)-6). The stereocenter in geminal ester (S)-6 could be derived from (R)-2-methyloxirane ((R)-2) via a ring-opening reaction and a stereospecific inversion of the chiral secondary tosylate (R)-5. Following the similar procedure for (4R,8R)-1, the other constituents of the aggregation pheromone (4R,8S)-1, (4S,8R)-1 and (4S,8S)-1 could be prepared.

Scheme 1: Retrosynthetic analysis of the aggregation pheromone (4R,8R)-1.

Based on the retrosynthetic analysis of the aggregation pheromone (4R,8R)-1, our synthesis began with the preparation of chiral tosylate (S)-10 (Scheme 2). The ring-opening reaction of (R)-2-methyloxirane ((R)-2) with allylmagnesium bromide (3) catalyzed by CuI produced a mixture of (R)-hex-5-en-2-ol ((R)-4) and (S)-2-methylpent-4-en-1-ol ((S)-4’) (ratio 8:1, determined by 1H NMR spectroscopy) . The primary alcohol (S)-4’ could be easily removed by a selective TEMPO oxidation. The optical purity of the chiral secondary alcohol (R)-4 was more than 99% ee, determined by 1H NMR spectrum of its Mosher ester . The subsequent tosylation with p-tosyl chloride gave (R)-hex-5-en-2-yl 4-methylbenzenesulfonate ((R)-5) in 88% yield . The reaction of (R)-5 with the enolate of diethyl malonate yielded (S)-2-(hex-5-en-2-yl)malonate ((S)-6), and realized a stereospecific inversion of chiral secondary tosylate (R)-5 . The geminal ester (S)-6 was next treated with NaOH in methanol to afford (S)-2-(hex-5-en-2-yl)malonic acid ((S)-7) in 96% yield . Then, geminal acid (S)-7 was decarboxylated with DMSO to yield chiral acid (S)-8 , followed by TiCl4-catalyzed reduction with ammonia-borane to obtain the chiral alkenyl alcohol (S)-9 . The final tosylation with p-tosyl chloride provided (S)-3-methylhept-6-en-1-yl 4-methylbenzenesulfonate ((S)-10) .

Scheme 2: Synthesis of chiral tosylate (S)-10.

Similarly, chiral tosylate (R)-10 could be prepared from (S)-2-methyloxirane ((S)-2) through the ring-opening reaction, tosylation, stereospecific inversion, hydrolysis, decarboxylation, reduction, and second tosylation (Scheme 3).

Scheme 3: Synthesis of chiral tosylate (R)-10.

With two the chiral building blocks (R)-10 and (S)-10 in hand, we next prepared the target aggregation pheromone (4R,8R)-1, (4R,8S)-1, (4S,8R)-1, and (4S,8S)-1 (Scheme 4). Li2CuCl4-catalyzed coupling of chiral tosylate (S)-10 with the Grignard reagent derived from (R)-1-bromo-2-methylbutane ((R)-11) and Mg afforded (5R,9R)-5,9-dimethylundec-1-ene ((5R,9R)-12) in 80% yield . (4R,8R)-4,8-Dimethyldecanal ((4R,8R)-1) was obtained from chiral terminal olefine (5R,9R)-12 through the oxidation with RuCl3 and NaIO4, and its specific rotation and NMR spectrum matched with the reference . Moreover, using the similar procedure for (4R,8R)-1, the other three constituents of the aggregation pheromone (4R,8S)-1, (4S,8R)-1, and (4S,8S)-1 were prepared through Li2CuCl4-catalyzed coupling and oxidation with RuCl3/NaIO4 from chiral building blocks (R)-10, (S)-10, (R)-11 and (S)-11, which were characterized by NMR spectroscopy and HRMS.

Scheme 4: Synthesis of the aggregation pheromone of Tribolium castaneum.

Conclusion

In summary, we have achieved a novel and effective synthesis of the aggregation pheromone of T. castaneum, (4R,8R)-, (4R,8S)-, (4S,8R)- and (4S,8S)-4,8-dimethyldecanal. In our strategy, (S)- and (R)-2-methyloxirane acted as chiral sources, whereas a Li2CuCl4-catalyzed coupling was used to connect two key building blocks, a chiral tosylate and a chiral Grignard reagent. The synthetic pheromone could be valuable for the control of the red flour beetle.

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